Secreted and transmembrane polypeptides and nucleic acids encoding the same (2025)

U.S. patent number 7,355,002 [Application Number 10/771,187] was granted by the patent office on 2008-04-08 for secreted and transmembrane polypeptides and nucleic acids encoding the same. This patent grant is currently assigned to Genentech, Inc.. Invention is credited to Napoleone Ferrara, Audrey Goddard, Paul J. Godowski, Austin L. Gurney, William I. Wood.

Secreted and transmembrane polypeptides and nucleic acids encodingthe same

Abstract

The present invention is directed to novel polypeptides and tonucleic acid molecules encoding those polypeptides. Also providedherein are vectors and host cells comprising those nucleic acidsequences, chimeric polypeptide molecules comprising thepolypeptides of the present invention fused to heterologouspolypeptide sequences, antibodies which bind to the polypeptides ofthe present invention and to methods for producing the polypeptidesof the present invention.

Prior Publication Data

Related U.S. Patent Documents

Other References

Primary Examiner: Kemmerer; Elizabeth C.
Attorney, Agent or Firm: Barnes; Elizabeth M. Kresnak; MarkT. Dreger; Ginger R.

Parent Case Text

RELATED APPLICATIONS

This application is a continuation of, and claims priority under 35USC .sctn.120 to, U.S. application Ser. No. 09/909,064 filed Jul.18, 2001 now U.S. Pat. No. 6,818,449, which is a continuation of,and claims priority under 35 USC .sctn.120 to, U.S. applicationSer. No. 09/665,350 filed Sep. 18, 2000 now abandoned, which is acontinuation of, and claims priority under 35 USC .sctn.120 to, PCTApplication PCT/US00/04414 filed Feb. 22, 2000, which is acontinuation-in-part of, and claims priority under 35 USC .sctn.120to, PCT Application PCT/US98/19437 filed Sep. 17, 1998, which is acontinuation-in-part of, and claims priority under 35 USC .sctn.120to, PCT Application PCT/US98/19330 filed Sep. 16, 1998, whichclaims priority under 35 USC .sctn.119 to U.S. ProvisionalApplication 60/088,026 filed Jun. 4, 1998, to U.S. ProvisionalApplication 60/066,770 filed Nov. 24, 1997, and to U.S. ProvisionalApplication 60/065,186 filed Nov. 12, 1997.

Claims

What is claimed is:

1. An isolated polypeptide having at least 95% amino acid sequenceidentity to: (a) the amino acid sequence of the polypeptide of SEQID NO: 292; (b) the amino acid sequence of the polypeptide of SEQID NO: 292, lacking its associated signal peptide; or (c) the aminoacid sequence of the polypeptide encoded by the full-length codingsequence of the cDNA deposited under ATCC accession number 209439,wherein said polypeptide inhibits VEGF stimulated proliferation ofendothelial cell growth.

2. The isolated polypeptide of claim 1 having at least 99% aminoacid sequence identity to: (a) the amino acid sequence of thepolypeptide of SEQ ID NO: 292; (b) the amino acid sequence of thepolypeptide of SEQ ID NO: 292, lacking its associated signalpeptide; or (c) the amino acid sequence of the polypeptide encodedby the full-length coding sequence of the cDNA deposited under ATCCaccession number 209439, wherein said polypeptide inhibits VEGFstimulated proliferation of endothelial cell growth.

3. An isolated polypeptide comprising: (a) the amino acid sequenceof the polypeptide of SEQ ID NO: 292; (b) the amino acid sequenceof the polypeptide of SEQ lID NO: 292, lacking its associatedsignal peptide; or (c) the amino acid sequence of the polypeptideencoded by the full-length coding sequence of the cDNA depositedunder ATCC accession number 209439.

4. The isolated polypeptide of claim 3 comprising the amino acidsequence of the polypeptide of SEQ ID NO: 292.

5. The isolated polypeptide of claim 3 comprising the amino acidsequence of the polypeptide of SEQ ID NO: 292, lacking itsassociated signal peptide.

6. The isolated polypeptide of claim 3 comprising the amino acidsequence of the polypeptide encoded by the full-length codingsequence of the cDNA deposited under ATCC accession number209439.

7. A chimeric polypeptide comprising a polypeptide according toclaim 1 fused to a heterologous polypeptide.

8. The chimeric polypeptide of claim 1, wherein said heterologouspolypeptide is an epitope tag or an Fc region of an immunoglobulin.

Description

FIELD OF THE INVENTION

The present invention relates generally to the identification andisolation of novel DNA and to the recombinant production of novelpolypeptides.

BACKGROUND OF THE INVENTION

Extracellular proteins play important roles in, among other things,the formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/orthe immediate environment. This information is often transmitted bysecreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides,and hormones) which are, in turn, received and interpreted bydiverse cell receptors or membrane-bound proteins. These secretedpolypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment.

Secreted proteins have various industrial applications, includingas pharmaceuticals, diagnostics, biosensors and bioreactors. Mostprotein drugs available at present, such as thrombolytic agents,interferons, interleukins, erythropoietins, colony stimulatingfactors, and various other cytokines, are secretory proteins. Theirreceptors, which are membrane proteins, also have potential astherapeutic or diagnostic agents. Efforts are being undertaken byboth industry and academia to identify new, native secretedproteins. Many efforts are focused on the screening of mammalianrecombinant DNA libraries to identify the coding sequences fornovel secreted proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Kleinet al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

Membrane-bound proteins and receptors can play important roles in,among other things, the formation, differentiation and maintenanceof multicellular organisms. The fate of many individual cells,e.g., proliferation, migration, differentiation, or interactionwith other cells, is typically governed by information receivedfrom other cells and/or the immediate environment. This informationis often transmitted by secreted polypeptides (for instance,mitogenic factors, survival factors, cytotoxic factors,differentiation factors, neuropeptides, and hormones) which are, inturn, received and interpreted by diverse cell receptors ormembrane-bound proteins. Such membrane-bound proteins and cellreceptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved incell-cell interactions, and cellular adhesin molecules likeselectins and integrins. For instance, transduction of signals thatregulate cell growth and differentiation is regulated in part byphosphorylation of various cellular proteins. Protein tyrosinekinases, enzymes that catalyze that process, can also act as growthfactor receptors. Examples include fibroblast growth factorreceptor and nerve growth factor receptor.

Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interactions. Themembrane-bound proteins can also be employed for screening ofpotential peptide or small molecule inhibitors of the relevantreceptor/ligand interaction.

Efforts are being undertaken by both industry and academia toidentify new, native receptor or membrane-bound proteins. Manyefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel receptor ormembrane-bound proteins.

1. PRO211 and PRO217

Epidermal growth factor (EGF) is a conventional mitogenic factorthat stimulates the proliferation of various types of cellsincluding epithelial cells and fibroblasts. EGF binds to andactivates the EGF receptor (EGFR), which initiates intracellularsignaling and subsequent effects. The EGFR is expressed in neuronsof the cerebral cortex, cerebellum, and hippocampus in addition toother regions of the central nervous system (CNS). In addition, EGFis also expressed in various regions of the CNS. Therefore, EGFacts not only on mitotic cells, but also on postmitotic neurons. Infact, many studies have indicated that EGF has neurotrophic orneuromodulatory effects on various types of neurons in the CNS. Forexample, EGF acts directly on cultured cerebral cortical andcerebellar neurons, enhancing neurite outgrowth and survival. Onthe other hand, EGF also acts on other cell types, including septalcholinergic and mesencephalic dopaminergic neurons, indirectlythrough glial cells. Evidence of the effects of EGF on neurons inthe CNS is accumulating, but the mechanisms of action remainessentially unknown. EGF-induced signaling in mitotic cells isbetter understood than in postmitotic neurons. Studies of clonedpheochromocytoma PC12 cells and cultured cerebral cortical neuronshave suggested that the EGF-induced neurotrophic actions aremediated by sustained activation of the EGFR and mitogen-activatedprotein kinase (MAPK) in response to EGF. The sustainedintracellular signaling correlates with the decreased rate of EGFRdown-regulation, which might determine the response of neuronalcells to EGF. It is likely that EGF is a multi-potent growth factorthat acts upon various types of cells including mitotic cells andpostmitotic neurons.

EGF is produced by the salivary and Brunner's glands of thegastrointestinal system, kidney, pancreas, thyroid gland, pituitarygland, and the nervous system, and is found in body fluids such assaliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid,prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman,Peptides 12: 653-663 (1991).

EGF is mediated by its membrane specific receptor, which containsan intrinsic tyrosine kinase. Stoscheck et al., J. Cell Biochem.31: 135-152 (1986). EGF is believed to function by binding to theextracellular portion of its receptor which induces a transmembranesignal that activates the intrinsic tyrosine kinase.

Purification and sequence analysis of the EGF-like domain hasrevealed the presence of six conserved cysteine residues whichcross-bind to create three peptide loops, Savage et al., J. Bid.Chem. 248: 7669-7672 (1979). It is now generally known that severalother peptides can react with the EGF receptor which share the samegeneralized motif. Non isolated peptides having this motif includeTGF-.alpha., amphiregulin, schwannoma-derived growth factor (SDGF),heparin-binding EGF-like growth factors and certain virally encodedpeptides (e.g., Vaccinia virus, Reisner, Nature 313: 801-803(1985), Shope fibroma virus, Chang et al., Mol Cell Biol. 7:535-540 (1987), Molluscum contagiosum, Porter and Archard, J. Gen.Virol. 68: 673-682 (1987), and Myxoma virus, Upton et al., J.Virol. 61: 1271-1275 (1987), Prigent and Lemoine, Prog. GrowthFactor Res. 4: 1-24 (1992).

EGF-like domains are not confined to growth factors but have beenobserved in a variety of cell-surface and extracellular proteinswhich have interesting properties in cell adhesion, protein-proteininteraction and development, Laurence and Gusterson, Tumor Biol.11: 229-261 (1990). These proteins include blood coagulationfactors (factors VI, IX, X, XII, protein C, protein S, protein Z,tissue plasminogen activator, urokinase), extracellular matrixcomponents (laminin, cytotactin, entactin), cell surface receptors(LDL receptor, thrombomodulin receptor) and immunity-relatedproteins (complement C1r, uromodulin).

Even more interesting, the general structure pattern of EGF-likeprecursors is preserved through lower organisms as well as inmammalian cells. A number of genes with developmental significancehave been identified in invertebrates with EGF-like repeats. Forexample, the notch gene of Drosophila encodes 36 tandemly arranged40 amino acid repeats which show homology to EGF, Wharton et al.,Cell 43: 557-581 (1985). Hydropathy plots indicate aputativemembrane spanning domain, with the EGF-related sequences beinglocated on the extracellular side of the membrane. Other homeoticgenes with EGF-like repeats include Delta, 95F and 5ZD which wereidentified using probes based on Notch, and the nematode geneLin-12 which encodes a putative receptor for a developmental signaltransmitted between two specified cells.

Specifically, EGF has been shown to have potential in thepreservation and maintenance of gastrointestinal mucosa and therepair of acute and chronic mucosal lesions, Konturek et al., Eur.J. Gastroenterol Hepatol. 7 (10), 933-37 (1995), including thetreatment of necrotizing enterocolitis, Zollinger-Ellison syndrome,gastrointestinal ulceration gastrointestinal ulcerations andcongenital microvillus atrophy, Guglietta and Sullivan, Eur. J.Gastroenterol Hepatol, 7(10), 945-50 (1995). Additionally, EGF hasbeen implicated in hair follicle differentiation; du Cros, J.Invest. Dermatol. 101 (1 Suppl.), 106S-113S (1993), Hillier, Clin.Endocrinol. 33(4), 427-28 (1990); kidney function, Hamm et al.,Semin. Nephrol. 13 (1): 109-15 (1993), Harris, Am. J. Kidney Dis.17(6): 627-30 (1991); tear fluid, van Setten et al., Int.Ophthalmol 15(6); 359-62 (1991); vitamin K mediated bloodcoagulation, Stenflo et al., Blood 78(7): 1637-51 (1991). EGF isalso implicated various skin disease characterized by abnormalkeratinocyte differentiation, e.g., psoriasis, epithelial cancerssuch as squamous cell carcinomas of the lung, epidermoid carcinomaof the vulva and gliomas. King et al., Am. J. Med. Sci. 296:154-158 (1988).

Of great interest is mounting evidence that genetic alterations ingrowth factors signaling pathways are closely linked todevelopmental abnormalities and to chronic diseases includingcancer. Aaronson, Science 254: 1146-1153 (1991). For example,c-erb-2 (also known as HER-2), a proto-oncogene with closestructural similarity to EGF receptor protein, is overexpressed inhuman breast cancer. King et al., Science 229: 974-976 (1985);Gullick, Hormones and their actions, Cooke et al., eds, Amsterdam,Elsevier, pp 349-360 (1986).

We herein describe the identification and characterization of novelpolypeptides having homology to EGF, wherein those polypeptides areherein designated PRO211 and PRO217.

2. PRO230

Nepbritis is a condition characterized by inflammation of thekidney affecting the structure and normal function of the kidney.This condition can be chronic or acute and is generally caused byinfection, degenerative process or vascular disease. In all cases,early detection is desirable so that the patient with nephritis canbegin treatment of the condition.

An approach to detecting nephritis is to determine the antigensassociated with nephritis and antibodies thereto. In rabbit, atubulointerstitial nephritis antigen (TIN-ag) has been reported inNelson, T. R., et al., J. Biol. Chem., 270(27):16265-70 (July 1995)(GENBANK/U24270). This study reports that the rabbit TIN-ag is abasement membrane glycoprotein having a predicted amino acidsequence which has a carboxyl-terminal region exhibiting 30%homology with human preprocathepsin B, a member of the cysteinproteinase family of proteins. It is also reported that the rabbitTIN-ag has a domain in the amino-terminal region containing anepidermal growth factor-ike motif that shares homology with lamininA and S chains, alpha 1 chain of type I collagen, von Willebrand'sfactor and mucin, indicating structural and functionalsimilarities. Studies have also been conducted in mice. However, itis desirable to identify tubulointerstitial nephritis antigens inhumans to aid in the development of early detection methods andtreatment of nephritis.

Proteins which have homology to tubulointerstitial nephritisantigens are of particular interest to the medical and industrialcommunities. Often, proteins having homology to each other havesimilar function. It is also of interest when proteins havinghomology do not have similar functions, indicating that certainstructural motifs identify information other than function, such aslocality of function. We herein describe the identification andcharacterization of a novel polypeptide, designated hgerein asPRO230, which has homology to tubulointerstitial nephritisantigens.

3. PRO232

Stem cells are undifferentiated cells capable of (a) proliferation,(b) self maintenance, (c) the production of a large number ofdifferentiated functional progeny, (d) regeneration of tissue afterinjury and/or (e) a flexibility in the use of these options. Stemcells often express cell surface antigens which are capable ofserving as cell specific markers that can be exploited to identifystem cells, thereby providing a means for identifying and isolatingspecific stem cell populations.

Having possession of different stem cell populations will allow fora number of important applications. For example, possessing aspecific stem cell population will allow for the identification ofgrowth factors and other proteins which are involved in theirproliferation and differentiation. In addition, there may be as yetundiscovered proteins which are associated with (1) the early stepsof dedication of the stem cell to a particular lineage, (2)prevention of such dedication, and (3) negative control of stemcell proliferation, all of which may be identified if one haspossession of the stem cell population. Moreover, stem cells areimportant and ideal targets for gene therapy where the insertedgenes promote the health of the individual into whom the stem cellsare transplanted. Finally, stem cells may play important roles intransplantation of organs or tissues, for example liverregeneration and skin grafting.

Given the importance of stem cells in various differentapplications, efforts are currently being undertaken by bothindustry and academia to identify new, native stem cell antigenproteins so as to provide specific cell surface markers foridentifying stem cell populations as well as for providing insightinto the functional roles played by stem cell antigens in cellproliferation and differentiation. We herein describe theidentification and characterization of novel polypeptides havinghomology to a stem cell antigen, wherein those polypeptides areherein designated as PRO232 polypeptides.

4. PRO187

Growth factors are molecular signals or mediators that enhance cellgrowth or proliferation, alone or in concert, by binding tospecific cell surface receptors. However, there are other cellularreactions than only growth upon expression to growth factors. As aresult, growth factors are better characterized as multifunctionaland potent cellular regulators. Their biological effects includeproliferation, chemotaxis and stimulation of extracellular matrixproduction. Growth factors can have both stimulatory and inhibitoryeffects. For example, transforming growth factor (TGF-.beta.) ishighly pleiotropic and can stimulate proliferation in some cells,especially connective tissue, while being a potent inhibitor ofproliferation in others, such as lymphocytes and epithelialcells.

The physiological effect of growth stimulation or inhibition bygrowth factors depends upon the state of development anddifferentiation of the target tissue. The mechanism of localcellular regulation by classical endocrine molecules involvescomprehends autocrine (same cell), juxtacrine (neighbor cell), andparacrine (adjacent cells) pathways. Peptide growth factors areelements of a complex biological language, providing the basis forintercellular communication. They permit cells to conveyinformation between each other, mediate interaction between cellsand change gene expression. The effect of these multifunctional andpluripotent factors is dependent on the presence or absence ofother peptides.

FGF-8 is a member of the fibroblast growth factors (FGFs) which area family of heparin-binding, potent mitogens for both normaldiploid fibroblasts and established cell lines, Gospodarowicz etal. (1984), Proc. Natl. Acad. Sci. USA 81:6963. The FGF familycomprises acidic FGF (FGF-1), basic FGF (FGF-2), INT-2 (FGF-3),K-FGF/HST (FGF-4), FGF-5, FGF-6, KGF (FGF-7), AIGF (FGF-8) amongothers. All FGFs have two conserved cysteine residues and share30-50% sequence homology at the amino acid level. These factors aremitogenic for a wide variety of normal diploid mesoderm-derived andneural crest-derived cells, including granulosa cells, adrenalcortical cells, chondrocytes, myoblasts, corneal and vascularendothelial cells (bovine or human), vascular smooth muscle cells,lens, retina and prostatic epithelial cells, oligodendrocytes,astrocytes, chrondocytes, myoblasts and osteoblasts.

Fibroblast growth factors can also stimulate a large number of celltypes in a non-mitogenic manner. These activities include promotionof cell migration into wound area (chemotaxis), initiation of newblood vessel formulation (angiogenesis), modulation of nerveregeneration and survival (neurotrophism), modulation of endocrinefunctions, and stimulation or suppression of specific cellularprotein expression, extracellular matrix production and cellsurvival. Baird & Bohlen, Handbook of Exp. Pharmacol. 95(1):369-418, Springer, (1990). These properties provide a basis forusing fibroblast growth factors in therapeutic approaches toaccelerate wound healing, nerve repair, collateral blood vesselformation, and the like. For example, fibroblast growth factorshave been suggested to minimize myocardium damage in heart diseaseand surgery (U.S. Pat. No. 4,378,347).

FGF-8, also known as androgen-induced growth factor (AIGF), is a215 amino acid protein which shares 30-40% sequence homology withthe other members of the FGF family. FGF-8 has been proposed to beunder androgenic regulation and induction in the mouse mammarycarcinoma cell line SC3. Tanaka et al., Proc. Natl. Acad. Sci. USA89: 8928-8932 (1992); Sato et al., J. Steroid Biochem. Molec. Biol.47: 91-98 (1993). As a result, FGF-8 may have a local role in theprostate, which is known to be an androgen-responsive organ. FGF-8can also be oncogenic, as it displays transforming activity whentransfected into NIH-3T3 fibroblasts. Kouhara et al., Oncogene 9455-462 (1994). While FGF-8 has been detected in heart, brain,lung, kidney, testis, prostate and ovary, expression was alsodetected in the absence of exogenous androgens. Schmitt et al., J.Steroid Biochem. Mol. Biol. 57 (3-4): 173-78 (1996).

FGF-8 shares the property with several other FGFs of beingexpressed at a variety of stages of murine embryogenesis, whichsupports the theory that the various FGFs have multiple and perhapscoordinated roles in differentiation and embryogenesis. Moreover,FGF-8 has also been identified as a protooncogene that cooperateswith Wnt-1 in the process of mammary tumorigenesis (Shackleford etal., Proc. Natl. Acad. Sci. USA 90, 740-744 (1993); Heikinheimo etal., Mech. Dev. 48: 129-138 (1994)).

In contrast to the other FGFs, FGF-8 exists as three proteinisoforms, as a result of alternative splicing of the primarytranscript. Tanaka et al., supra. Normal adult expression of FGF-8is weak and confined to gonadal tissue, however northern blotanalysis has indicated that FGF-8 mRNA is present from day 10through day 12 or murine gestation, which suggests that FGF-8 isimportant to normal development. Heikinheimo et al., Mech Dev.48(2): 129-38 (1994). Further in situ hybridization assays betweenday 8 and 16 of gestation indicated initial expression in thesurface ectoderm of the first bronchial arches, the frontonasalprocess, the forebrain and the midbrain-hindbrain junction. At days10-12, FGF-8 was expressed in the surface ectoderm of the forelimband hindlimb buds, the nasal its and nasopharynx, the infundibulumand in the telencephalon, diencephalon and metencephalon.Expression continues in the developing hindlimbs through day 13 ofgestation, but is undetectable thereafter. The results suggest thatFGF-8 has a unique temporal and spatial pattern in embryogenesisand suggests a role for this growth factor in multiple regions ofectodermal differentiation in the post-gastrulation embryo.

We herein describe the identification of novel poypeptides havinghomology to FGF-8, wherein those polypeptides are heein designatedPRO187 polypeptides.

5. PRO265

Protein-protein interactions include receptor and antigen complexesand signaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated toregulate the particular result of the protein-protein interaction.Thus, the underlying mechanisms of protein-protein interactions areof interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to beinvolved in protein-protein interactions. Leucine-rich repeats areshort sequence motifs present in a number of proteins with diversefunctions and cellular locations. The crystal structure ofribonuclease inhibitor protein has revealed that leucine-richrepeats correspond to beta-alpha structural units. These units arearranged so that they form a parallel beta-sheet with one surfaceexposed to solvent, so that the protein acquires an unusual,nonglubular shape. These two features have been indicated asresponsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serveas tissue organizers, orienting and ordering collagen fibrilsduring ontogeny and are involved in pathological processes such aswound healing, tissue repair, and tumor stroma formation. Iozzo, R.V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Othersstudies implicating leucine rich proteins in wound healing andtissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol.(Germany), 37(4):215-222 (1995), reporting mutations in the leucinerich motif in a complex associated with the bleeding disorderBernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost.(Germany), 74(1): 111-116 (July 1995), reporting that plateletshave leucine rich repeats. Another protein of particular interestwhich has been reported to have leucine-rich repeats is the SLITprotein which has been reported to be useful in treatingneuro-degenerative diseases such as Alzheimer's disease, nervedamage such as in Parkinson's disease, and for diagnosis of cancer,see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 byYale University. Other studies reporting on the biologicalfunctions of proteins having leucine-rich repeats include: Tayar,N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70(December 1996) (gonadotropin receptor involvement); Miura, Y., etal., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosisinvolvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement); andRuoslahti, E. I., et al., WO9110727-A by La Jolla Cancer ResearchFoundation (decorin binding to transforming growth factor-.beta.involvement for treatment for cancer, wound healing and scarring).Also of particular interest is fibromodulin and its use to preventor reduce dermal scarring. A study of fibromodulin is found in U.S.Pat. No. 5,654,270 to Ruoslahti, et al.

Efforts are therefore being undertaken by both industry andacademia to identify new proteins having leucine rich repeats tobetter understand protein-protein interactions. Of particularinterest are those proteins having leucine rich repeats andhomology to known proteins having leucine rich repeats such asfibromodulin, the SLIT protein and platelet glycoprotein V. Manyefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound proteins having leucine rich repeats. We hereindescribe the identification and characterization of novelpolypeptides having homology to fibromodulin, herein designated asPRO265 polypeptides.

6. PRO219

Human matrilin-2 polypeptide is a member of the von Willebrandfactor type A-like module superfamily. von Willebrand factor is aprotein which plays an important role in the maintenence ofhemostasis. More specifically, von Willebrand factor is a proteinwhich is known to participate in platelet-vessel wall interactionsat the site of vascular injury via its ability to interact and forma complex with Factor VIII. The absence of von Willebrand factor inthe blood causes an abnormality with the blood platelets thatprevents platelet adhesion to the vascular wall at the site of thevascular injury. The result is the propensity for brusing, nosebleeds, intestinal bleeding, and the like comprising vonWillebrand's disease.

Given the physiological importance of the blood clotting factors,efforts are currently being undertaken by both industry andacademia to identify new, native proteins which may be involved inthe coagulation process. We herein describe the identification of anovel full-length polypeptide which possesses homology to the humanmatrilin-2 precursor polypeptide.

7. PRO246

The cell surface protein HCAR is a membrane-bound protein that actsas a receptor for subgroup C of the adenoviruses and subgroup B ofthe coxsackieviruses. Thus, HCAR may provide a means for mediatingviral infection of cells in that the presence of the HCAR receptoron the cellular surface provides a binding site for viralparticles, thereby facilitating viral infection.

In light of the physiological importance of membrane-bound proteinsand specficially those which serve a cell surface receptor forviruses, efforts are currently being undertaken by both industryand academia to identify new, native membrane-bound receptorproteins. Many of these efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the codingsequences for novel receptor proteins. We herein describe a novelmembrane-bound polypeptide (designated herein as PRO246) havinghomology to the cell surface protein HCAR and to various tumorantigens including A33 and carcinoembryonic antigen, wherein thispolypeptide may be a novel cell surface virus receptor or tumorantigen.

8. PRO228

There are a number of known seven transmembrane proteins and withinthis family is a group which includes CD97 and EMR1. CD97 is aseven-span transmembrane receptor which has a cellular ligand,CD55, DAF. Hamann, et al., J. Exp. Med. (U.S.), 184(3):1189 (1996).Additionally, CD97 has been reported as being a dedifferentiationmarker in human thyroid carcinomas and as associated withinflammation. Aust, et al., Cancer Res. (U.S.), 57(9):1798 (1997);Gray, et al., J. Immunol. (U.S.), 157(12):5438 (1996). CD97 hasalso been reported as being related to the secretin receptorsuperfamily, but unlike known members of that family, CD97 and EMR1have extended extracellular regions that possess several EGFdomains at the N-terminus. Hamann, et al., Genomics, 32(1):144(1996); Harmann, et al., J. Immunol., 155(4):1942 (1995). EMR1 isfurther described in Lin, et al., Genomics, 41(3):301 (1997) andBaud, et al., Genomics, 26(2):334 (1995). While CD97 and EMR1appear to be related to the secretin receptors, a known member ofthe secretin family of G protein-coupled receptors includes thealpha-latroxin receptor, latrophilin, which has been described ascalcium independent and abundant among neuronal tissues. Lelianova,et al., J. Biol. Chem., 272(34), 21504 (1997); Davletov, et al., J.Biol. Chem. (U.S.), 271(38):23239 (1996). Both members of thesecretin receptor superfamily and non-members which are related tothe secretin receptor superfamily, or CRF and calcitonin receptorsare of interest. In particular, new members of these families,identified by their homology to known proteins, are ofinterest.

Efforts are being undertaken by both industry and academia toidentify new membrane-bound receptor proteins, particularlytransmembrane proteins with EGF repeats and large N-terminuseswhich may belong to the family of seven-transmembrane proteins ofwhich CD97 and EMR1 are members. We herein describe theidentification and charactization of novel polypeptides havinghomology to CD97 and EMR1, designated herein as PRO228polypeptides.

9. PRO533

Growth factors are molecular signals or mediators that enhance cellgrowth or proliferation, alone or in concert, by binding tospecific cell surface receptors. However, there are other cellularreactions than only growth upon expression to growth factors. As aresult, growth factors are better characterized as multifunctionaland potent cellular regulators. Their biological effects includeproliferation, chemotaxis and stimulation of extracellular matrixproduction. Growth factors can have both stimulatory and inhibitoryeffects. For example, transforming growth factors (TGF-.beta.) ishighly pleiotropic and can stimulate proliferation in some cells,especially connective tissues, while being a potent inhibitor ofproliferation in others, such as lymphocytes and epithelialcells.

The physiological effect of growth stimulation or inhibition bygrowth factors depends upon the state of development anddifferentiation of the target tissue. The mechanism of localcellular regulation by classical endocrine molecules comprehendsautocrine (same cell), juxtacrine (neighbor cell), and paracrine(adjacent cell) pathways. Peptide growth factors are elements of acomplex biological language, providing the basis for intercellularcommunication. They permit cells to convey information between eachother, mediate interaction between cells and change geneexpression. The effect of these multifunctional and pluripotentfactors is dependent on the presence or absence of otherpeptides.

Fibroblast growth factors (FGFs) are a family of heparin-binding,potent mitogens for both normal diploid fibroblasts and establishedcell lines, Godpodarowicz, D. et al. (1984), Proc. Natl. Acad. Sci.USA 81: 6983, the FGF family comprises acidic FGF (FGF-1), basicFGF (FGF-2), INT-2 (FGF-3), K-FGF/HST (FGF-4), FGF-5, FGF-6, KGF(FGF-7), AIGF (FGF-8) among others. All FGFs have two conservedcysteine residues and share 30-50% sequence homology at the aminoacid level. These factors are mitogenic for a wide variety ofnormal diploid mesoderm-derived and neural crest-derived cells,inducing granulosa cells, adrenal cortical cells, chrondocytes,myoblasts, corneal and vascular endothelial cells (bovine orhuman), vascular smooth muscle cells, lens, retina and prostaticepithelial cells, oligodendrocytes, astrocytes, chrondocytes,myoblasis and osteoblasts.

Fibroblast growth factors can also stimulate a large number of celltypes in a non-mitogenic manner. These activities include promotionof cell migration into a wound area (chemotaxis), initiation of newblood vessel formulation (angiogenesis), modulation of nerveregeneration and survival (neurotrophism), modulation of endocrinefunctions, and stimulation or suppression of specific cellularprotein expression, extracellular matrix production and cellsurvival. Baird, A. & Bohlen, P., Handbook of Exp. Phrmacol.95(1): 369-418 (1990). These properties provide a basis for usingfibroblast growth factors in therapeutic approaches to acceleratewound healing, nerve repair, collateral blood vessel formation, andthe like. For example, fibroblast growth factors, have beensuggested to minimize myocardium damage in heart disease andsurgery (U.S. Pat. No. 4,378,437).

We herein describe the identification and characterization of novelpolypeptides having homology to FGF, herein designated PRO533polypeptides.

10. PRO245

Some of the most important proteins involved in the above describedregulation and modulation of cellular processes are the enzymeswhich regulate levels of protein phosphorylation in the cell. Forexample, it is known that the transduction of signals that regulatecell growth and differentiation is regulated at least in part byphosphorylation and dephosphorylation of various cellular proteins.The enzymes that catalyze these processes include the proteinkinases, which function to phosphorylate various cellular proteins,and the protein phosphatases, which function to remove phosphateresidues from various cellular proteins. The balance of the levelof protein phosphorylation in the cell is thus mediated by therelative activities of these two types of enzymes.

Although many protein kinase enzymes have been identified, thephysiological role played by many of these catalytic proteins hasyet to be elucidated. It is well known, however, that a number ofthe known protein kinases function to phosphorylate tyrosineresidues in proteins, thereby leading to a variety of differenteffects. Perhaps most importantly, there has been a great deal ofinterest in the protein tyrosine kinases since the discovery thatmany oncogene products and growth factors possess intrinsic proteintyrosine kinase activity. There is, therefore, a desire to identifynew members of the protein tyrosine kinase family.

Given the physiological importance of the protein kinases, effortsare being undertaken by both industry and academia to identify new,native kinase proteins. Many of these efforts are focused on thescreening of mammalian recombinant DNA libraries to identify thecoding sequences for novel kinase proteins. We herein describe theidentification and characterization of novel polypeptides havinghomology to tyrosine kinase proteins, designated herein as PRO245polypeptides.

11. PRO220, PRO221 and PRO227

Protein-protein interactions include receptor and antigen complexesand signaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated toregulate the particular result of the protein-protein interaction.Thus, the underlying mechanisms of protein-protein interactions areof interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to beinvolved in protein-protein interactions. Leucine-rich repeats areshort sequence motifs present in a number of proteins with diversefunctions and cellular locations. The crystal structure ofribonuclease inhibitor protein has revealed that leucine-richrepeats correspond to beta-alpha structural units. These units arearranged so that they form a parallel beta-sheet with one surfaceexposed to solvent, so that the protein acquires an unusual,nonglubular shape. These two features have been indicated asresponsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serveas tissue organizers, orienting and ordering collagen fibrilsduring ontogeny and are involved in pathological processes such aswound healing, tissue repair, and tumor stroma formation. Iozzo, R.V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Othersstudies implicating leucine rich proteins in wound healing andtissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol.(Germany), 37(4):215-222 (1995), reporting mutations in the leucinerich motif in a complex associated with the bleeding disorderBernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost.(Germany), 74(1):111-116 (July 1995), reporting that platelets haveleucine rich repeats. Another protein of particular interest whichhas been reported to have leucine-rich repeats is the SLIT proteinwhich has been reported to be useful in treating neuro-degenerativediseases such as Alzheimer's disease, nerve damage such as inParkinson's disease, and for diagnosis of cancer, see,Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by YaleUniversity. Other studies reporting on the biological functions ofproteins having leucine-rich repeats include: Tayar, N., et al.,Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., NipponRinsho (Japan), 54(7): 1784-1789 (July 1996) (apoptosisinvolvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement); andRuoslahti, E. I., et al., WO9110727-A by La Jolla Cancer ResearchFoundation (decorin binding to transforming growth factorsinvolvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry andacademia to identify new proteins having leucine rich repeats tobetter understand protein-protein interactions. Of particularinterest are those proteins having leucine rich repeats andhomology to known proteins having leucine rich repeats such as theSLIT protein and platelet glycoprotein V.

12. PRO258

Immunoglobulins are antibody molecules, the proteins that functionboth as receptors for antigen on the B-cell membrane and as thesecreted products of the plasma cell. Like all antibody molecules,immunoglobulins perform two major functions: they bind specificallyto an antigen and they participate in a limited number ofbiological effector functions. Therefore, new members of the Igsuperfamily are always of interest. Molecules which act asreceptors by various viruses and those which act to regulate immunefunction are of particular interest. Also of particular interestare those molecules which have homology to known Ig family memberswhich act as virus receptors or regulate immune function. Thus,molecules having homology to poliovirus receptors, CRTAM and CD166(a ligand for lymphocyte antigen CD6) are of particularinterest.

Extracellular and membrane-bound proteins play important roles inthe formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/orthe immediate environment. This information is often transmitted bysecreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides,and hormones) which are, in turn, received and interpreted bydiverse cell receptors or membrane-bound proteins. These secretedpolypeptides or signaling molecules normally pass through thecellular secretory pathway to reach their site of action in theextracellular environment, usually at a membrane-bound receptorprotein.

We herein describe the identification and characterization of novelpolypeptides having homology to CRTAM, designated herein as PRO258polypeptides.

13. PRO266

Protein-protein interactions include receptor and antigen complexesand signaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated toregulate the particular result of the protein-protein interaction.Thus, the underlying mechanisms of protein-protein interactions areof interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to beinvolved in protein-protein interactions. Leucine-rich repeats areshort sequence motifs present in a number of proteins with diversefunctions and cellular locations. The crystal structure ofribonuclease inhibitor protein has revealed that leucine-richrepeats correspond to beta-alpha structural units. These units arearranged so that they form a parallel beta-sheet with one surfaceexposed to solvent, so that the protein acquires an unusual,nonglobular shape. These two features have been indicated asresponsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serveas tissue organizers, orienting and ordering collagen fibrilsduring ontogeny and are involved in pathological processes such aswound healing, tissue repair, and tumor stroma formation. Iozzo, R.V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Othersstudies implicating leucine rich proteins in wound healing andtissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol.(Germany), 37(4):215-222 (1995), reporting mutations in the leucinerich motif in a complex associated with the bleeding disorderBernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost.(Germany), 74(1):111-116 (July 1995), reporting that platelets haveleucine rich repeats. Another protein of particular interest whichhas been reported to have leucine-rich repeats is the SLIT proteinwhich has been reported to be useful in treating neuro-degenerativediseases such as Alzheimer's disease, nerve damage such as inParkinson's disease, and for diagnosis of cancer, see,Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by YaleUniversity. Other studies reporting on the biological functions ofproteins having leucine-rich repeats include: Tayar, N., et al.,Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., NipponRinsho (Japan), 54(7): 1784-1789 (July 1996) (apoptosisinvolvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement); andRuoslahti, E. I., et al., WO9110727-A by La Jolla Cancer ResearchFoundation (decorin binding to transforming growth factorsinvolvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry andacademia to identify new proteins having leucine rich repeats tobetter understand protein-protein interactions, neuronaldevelopment and adhesin molecules. Of particular interest are thoseproteins having leucine rich repeats and homology to known proteinshaving leucine rich repeats such as the SLIT protein. We hereindescribe novel polypeptides having homology to SLIT, designatedherein as PRO266 polypeptides.

14. PRO269

Thrombomodulin binds to and regulates the activity of thrombin. Itis important in the control of blood coagulation. Thrombomodulinfunctions as a natural anticoagulant by accelerating the activationof protein C by thrombin. Soluble thrombomodulin may havetherapeutic use as an antithrombotic agent with reduced risk forhemorrhage as compared with heparin. Thrombomodulin is a cellsurface trans-membrane glycoprotein, present on endothelial cellsand platelets. A smaller, functionally active form ofthrombomodulin circulates in the plasma and is also found in urine.(In Haeberli, A., Human Protein Data, VCH Oub., N.Y., 1992).Peptides having homology to thrombomodulin are particularlydesirable.

We herein describe the identification and characterization of novelpolypeptides having homology to thrombomodulin, designated hereinas PRO269 polypeptides.

15. PRO287

Procollagen C-proteinase enhancer protein binds to and enhances theactivity of bone morphogenic protein "BMP1"/procollagenC-proteinase (PCP). It plays a role in extracellular matrixdeposition. BMP1 proteins may be used to induce bone and/orcartilage formation and in wound healing and tissue repair.Therefore, procollagen C-proteinase enhancer protein, BMP1 andproteins having homology thereto, are of interest to the scientificand medical communities.

We herein describe the identification and characterization of novelpolypeptides having homology to procollagen C-proteinase enhancerprotein precursor and procollagen C-proteinase enhancer protein,designated herein as PRO287 polypeptides.

16. PRO214

Growth factors are molecular signals or mediators that enhancescell growth or proliferation, alone or in concert, by binding tospecific cell surface receptors. However, there are other cellularreactions than only growth upon expression to growth factors. As aresult, growth factors are better characterized as multifunctionaland potent cellular regulators. Their biological effects includeproliferation, chemotaxis and stimulation of extracellular matrixproduction. Growth factors can have both stimulatory and inhibitoryeffects. For example, transforming growth factor .beta.(TGF-.beta.) is highly pleiotropic and can stimulate proliferationin some cells, especially connective tissue, while being a potentinhibitor of proliferation in others, such as lymphocytes andepithelial cells.

The physiological effect of growth stimulation or inhibition bygrowth factors depends upon the state of development anddifferentiation of the target tissue. The mechanism of localcellular regulation by classical endocrine molecules involvescomprehends autocrine (same cell), juxtacrine (neighbor cell), andparacrine (adjacent cells) pathways. Peptide growth factors areelements of a complex biological language, providing the basis forintercellular communication. They permit cells to conveyinformation between each other, mediate interaction between cellsand change gene expression. The effect of these multifunctional andpluripotent factors is dependent on the presence or absence ofother peptides.

Epidermal growth factor (EGF) is a conventional mitogenic factorthat stimulates the proliferation of various types of cellsincluding epithelial cells and fibroblasts. EGF binds to andactivates the EGF receptor (EGFR), which initiates intracellularsignaling and subsequent effects. The EGFR is expressed in neuronsof the cerebral cortex, cerebellum, and hippocampus in addition toother regions of the central nervous system (CNS). In addition, EGFis also expressed in various regions of the CNS. Therefore, EGFacts not only on mitotic cells, but also on postnitotic neurons. Infact, many studies have indicated that EGF has neurotrophic orneuromodulatory effects on various types of neurons in the CNS. Forexample, EGF acts directly on cultured cerebral cortical andcerebellar neurons, enhancing neurite outgrowth and survival. Onthe other hand, EGF also acts on other cell types, including septalcholinergic and mesencephalic dopaminergic neurons, indirectlythrough glial cells. Evidence of the effects of EGF on neurons inthe CNS is accumulating, but the mechanisms of action remainessentially unknown. EGF-induced signaling in mitotic cells isbetter understood than in postmitotic neurons. Studies of clonedpheochromocytoma PC12 cells and cultured cerebral cortical neuronshave suggested that the EGF-induced neurotrophic actions aremediated by sustained activation of the EGFR and mitogen-activatedprotein kinase (MAPK) in response to EGF. The sustainedintracellular signaling correlates with the decreased rate of EGFRdown-regulation, which might determine the response of neuronalcells to EGF. It is likely that EGF is a multi-potent growth factorthat acts upon various types of cells including mitotic cells andpostmitotic neurons.

EGF is produced by the salivary and Brunner's glands of thegastrointestinal system, kidney, pancreas, thyroid gland, pituitarygland, and the nervous system, and is found in body fluids such assaliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid,prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman,C R Peptides 12: 653-663 (1991).

EGF is mediated by its membrane specific receptor, which containsan intrinsic tyrosine kinase. Stoscheck C M et al., J. CellBiochem. 31: 135-152 (1986). EGF is believed to function by bindingto the extracellular portion of its receptor which induces atransmembrane signal that activates the intrinsic tyrosinekinase.

Purification and sequence analysis of the EGF-like domain hasrevealed the presence of six conserved cysteine residues whichcross-bind to create three peptide loops, Savage C R et al., J.Biol. Chem. 248: 7669-7672 (1979). It is now generally known thatseveral other peptides can react with the EGF receptor which sharethe same generalized motifX.sub.nCX.sub.7CX.sub.4/5CX.sub.10CXCX.sub.5GX.sub.2CX.sub.n, whereX represents any non-cysteine amino acid, and n is a variablerepeat number. Non isolated peptides having this motif includeTGF-.alpha., amphiregulin, schwannoma-derived growth factor (SDGF),heparin-binding EGF-like growth factors and certain virally encodedpeptides (e.g., Vaccinia virus, Reisner A H, Nature 313: 801-803(1985), Shope fibroma virus, Chang W., et al., Mol Cell Biol. 7:535-540 (1987), Molluscum contagiosum, Porter C D & Archard LC, J. Gen. Virol. 68: 673-682 (1987), and Myxoma virus, Upton C etal., J. Virol. 61: 1271-1275 (1987). Prigent SA & Lemoine N.R., Prog. Growth Factor Res. 4: 1-24 (1992).

EGF-like domains are not confined to growth factors but have beenobserved in a variety of cell-surface and extracellular proteinswhich have interesting properties in cell adhesion, protein-proteininteraction and development, Laurence D J R & Gusterson B A,Tumor Biol. 11: 229-261 (1990). These proteins include bloodcoagulation factors (factors VI, IX, X, XII, protein C, protein S,protein Z, tissue plasminogen activator, urokinase), extracellularmatrix components (laminin, cytotactin, entactin), cell surfacereceptors (LDL receptor, thrombomodulin receptor) andimmunity-related proteins (complement C1r, uromodulin).

Even more interesting, the general structure pattern of EGF-likeprecursors is preserved through lower organisms as well as inmammalian cells. A number of genes with developmental significancehave been identified in invertebrates with EGF-like repeats. Forexample, the notch gene of Drosophila encodes 36 tandemly arranged40 amino acid repeats which show homology to EGF, Wharton W et al.,Cell 43: 557-581 (1985). Hydropathy plots indicate a putativemembrane spanning domain, with the EGF-related sequences beinglocated on the extracellular side of the membrane. Other homeoticgenes with EGF-like repeats include Delta, 95F and 5ZD which wereidentified using probes based on Notch, and the nematode geneLin-12 which encodes a putative receptor for a developmental signaltransmitted between two specified cells.

Specifically, EGF has been shown to have potential in thepreservation and maintenance of gastrointestinal mucosa and therepair of acute and chronic mucosal lesions, Konturek, P C et al.,Eur. J. Gastroenterol Hepatol. 7 (10), 933-37 (1995), including thetreatment of necrotizing enterocolitis, Zollinger-Ellison syndrome,gastrointestinal ulceration gastrointestinal ulcerations andcongenital microvillus atrophy, A. Guglietta & P B Sullivan,Eur. J. Gastroenterol Hepatol, 7(10), 945-50 (1995). Additionally,EGF has been implicated in hair follicle differentiation; C. L. duCros, J. Invest. Dermatol. 101 (1 Suppl.), 106S-113S (1993), S GHillier, Clin. Endocrinol. 33(4),427-28(1990); kidney function, L.L. Hamm et al., Semin. Nephrol. 13 (1): 109-15 (1993), R C Harris,Am. J. Kidney Dis. 17(6): 627-30 (1991); tear fluid, G B van Settenet al., Int. Ophthalmol 15(6); 359-62 (1991); vitamin K mediatedblood coagulation, J. Stenflo et al., Blood 78(7): 1637-51 (1991).EGF is also implicated various skin disease characterized byabnormal keratinocyte differentiation, e.g., psoriasis, epithelialcancers such as squamous cell carcinomas of the lung, epidermoidcarcinoma of the vulva and gliomas. King, L E et al., Am. J. Med.Sci. 296: 154-158 (1988).

Of great interest is mounting evidence that genetic alterations ingrowth factors signaling pathways are closely linked todevelopmental abnormalities and to chronic diseases includingcancer. Aaronson S A, Science 254: 1146-1153 (1991). For example,c-erb-2 (also known as HER-2), a proto-oncogene with closestructural similarity to EGF receptor protein, is overexpressed inhuman breast cancer. King et al., Science 229: 974-976 (1985);Gullick, W J, Hormones and their actions, Cooke B A et al., eds,Amsterdam, Elsevier, pp 349-360 (1986).

17. PRO317

The TGF-.beta. supergene family, or simply TGF-.beta. superfamily,a group of secreted proteins, includes a large number of relatedgrowth and differentiation factors expressed in virtually allphyla. Superfamily members bind to specific cell surface receptorsthat activate signal transduction mechanisms to elicit theirmultifunctional cytokine effects. Kolodziejczyk and Hall, Biochem.Cell. Biol., 74: 299-314 (1996); Attisano and Wrana, CytokineGrowth Factor Rev., 7: 327-339 (1996); and Hill, CellularSignaling, 8: 533-544 (1996).

Members of this family include five distinct forms of TGF-.beta.(Sporn and Roberts, in Peptide Growth Factors and Their Receptors,Sporn and Roberts, eds. (Springer-Verlag: Berlin, 1990) pp.419-472), as well as the differentiation factors vg1 (Weeks andMelton, Cell, 51: 861-867 (1987)) and DPP-C polypeptide (Padgett etal., Nature, 325: 81-84 (1987)), the hormones activin and inhibin(Mason et al., Nature, 318: 659-663 (1985); Mason et al., GrowthFactors, 1: 77-88 (1987)), the Mullerian-inhibiting substance (MIS)(Cate et al., Cell, 45: 685-698 (1986)), the bone morphogeneticproteins (BMPs) (Wozney et al., Science, 242: 1528-1534 (1988); PCTWO 88/00205 published Jan. 14, 1988; U.S. Pat. No. 4,877,864 issuedOct. 31, 1989), the developmentally regulated proteins Vgr-1 (Lyonset al., Proc. Natl. Acad. Sci. USA. 86: 4554-4558 (1989)) and Vgr-2(Jones et al., Molec. Endocrinol., 6: 1961-1968 (1992)), the mousegrowth differentiation factor (GDF), such as GDF-3 and GDF-9(Kingsley, Genes Dev., 8: 133-146 (1994); McPherron and Lee, J.Biol. Chem., 268: 3444-3449 (1993)), the mouse lefty/Stra1 (Meno etal., Nature, 381: 151-155 (1996); Bouillet et al., Dev. Biol., 170:420-433 (1995)), glial cell line-derived neurotrophic factor (GDNF)(Lin et al., Science, 260: 1130-1132 (1993), neurturin (Kotzbaueret al., Nature, 384: 467-470 (1996)), and endometrialbleeding-associated factor (EBAF) (Kothapalli et al., J. Clin.Invest., 99: 2342-2350 (1997)). The subset BMP-2A and BMP-2B isapproximately 75% homologous in sequence to DPP-C and may representthe mammalian equivalent of that protein.

The proteins of the TGF-.beta. superfamily are disulfide-linkedhomo- or heterodimers encoded by larger precursor polypeptidechains containing a hydrophobic signal sequence, a long andrelatively poorly conserved N-terminal pro region of severalhundred amino acids, a cleavage site (usually polybasic), and ashorter and more highly conserved C-terminal region. ThisC-terminal region corresponds to the processed mature protein andcontains approximately 100 amino acids with a characteristiccysteine motif, i.e., the conservation of seven of the ninecysteine residues of TGF-.beta. among all known family members.Although the position of the cleavage site between the mature andpro regions varies among the family members, the C-terminus of allof the proteins is in the identical position, ending in thesequence Cys-X-Cys-X, but differing in every case from theTGF-.beta. consensus C-terminus of Cys-Lys-Cys-Ser. Sporn andRoberts, 1990, supra.

There are at least five forms of TGF-.beta. currently identified,TGF-.beta.1, TGF-.beta.2, TGF-.beta.3, TGF-.beta.4, andTGF-.beta.5. The activated form of TGF-.beta.1 is a homodimerformed by dimerization of the carboxy-terminal 112 amino acids of a390 amino acid precursor. Recombinant TGF-.beta.1 has been cloned(Derynck et al., Nature, 316:701-705 (1985)) and expressed inChinese hamster ovary cells (Gentry et al., Mol. Cell. Biol., 7:3418-3427 (1987)). Additionally, recombinant human TGF-.beta.2(deMartin et al., EMBO J., 6: 3673 (1987)), as well as human andporcine TGF-.beta.3 (Derynck et al., EMBO J., 7: 3737-3743 (1988);ten Dijke et al., Proc. Natl. Acad. Sci. USA, 85: 4715 (1988)) havebeen cloned. TGF-.beta.2 has a precursor form of 414 amino acidsand is also processed to a homodimer from the carboxy-terminal 112amino acids that shares approximately 70% homology with the activeform of TGF-.beta.1 (Marquardt et al., J. Biol. Chem., 262: 12127(1987)). See also EP 200,341; 169,016; 268,561; and 267,463; U.S.Pat. No. 4,774,322; Cheifetz et al., Cell, 48: 409-415 (1987);Jakowlew et al., Molecular Endocrin., 2: 747-755 (1988); Derynck etal., J. Biol. Chem., 261: 4377-4379 (1986); Sharples et al., DNA,6: 239-244 (1987); Derynck et al., Nucl. Acids. Res., 15: 3188-3189(1987); Derynck et al., Nucl. Acids. Res., 15: 3187 (1987); Seyedinet al., J. Biol. Chem., 261: 5693-5695 (1986); Madisen et al., DNA,7: 1-8 (1988); and Hanks et al., Proc. Natl. Acad. Sci. (U.S.A.),85: 79-82 (1988).

TGF-.beta.4 and TGF-.beta.5 were cloned from a chicken chondrocytecDNA library (Jakowlew et al., Molec. Endocrinol., 2: 1186-1195(1988)) and from a frog oocyte cDNA library, respectively.

The pro region of TGF-.beta. associates non-covalently with themature TGF-.beta. dimer (Wakefield et al., J. Biol. Chem., 263:7646-7654 (1988); Wakefield et al., Growth Factors, 1: 203-218(1989)), and the pro regions are found to be necessary for properfolding and secretion of the active mature dimers of bothTGF-.beta. and activin (Gray and Mason, Science, 247: 1328-1330(1990)). The association between the mature and pro regions ofTGF-.beta. masks the biological activity of the mature dimer,resulting in formation of an inactive latent form. Latency is not aconstant of the TGF-.beta. superfamily, since the presence of thepro region has no effect on activin or inhibin biologicalactivity.

A unifying feature of the biology of the proteins from theTGF-.beta. superfamily is their ability to regulate developmentalprocesses. TGF-.beta. has been shown to have numerous regulatoryactions on a wide variety of both normal and neoplastic cells.TGF-.beta. is multifunctional, as it can either stimulate orinhibit cell proliferation, differentiation, and other criticalprocesses in cell function (Sporn and Roberts, supra).

One member of the TGF-.beta. superfamily, EBAF, is expressed inendometrium only in the late secretory phase and during abnormalendometrial bleeding. Kothapalli et al., J. Clin. Invest., 99:2342-2350 (1997). Human endometrium is unique in that it is theonly tissue in the body that bleeds at regular intervals. Inaddition, abnormal endometrial bleeding is one of the most commonmanifestations of gynecological diseases, and is a prime indicationfor hysterectomy. In situ hybridization showed that the mRNA ofEBAF was expressed in the stroma without any significant mRNAexpression in the endometrial glands or endothelial cells.

The predicted protein sequence of EBAF showed a strong homology tothe protein encoded by mouse lefty/stra3 of the TGF-.beta.superfamily. A motif search revealed that the predicted EBAFprotein contains most of the cysteine residues which are conservedamong the TGF-.beta.-related proteins and which are necessary forthe formation of the cysteine knot structure. The EBAF sequencecontains an additional cysteine residue, 12 amino acids upstreamfrom the first conserved cysteine residue. The only other familymembers known to contain an additional cysteine residue areTGF-.beta.s, inhibins, and GDF-3. EBAF, similar to LEFTY,GDF-3/Vgr2, and GDF-9, lacks the cysteine residue that is known toform the intermolecular disulfide bond. Therefore, EBAF appears tobe an additional member of the TGF-.beta. superfamily with anunpaired cysteine residue that may not exist as a dimer. However,hydrophobic contacts between the two monomer subunits may promotedimer formation. Fluorescence in situ hybridization showed that theebaf gene is located on human chromosome 1 at band q42.1.

Additional members of the TGF-.beta. superfamily, such as thoserelated to EBAF, are being searched for by industry and academics.We herein describe the identification and characterization of novelpolypeptides having homology to EBAF, designated herein as PRO317polypeptides.

18. PRO301

The widespread occurrence of cancer has prompted the devotion ofconsiderable resources and discovering new treatments of treatment.One particular method involves the creation of tumor or cancerspecific monoclonal antibodies (mAbs) which are specific to tumorantigens. Such mAbs, which can distinguish between normal andcancerous cells are useful in the diagnosis, prognosis andtreatment of the disease. Particular antigens are known to beassociated with neoplastic diseases, such as colorectal cancer.

One particular antigen, the A33 antigen is expressed in more than90% of primary or metastatic colon cancers as well as normal colonepithelium. Since colon cancer is a widespread disease, earlydiagnosis and treatment is an important medical goal. Diagnosis andtreatment of colon cancer can be implemented using monoclonalantibodies (mAbs) specific therefore having fluorescent, nuclearmagnetic or radioactive tags. Radioactive gene, toxins and/or drugtagged mAbs can be used for treatment in situ with minimal patientdescription. mAbs can also be used to diagnose during the diagnosisand treatment of colon cancers. For example, when the serum levelsof the A33 antigen are elevated in a patient, a drop of the levelsafter surgery would indicate the tumor resection was successful. Onthe other hand, a subsequent rise in serum A33 antigen levels aftersurgery would indicate that metastases of the original tumor mayhave formed or that new primary tumors may have appeared. Suchmonoclonal antibodies can be used in lieu of, or in conjunctionwith surgery and/or other chemotherapies. For example, U.S. Pat.No. 4,579,827 and U.S. Ser. No. 424,991 (E.P. 199,141) are directedto therapeutic administration of monoclonal antibodies, the latterof which relates to the application of anti-A33 mAb.

Many cancers of epithelial origin have adenovirus receptors. Infact, adenovirus-derived vectors have been proposed as a means ofinserting antisense nucleic acids into tumors (U.S. Pat. No.5,518,885). Thus, the association of viral receptors withneoplastic tumors is not unexpected.

We herein describe the identification and characterization of novelpolypeptides having homology to certain cancer-associated antigens,designated herein as PRO301 polypeptides.

19. PRO224

Cholesterol uptake can have serious implications on one's health.Cholesterol uptake provides cells with most of the cholesterol theyrequire for membrane synthesis. If this uptake is blocked,cholesterol accumulates in the blood and can contribute to theformation of atherosclerotic plaques in blood vessel walls. Mostcholesterol is transported in the blood bound to protein in theform of complexes known as low-density lipoproteins (LDLs). LDLsare endocytosed into cells via LDL receptor proteins. Therefore,LDL receptor proteins, and proteins having homology thereto, are ofinterest to the scientific and medical communities.

Membrane-bound proteins and receptors can play an important role inthe formation, differentiation and maintenance of multicellularorganisms. The LDL receptors are an example of membrane-boundproteins which are involved in the synthesis and formation of cellmembranes, wherein the health of an individual is affected directlyand indirectly by its function. Many membrane-bound proteins act asreceptors such as the LDL receptor. These receptors can function toendocytose substrates or they can function as a receptor for achannel. Other membrane-bound proteins function as signals orantigens.

Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. The membrane-bound proteins can also be employed forscreening of potential peptide or small molecule regulators of therelevant receptor/ligand interaction. In the case of the LDLreceptor, it is desirable to find molecules which enhanceendocytosis so as to lower blood cholesterol levels and plaqueformation. It is also desirable to identify molecules which inhibitendocytosis so that these molecules can be avoided or regulated byindividuals having high blood cholesterol. Polypeptides which arehomologous to lipoprotein receptors but which do not function aslipoprotein receptors are also of interest in the determination ofthe function of the fragments which show homology.

The following studies report on previously known low densitylipoprotein receptors and related proteins includingapolipoproteins: Sawamura, et al., Nippon Chemiphar Co, Japanpatent application J09098787; Novak, S., et al., J. Biol. Chem.,271: (20)11732-6 (1996); Blaas, D., J. Virol., 69(11)7244-7(November 1995); Scott, J., J. Inherit. Metab. Dis. (UK), 9/Supp. 1(3-16) (1986); Yamamoto, et al., Cell, 39:27-38 (1984); Rebece, etal., Neurobiol. Aging, 15:5117(1994); Novak, S., et al., J. Biol.Chemistry, 271:11732-11736(1996); and Sestavel and Fruchart, CellMol. Biol., 40(4):461-81 (June 1994). These publications and otherspublished prior to the filing of this application provide furtherbackground to peptides already known in the art.

Efforts are being undertaken by both industry and academia toidentify new, native membrane-bound receptor proteins, particularlythose having homology to lipoprotein receptors. We herein describethe identification and characterization of novel polypeptideshaving homology to lipoprotein receptors, designated herein asPRO224 polypeptides.

20. PRO222

Complement is a group of proteins found in the blood that areimportant in humoral immunity and inflammation. Complement proteinsare sequentially activated by antigen-antibody complexes or byproteolytic enzymes. When activated, complement proteins killbacteria and other microorganisms, affect vascular permeability,release histamine and attract white blood cells. Complement alsoenhances phagocytosis when bound to target cells. In order toprevent harm to autologous cells, the complement activation pathwayis tightly regulated.

Deficiencies in the regulation of complement activation or in thecomplement proteins themselves may lead to immune-complex diseases,such as systemic lupus erythematosus, and may result in increasedsusceptibility to bacterial infection. In all cases, earlydetection of complement deficiency is desirable so that the patientcan begin treatment. Thus, research efforts are currently directedtoward identification of soluble and membrane proteins thatregulate complement activation.

Proteins known to be important in regulating complement activationin humans include Factor H and Complement receptor type 1 (CR1).Factor H is a 150 kD soluble serum protein that interacts withcomplement protein C3b to accelerate the decay of C3 convertase andacts as a cofactor for Factor I-mediated cleavage of complementprotein C4b. Complement receptor type 1 is a 190-280 kD membranebound protein found in mast cells and most blood cells. CR1interacts with complement proteins C3b, C4b, and C3b to acceleratedissociation of C3 convertases, acts as a cofactor for FactorI-mediated cleavage of C3b and C4b, and binds immune complexes andpromotes their dissolution and phagocytosis.

Proteins which have homology to complement proteins are ofparticular interest to the medical and industrial communities.Often, proteins having homology to each other have similarfunction. It is also of interest when proteins having homology donot have similar functions, indicating that certain structuralmotifs identify information other than function, such as localityof function.

Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound proteins,particularly those having homology to known proteins involved inthe complement pathway. Proteins involved in the complement pathwaywere reviewed in Birmingham D J (1995), Critical Reviews inImmunology, 15(2):133-154 and in Abbas A K, et al. (1994) Cellularand Molecular Immunology, 2nd Ed. W. B. Saunders Company,Philadelphia, pp 295-315.

We herein describe the identification and characterization of novelpolypeptides having homology to complement receptors, designatedherein as PRO222 polypeptides.

21. PRO234

The successful function of many systems within multicellularorganisms is dependent on cell-cell interactions. Such interactionsare affected by the alignment of particular ligands with particularreceptors in a manner which allows for ligand-receptor binding andthus a cell-cell adhesion. While protein-protein interactions incell recognition have been recognized for some time, only recentlyhas the role of carbohydrates in physiologically relevantrecognition been widely considered (see B. K. Brandley et al., J.Leuk. Biol. 40: 97 (1986) and N. Sharon et al., Science 246: 227(1989). Oligosaccharides are well positioned to act as recognitionnovel lectins due to their cell surface location and structuraldiversity. Many oligosaccharide structures can be created throughthe differential activities of a smaller number ofglycosyltransferases. The diverse structures of oligosaccharidescan be generated by transcription of relatively few gene products,which suggests that the oligosaccharides are a plausible mechanismby which is directed a wide range of cell-cell interactions.Examples of differential expression of cell surface carbohydratesand putative carbohydrate binding proteins (lectins) on interactingcells have been described (J. Dodd & T. M. Jessel, J. Neurosci.5: 3278 (1985); L. J. Regan et al., Proc. Natl. Acad. Sci. USA 83:2248 (1986); M. Constantine-Paton et al., Nature 324: 459 (1986);and M. Tiemeyer et al., J. Biol. Chem. 263: 1671 (1989). Oneinteresting member of the lectin family are selectins.

The migration of leukocytes to sites of acute or chronicinflammation involves adhesive interactions between these cells andthe endothelium. This specific adhesion is the initial event in thecascade that is initiated by inflammatory insults, and it is,therefore, of paramount importance to the regulated defense of theorganism.

The types of cell adhesion molecules that are involved in theinteraction between leukocytes and the endothelium during aninflammatory response currently stands at four: (1) selectins; (2)(carbohydrate and glycoprotein) ligands for selecting; (3)integrins; and (4) integrin ligands, which are members of theimmunoglobulin gene superfamily.

The selectins are cell adhesion molecules that are unified bothstructurally and functionally. Structurally, selectins arecharacterized by the inclusion of a domain with homology to acalcium-dependent lectin (C-lectins), an epidermal growth factor(egf)-like domain and several complement binding-like domains,Bevilacqua, M. P. et al., Science 243: 1160-1165 (1989); Johnstonet al., Cell 56: 1033-1044 (1989); Lasky et al, Cell 56: 1045-1055(1989); Siegalman, M. et al., Science 243: 1165-1172 (1989);Stoolman, L. M., Cell 56: 907-910 (1989). Functionally, selectinsshare the common property of their ability to mediate cell bindingthrough interactions between their lectin domains and cell surfacecarbohydrate ligands (Brandley, B, et al., Cell 63, 861-863 (1990);Springer, T. and Lasky, L. A., Nature 349, 19-197 (1991);Bevilacqua, M. P. and Nelson, R. M., J. Clin. Invest. 91 379-387(1993) and Tedder et al., J. Exp. Med. 170: 123-133 (1989).

There are three members identified so far in the selectin family ofcell adhesion molecules: L-selectin (also called peripheral lymphnode homing receptor (pnHR), LEC-CAM-1, LAM-1, gp90.sup.MEL,gp100.sup.MEL, gp110.sup.MEL, MEL-14 antigen, Leu-8 antigen, TQ-1antigen, DREG antigen), E-selectin (LEC-CAM-2, LECAM-2, ELAM-1) andP-selectin (LEC-CAM-3, LECAM-3, GMP-140, PADGEM).

The identification of the C-lectin domain has led to an intenseeffort to define carbohydrate binding ligands for proteinscontaining such domains. E-selectin is believed to recognize thecarbohydrate sequence NeuNAc.alpha.2-3Gal.beta.1-4(Fuc.alpha.1-3)GlcNAc (sialyl-Lewis x, or sLe.sup.x) and related oligosaccharides,Berg et al., J. Biol. Chem. 265: 14869-14872 (1991); Lowe et al.,Cell 63: 475-484 (1990); Phillips et al., Science 250:1130-1132(1990); Tiemeyer et al., Proc. Natl. Acad. Sci. USA 88:1138-1142(1991).

L-selectin, which comprises a lectin domain, performs its adhesivefunction by recognizing carbohydrate-containing ligands onendothelial cells. L-selectin is expressed on the surface ofleukocytes, such as lymphocytes, neutrophils, monocytes andeosinophils, and is involved with the trafficking of lymphocytes toperipheral lymphoid tissues (Gallatin et al., Nature 303: 30-34(1983)) and with acute neutrophil-medicated inflammatory responses(Watson, S. R., Nature 349: 164-167 (1991)). The amino acidsequence of L-selectin and the encoding nucleic acid sequence are,for example, disclosed in U.S. Pat. No. 5,098,833 issued Mar. 24,1992.

L-selectin (LECAM-1) is particularly interesting because of itsability to block neutrophil influx (Watson et al., Nature 349:164-167 (1991). It is expressed in chronic lymphocytic leukemiacells which bind to HEV (Spertini et al., Nature 349: 691-694(1991). It is also believed that HEV structures at sites of chronicinflammation are associated with the symptoms of diseases such asrheumatoid arthritis, psoriasis and multiple sclerosis.

E-selectin (ELAM-1), is particularly interesting because of itstransient expression on endothelial cells in response to IL-1 orTNF. Bevilacqua et al., Science 243: 1160 (1989). The time courseof this induced expression (2-8 h) suggests a role for thisreceptor in initial neutrophil induced extravasation in response toinfection and injury. It has further been reported that anti-ELAM-1antibody blocks the influx of neutrophils in a primate asthma modeland thus is beneficial for preventing airway obstruction resultingfrom the inflammatory response. Gundel et al., J. Clin. Invest. 88:1407 (1991).

The adhesion of circulating neutrophils to stimulated vascularendothelium is a primary event of the inflammatory response.P-selectin has been reported to recognize the Lewis x structure(Gal.beta.1-4(Fuc.alpha.1-3) GlcNAc), Larsen et al., Cell 63:467-474(1990). Others report that an additional terminal linkedsialic acid is required for high affinity binding, Moore et al., J.Cell. Biol. 112: 491-499 (1991). P-selectin has been shown to besignificant in acute lung injury. Anti-P-selectin antibody has beenshown to have strong protective effects in a rodent lung injurymodel. M. S. Mulligan et al., J. Clin. Invest. 90: 1600 (1991).

We herein describe the identification and characterization of novelpolypeptides having homology to lectin proteins, herein designatedas PRO234 polypeptides.

22. PRO231

Some of the most important proteins involved in the above describedregulation and modulation of cellular processes are the enzymeswhich regulate levels of protein phosphorylation in the cell. Forexample, it is known that the transduction of signals that regulatecell growth and differentiation is regulated at least in part byphosphorylation and dephosphorylation of various cellular proteins.The enzymes that catalyze these processes include the proteinkinases, which function to phosphorylate various cellular proteins,and the protein phosphatases, which function to remove phosphateresidues from various cellular proteins. The balance of the levelof protein phosphorylation in the cell is thus mediated by therelative activities of these two types of enzymes.

Protein phosphatases represent a growing family of enzymes that arefound in many diverse forms, including both membrane-bound andsoluble forms. While many protein phosphatases have been described,the functions of only a very few are beginning to be understood(Tonks, Semin. Cell Biol. 4:373-453 (1993) and Dixon, Recent Prog.Horm. Res. 51:405-414 (1996)). However, in general, it appears thatmany of the protein phosphatases function to modulate the positiveor negative signals induced by various protein kinases. Therefore,it is likely that protein phosphatases play critical roles innumerous and diverse cellular processes.

Given the physiological importance of the protein phosphatases,efforts are being undertaken by both industry and academia toidentify new, native phosphatase proteins. Many of these effortsare focused on the screening of mammalian recombinant DNA librariesto identify the coding sequences for novel phosphatase proteins.Examples of screening methods and techniques are described in theliterature [see, for example, Klein et al., Proc. Natl. Acad. Sci.,93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to acid phosphatases, designatedherein as PRO231 polypeptides.

23. PRO229

Scavenger receptors are known to protect IgG molecules fromcatabolic degradation. Riechmann and Hollinger, NatureBiotechnology, 15:617 (1997). In particular, studies of the CH2 andCH3 domains have shown that specific sequences of these domains areimportant in determining the half-lives of antibodies. Ellerson, etal., J. Immunol., 116: 510 (1976); Yasmeen, et al., J. Immunol.116: 518 (1976; Pollock, et al., Eur. J. Immunol., 20: 2021 (1990).Scavenger receptor proteins and antibodies thereto are furtherreported in U.S. Pat. No. 5,510,466 to Krieger, et al. Due to theability of scavenger receptors to increase the half-life ofpolypeptides and their involvement in immune function, moleculeshaving homology to scavenger receptors are of importance to thescientific and medical community.

Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins,particularly those having homology to scavenger receptors. Manyefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound receptor proteins. Examples of screening methods andtechniques are described in the literature [see, for example, Kleinet al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to scavenger receptors, designatedherein as PRO229 polypeptides.

24. PRO238

Oxygen free radicals and antioxidants appear to play an importantrole in the central nervous system after cerebral ischemia andreperfusion. Moreover, cardiac injury, related to ischaemia andreperfusion has been reported to be caused by the action of freeradicals. Additionally, studies have reported that the redox stateof the cell is a pivotal determinant of the fate of the cells.Furthermore, reactive oxygen species have been reported to becytotoxic, causing inflammatory disease, including tissue necrosis,organ failure, atherosclerosis, infertility, birth defects,premature aging, mutations and malignancy. Thus, the control ofoxidation and reduction is important for a number of reasonsincluding for control and prevention of strokes, heart attacks,oxidative stress and hypertension. In this regard, reductases, andparticularly, oxidoreductases, are of interest. Publicationsfurther describing this subject matter include Kelsey, et al., Br.J. Cancer, 76(7):8524 (1997); Friedrich and Weiss, J. Theor. Biol.,187(4):52940 (1997) and Pieulle, et al., J. Bacteriol.,179(18):5684-92 (1997).

Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins,particularly secreted proteins which have homology to reductase.Many efforts are focused on the screening of mammalian recombinantDNA libraries to identify the coding sequences for novel secretedand membrane-bound receptor proteins. Examples of screening methodsand techniques are described in the literature [see, for example,Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to reductase, designated herein asPRO238 polypeptides.

25. PRO233

Studies have reported that the redox state of the cell is animportant determinant of the fate of the cell. Furthermore,reactive oxygen species have been reported to be cytotoxic, causinginflammatory disease, including tissue necrosis, organ failure,atherosclerosis, infertility, birth defects, premature aging,mutations and malignancy. Thus, the control of oxidation andreduction is important for a number of reasons, including thecontrol and prevention of strokes, heart attacks, oxidative stressand hypertension. Oxygen free radicals and antioxidants appear toplay an important role in the central nervous system after cerebralischemia and reperfusion. Moreover, cardiac injury, related toischaemia and reperfusion has been reported to be caused by theaction of free radicals. In this regard, reductases, andparticularly, oxidoreductases, are of interest. In addition, thetranscription factors, NF-kappa B and AP-1, are known to beregulated by redox state and to affect the expression of a largevariety of genes thought to be involved in the pathogenesis ofAIDS, cancer, atherosclerosis and diabetic complications.Publications further describing this subject matter include Kelsey,et al., Br. J. Cancer, 76(7):8524 (1997); Friedrich and Weiss, J.Theor. Biol., 187(4):529-40 (1997) and Pieulle, et al., J.Bacteriol., 179(18):5684-92 (1997). Given the physiologicalimportance of redox reactions in vivo, efforts are currently beingunder taken to identify new, native proteins which are involved inredox reactions. We describe herein the identification of novelpolypeptides which have homology to reductase, designated herein asPRO233 polypeptides.

26. PRO223

The carboxypeptidase family of exopeptidases constitutes a diversegroup of enzymes that hydrolyze carboxyl-terminal amide bonds inpolypeptides, wherein a large number of mammalian tissues producethese enzymes. Many of the carboxypeptidase enzymes that have beenidentified to date exhibit rather strong cleavage specificities forcertain amino acids in polypeptides. For example, carboxypeptidaseenzymes have been identified which prefer lysine, arginine, serineor amino acids with either aromatic or branched aliphatic sidechains as substrates at the carboxyl terminus of thepolypeptide.

With regard to the serine carboxypeptidases, such amino acidspecific enzymes have been identified from a variety of differentmammalian and non-mammalian organisms. The mammalian serinecarboxypeptidase enzymes play important roles in many differentbiological processes including, for example, protein digestion,activation, inactivation, or modulation of peptide hormoneactivity, and alteration of the physical properties of proteins andenzymes.

In light of the physiological importance of the serinecarboxypeptidases, efforts are being undertaken by both industryand academia to identify new, native secreted and membrane-boundreceptor proteins and specifically novel carboxypeptidases. Many ofthese efforts are focused on the screening of mammalian recombinantDNA libraries to identify the coding sequences for novel secretedand membrane-bound receptor proteins. We describe herein novelpolypeptides having homology to one or more serine carboxypeptidasepolypeptides, designated herein as PRO223 polypeptides.

27. PRO235

Plexin was first identified in Xenopus tadpole nervous system as amembrane glycoprotein which was shown to mediate cell adhesion viaa homophilic binding mechanism in the presence of calcium ions.Strong evolutionary conservation between Xenopus, mouse and humanhomologs of plexin has been observed. [Kaneyama et al., Biochem.And Biophys. Res. Comm. 226: 52 4529 (1996)]. Given thephysiological importance of cell adhesion mechanisms in vivo,efforts are currently being under taken to identify new, nativeproteins which are involved in cell adhesion. We describe hereinthe identification of a novel polypeptide which has homology toplexin, designated herein as PRO235.

28. PRO236 and PRO262

.beta.-galactosidase is a well known enzymatic protein whichfunctions to hydrolyze .beta.-galactoside molecules..beta.-galactosidase has been employed for a variety of differentapplications, both in vitro and in vivo and has proven to be anextremely useful research tool. As such, there is an interest inobtaining novel polypeptides which exhibit homology to the.beta.-galactosidase polypeptide.

Given the strong interest in obtaining novel polypeptides havinghomology to .beta.-galactosidase, efforts are currently beingundertaken by both industry and academia to identify new, native.beta.-galactosidase homolog proteins. Many of these efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel .beta.-galactosidase-likeproteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc.Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].We herein describe novel poylpeptides having siginificant homologyto the .beta.-galactosidase enzyme, designated herein as PRO236 andPRO262 polypeptides.

29. PRO239

Densin is a glycoprotein which has been isolated from the brainwhich has all the hallmarks of an adhesion molecule. It is highlyconcentrated at synaptic sites in the brain and is expressedprominently in dendritic processes in developing neurons. Densinhas been characterized as a member of the O-linkedsialoglycoproteins. Densin has relevance to medically importantprocesses such as regeneration. Given the physiological importanceof synaptic processes and cell adhesion mechanisms in vivo, effortsare currently being under taken to identify new, native proteinswhich are involved in synaptic machinery and cell adhesion. Wedescribe herein the identification of novel polypeptides which havehomology to densin, designated herein as PRO239 polypeptides.

30. PRO257

Ebnerin is a cell surface protein associated with von Ebner glandsin mammals. Efforts are being undertaken by both industry andacademia to identify new, native cell surface receptor proteins andspecifically those which possess sequence homology to cell surfaceproteins such as ebnerin. Many of these efforts are focused on thescreening of mammalian recombinant DNA libraries to identify thecoding sequences for novel receptor proteins. We herein describethe identification of novel polypeptides having significanthomology to the von Ebner's gland-associated protein ebnerin,designated herein as PRO257 polypeptides.

31. PRO260

Fucosidases are enzymes that remove fucose residues from fucosecontaining proteoglycans. In some pathological conditions, such ascancer, rheumatoid arthritis, and diabetes, there is an abnormalfucosylation of serum proteins. Therefore, fucosidases, andproteins having homology to fucosidase, are of importance to thestudy and abrogation of these conditions. In particular, proteinshaving homology to the alpha-1-fucosidase precursor are ofinterest. Fucosidases and fucosidase inhibitors are furtherdescribed in U.S. Pat. Nos. 5,637,490, 5,382,709, 5,240,707,5,153,325, 5,100,797, 5,096,909 and 5,017,704. Studies are alsoreported in Valk, et al., J. Virol., 71(9):6796 (1997), Aktogu, etal., Monaldi. Arch. Chest Dis. (Italy), 52(2):118 (1997) andFocarelli, et al., Biochem. Biophys. Res. Commun. (U.S.), 234(1):54(1997).

Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins.Of particular interest are proteins having homology to thealpha-1-fucosidase precursor. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify thecoding sequences for novel secreted and membrane-bound receptorproteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc.Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to fucosidases, designated herein asPRO260 polypeptides.

32. PRO263

CD44 is a cell surface adhesion molecule involved in cell-cell andcell-matrix interactions. Hyaluronic acid, a component of theextracellular matrix is a major ligand. Other ligands includecollagen, fibronectin, laminin, chrondroitin sulfate, mucosaladdressin, serglycin and osteoponin. CD44 is also important inregulating cell traffic, lymph node homing, transmission of growthsignals, and presentation of chemokines and growth factors totraveling cells. CD44 surface proteins are associated withmetastatic tumors and CD44 has been used as a marker for HIVinfection. Certain splice variants are associated with metastasisand poor prognosis of cancer patients. Therefore, molecules havinghomology with CD44 are of particular interest, as their homologyindicates that they may have functions related to those functionsof CD44. CD44 is further described in U.S. Pat. Nos. 5,506,119,5,504,194 and 5,108,904; Gerberick, et al., Toxicol. Appl.Pharmacol., 146(1):1 (1997); Wittig, et al., Immunol. Letters(Netherlands), 57(1-3):217 (1997); and Oliveira and Odell, OralOncol. (England), 33(4):260 (1997).

Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins,particularly transmembrane proteins with homology to CD44 antigen.Many efforts are focused on the screening of mammalian recombinantDNA libraries to identify the coding sequences for novel secretedand membrane-bound receptor proteins. Examples of screening methodsand techniques are described in the literature [see, for example,Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to CD44 antigen, designated herein asPRO263 polypeptides.

33. PRO270

Thioredoxins effect reduction-oxidation (redox) state. Manydiseases are potentially related to redox state and reactive oxygenspecies may play a role in many important biological processes. Thetranscription factors, NF-kappa B and AP-1, are regulated by redoxstate and are known to affect the expression of a large variety ofgenes thought to be involved in the pathogenesis of AIDS, cancer,atherosclerosis and diabetic complications. Such proteins may alsoplay a role in cellular antioxidant defense, and in pathologicalconditions involving oxidative stress such as stroke andinflammation in addition to having a role in apoptosis. Therefore,thioredoxins, and proteins having homology thereto, are of interestto the scientific and medical communities.

We herein describe the identification and characterization of novelpolypeptides having homology to thioredoxin, designated herein asPRO270 polypeptides.

34. PRO271

The proteoglycan link protein is a protein which is intimatelyassociated with various extracellular matrix proteins and morespecifically with proteins such as collagen. For example, oneprimary component of collagen is a large proteoglycan calledaggrecan. This molecule is retained by binding to theglycosaminoglycan hyaluronan through the amino terminal G1 globulardomain of the core protein. This binding is stabilized by theproteoglycan link protein which is a protein that is alsoassociated with other tissues containing hyaluronan bindingproteoglycans such as versican.

Link protein has been identified as a potential target forautoimmune antibodies in individuals who suffer from juvenilerheumatoid arthritis (see Guerassimov et al., J. Rheumatology24(5):959-964 (1997)). As such, there is strong interest inidentifying novel proteins having homology to link protein. Weherein describe the identification and characterization of novelpolypeptides having such homology, designated herein as PRO271polypeptides.

35. PRO272

Reticulocalbin is an endoplasmic reticular protein which may beinvolved in protein transport and luminal protein processing.Reticulocalbin resides in the lumen of the endoplasmic rerticulum,is known to bind calcium, and may be involved in a luminalretention mechanism of the endoplasmic reticulum. It contains sixdomains of the EF-hand motif associated with high affinity calciumbinding. We describe herein the identification and characterizationof a novel polypeptide which has homology to the reticulocalbinprotein, designated herein as PRO272.

36. PRO294

Collagen, a naturally occurring protein, finds wide application inindustry. Chemically hydrolyzed natural collagen can be denaturedand renatured by heating and cooling to produce gelatin, which isused in photographic and medical, among other applications.Collagen has important properties such as the ability to forminterchain aggregates having a conformation designated as a triplehelix. We herein describe the identification and characterizationof a novel polypeptide which has homology to portions of thecollagen molecule, designated herein as PRO294.

37. PRO295

The integrins comprise a supergene family of cell-surfaceglycoprotein receptors that promote cellular adhesion. Each cellhas numerous receptors that define its cell adhesive capabilities.Integrins are involved in a wide variety of interaction betweencells and other cells or matrix components. The integrins are ofparticular importance in regulating movement and function of immunesystem cells The platelet IIb/IIIA integrin complex is ofparticular importance in regulating platelet aggregation. A memberof the integrin family, integrin .beta.-6, is expressed onepithelial cells and modulates epithelial inflammation. Anotherintegrin, leucocyte-associated antigen-1 (LFA-1) is important inthe adhesion of lymphocytes during an immune response. Theintegrins are expressed as heterodimers of non-covalentlyassociated alpha and beta subunits. Given the physiologicalimportance of cell adhesion mechanisms in vivo, efforts arecurrently being under taken to identify new, native proteins whichare involved in cell adhesion. We describe herein theidentification and characterization of a novel polypeptide whichhas homology to integrin, designated herein as PRO295.

38. PRO293

Protein-protein interactions include receptor and antigen complexesand signaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated toregulate the particular result of the protein-protein interaction.Thus, the underlying mechanisms of protein-protein interactions areof interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to beinvolved in protein-protein interactions. Leucine-rich repeats areshort sequence motifs present in a number of proteins with diversefunctions and cellular locations. The crystal structure ofribonuclease inhibitor protein has revealed that leucine-richrepeats correspond to beta-alpha structural units. These units arearranged so that they form a parallel beta-sheet with one surfaceexposed to solvent, so that the protein acquires an unusual,nonglubular shape. These two features have been indicated asresponsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serveas tissue organizers, orienting and ordering collagen fibrilsduring ontogeny and are involved in pathological processes such aswound healing, tissue repair, and tumor stroma formation. Iozzo, R.V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Othersstudies implicating leucine rich proteins in wound healing andtissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol.(Germany), 37(4):215-222 (1995), reporting mutations in the leucinerich motif in a complex associated with the bleeding disorderBernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost.(Germany), 74(1): 111-116 (July 1995), reporting that plateletshave leucine rich repeats. Another protein of particular interestwhich has been reported to have leucine-rich repeats is the SLITprotein which has been reported to be useful in treatingneuro-degenerative diseases such as Alzheimer's disease, nervedamage such as in Parkinson's disease, and for diagnosis of cancer,see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 byYale University. Other studies reporting on the biologicalfunctions of proteins having leucine-rich repeats include: Tayar,N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70(December 1996) (gonadotropin receptor involvement); Miura, Y., etal., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosisinvolvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement); andRuoslahti, E. I., et al., WO9110727-A by La Jolla Cancer ResearchFoundation (decorin binding to transforming growth factor.beta.involvement for treatment for cancer, wound healing andscarring).

Efforts are therefore being undertaken by both industry andacademia to identify new proteins having leucine rich repeats tobetter understand protein-protein interactions. Of particularinterest are those proteins having leucine rich repeats andhomology to known neuronal leucine rich repeat proteins. Manyefforts are focused on the screening of mammalian recombinant DNAlibraries to identify the coding sequences for novel secreted andmembrane-bound proteins having leucine rich repeats. Examples ofscreening methods and techniques are described in the literature[see, for example, Klein et al., Proc. Natl. Acad. Sci.,93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We describe herein the identification and characterization of anovel polypeptide which has homology to leucine rich repeatproteins, designated herein as PRO293.

39. PRO247

Protein-protein interactions include receptor and antigen complexesand signaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated toregulate the particular result of the protein-protein interaction.Thus, the underlying mechanisms of protein-protein interactions areof interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to beinvolved in protein-protein interactions. Leucine-rich repeats areshort sequence motifs present in a number of proteins with diversefunctions and cellular locations. The crystal structure ofribonuclease inhibitor protein has revealed that leucine-richrepeats correspond to beta-alpha structural units. These units arearranged so that they form a parallel beta-sheet with one surfaceexposed to solvent, so that the protein acquires an unusual,nonglubular shape. These two features have been indicated asresponsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serveas tissue organizers, orienting and ordering collagen fibrilsduring ontogeny and are involved in pathological processes such aswound healing, tissue repair, and tumor stroma formation. Iozzo, R.V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Othersstudies implicating leucine rich proteins in wound healing andtissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol.(Germany), 37(4):215-222 (1995), reporting mutations in the leucinerich motif in a complex associated with the bleeding disorderBernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost.(Germany), 74(1):111-116 (July 1995), reporting that platelets haveleucine rich repeats. Another protein of particular interest whichhas been reported to have leucine-rich repeats is the SLIT proteinwhich has been reported to be useful in treating neuro-degenerativediseases such as Alzheimer's disease, nerve damage such as inParkinson's disease, and for diagnosis of cancer, see,Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by YaleUniversity. Other studies reporting on the biological functions ofproteins having leucine-rich repeats include: Tayar, N., et al.,Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996)(gonadotropin receptor involvement); Miura, Y., et al., NipponRinsho (Japan), 54(7): 1784-1789 (July 1996) (apoptosisinvolvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement); andRuoslahti, E. I., et al., WO9110727-A by La Jolla Cancer ResearchFoundation (decorin binding to transforming growth factorsinvolvement for treatment for cancer, wound healing andscarring).

Densin is a glycoprotein which has been isolated from the brainwhich has all the hallmarks of an adhesion molecule. It is highlyconcentrated at synaptic sites in the brain and is expressedprominently in dendritic processes in developing neurons. Densinhas been characterized as a member of the O-linkedsialoglycoproteins. Densin has relevance to medically importantprocesses such as regeneration. Given the physiological importanceof synaptic processes and cell adhesion mechanisms in vivo, effortsare currently being under taken to identify new, native proteinswhich are involved in synaptic machinery and cell adhesion. Densinis further described in Kennedy, M. B, Trends Neurosci. (England),20(6):264 (1997) and Apperson, et al., J. Neurosci., 16(21):6839(1996).

Efforts are therefore being undertaken by both industry andacademia to identify new proteins having leucine rich repeats tobetter understand protein-protein interactions. Of particularinterest are those proteins having leucine rich repeats andhomology to known proteins having leucine rich repeats such asKIAA0231 and densin. Many efforts are focused on the screening ofmammalian recombinant DNA libraries to identify the codingsequences for novel secreted and membrane-bound proteins havingleucine rich repeats. Examples of screening methods and techniquesare described in the literature [see, for example, Klein et al.,Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We describe herein the identification and characterization of anovel polypeptide which has homology to leucine rich repeatproteins, designated herein as PRO247.

40. PRO302, PRO303, PRO304, PRO307 and PRO343

Proteases are enzymatic proteins which are involved in a largenumber of very important biological processes in mammalian andnon-mammalian organisms. Numerous different protease enzymes from avariety of different mammalian and non-mammalian organisms havebeen both identified and characterized. The mammalian proteaseenzymes play important roles in many different biological processesincluding, for example, protein digestion, activation,inactivation, or modulation of peptide hormone activity, andalteration of the physical properties of proteins and enzymes.

In light of the important physiological roles played by proteaseenzymes, efforts are currently being undertaken by both industryand academia to identify new, native protease homologs. Many ofthese efforts are focused on the screening of mammalian recombinantDNA libraries to identify the coding sequences for novel secretedand membrane-bound receptor proteins. Examples of screening methodsand techniques are described in the literature [see, for example,Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)]. We herein describe the identification ofnovel polypeptides having homology to various protease enzymes,designated herein as PRO302, PRO303, PRO304, PRO307 and PRO343polypeptides.

41. PRO328

The GLIP protein family has been characterized as comprisingzinc-finger proteins which play important roles in embryogenesis.These proteins may function as transcriptional regulatory proteinsand are known to be amplified in a subset of human tumors. Gliomapathogenesis protein is structurally related to a group of plantpathogenesis-related proteins. It is highly expressed inglioblastoma. See U.S. Pat. No. 5,582,981 (issued Dec. 10, 1996)and U.S. Pat. No. 5,322,801 (issued Jun. 21, 1996), Ellington, A.D. et al., Nature, 346:818 (1990), Grindley, J. C. et al., Dev.Biol., 188(2):337 (1997), Marine, J. C. et al., Mech. Dev.,63(2):211 (1997), The CRISP or cysteine rich secretory proteinfamily are a group of proteins which are also structurally relatedto a group of plant pathogenesis proteins. [Schwidetzky, U.,Biochem. J., 321:325 (1997), Pfisterer, P., Mol. Cell Biol.,16(11):6160 (1996), Kratzschmar, J. Eur. J. Biochem., 236(3):827(1996)]. We describe herein the identification of a novelpolypeptide which has homology to GLIP and CRISP, designated hereinas PRO328 polypeptides.

42. PRO335, PRO331 and PRO326

Protein-protein interactions include receptor and antigen complexesand signaling mechanisms. As more is known about the structural andfunctional mechanisms underlying protein-protein interactions,protein-protein interactions can be more easily manipulated toregulate the particular result of the protein-protein interaction.Thus, the underlying mechanisms of protein-protein interactions areof interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to beinvolved in protein-protein interactions. Leucine-rich repeats areshort sequence motifs present in a number of proteins with diversefunctions and cellular locations. The crystal structure ofribonuclease inhibitor protein has revealed that leucine-richrepeats correspond to beta-alpha structural units. These units arearranged so that they form a parallel beta-sheet with one surfaceexposed to solvent, so that the protein acquires an unusual,nonglubular shape. These two features have been indicated asresponsible for the protein-binding functions of proteinscontaining leucine-rich repeats. See, Kobe and Deisenhofer, TrendsBiochem. Sci., 19(10):415421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serveas tissue organizers, orienting and ordering collagen fibrilsduring ontogeny and are involved in pathological processes such aswound healing, tissue repair, and tumor stroma formation. Iozzo, R.V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Othersstudies implicating leucine rich proteins in wound healing andtissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol.(Germany), 37(4):215-222 (1995), reporting mutations in the leucinerich motif in a complex associated with the bleeding disorderBernard-Soulier syndrome, Chlemetson, K. J., Thromb. Haemost.(Germany), 74(1): 111-116 (July 1995), reporting that plateletshave leucine rich repeats and Ruoslahti, E. I., et al., WO9110727-Aby La Jolla Cancer Research Foundation reporting that decorinbinding to transforming growth factor.beta. has involvement in atreatment for cancer, wound healing and scarring. Related byfunction to this group of proteins is the insulin like growthfactor (IGF), in that it is useful in wound-healing and associatedtherapies concerned with re-growth of tissue, such as connectivetissue, skin and bone; in promoting body growth in humans andanimals; and in stimulating other growth-related processes. Theacid labile subunit of IGF (ALS) is also of interest in that itincreases the half-life of IGF and is part of the IGF complex invivo.

Another protein which has been reported to have leucine-richrepeats is the SLIT protein which has been reported to be useful intreating neuro-degenerative diseases such as Alzheimer's disease,nerve damage such as in Parkinson's disease, and for diagnosis ofcancer, see, Artavanistsakonas, S. and Rothberg, J. M.,WO9210518-A1 by Yale University. Of particular interest is LIG-1, amembrane glycoprotein that is expressed specifically in glial cellsin the mouse brain, and has leucine rich repeats andimmunoglobulin-like domains. Suzuki, et al., J. Biol. Chem. (U.S.),271(37):22522 (1996). Other studies reporting on the biologicalfunctions of proteins having leucine rich repeats include: Tayar,N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70(December 1996) (gonadotropin receptor involvement); Miura, Y., etal., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosisinvolvement); Harris, P. C., et al., J. Am. Soc. Nephrol.,6(4):1125-1133 (October 1995) (kidney disease involvement).

Efforts are therefore being undertaken by both industry andacademia to identify new proteins having leucine rich repeats tobetter understand protein-protein interactions. Of particularinterest are those proteins having leucine rich repeats andhomology to known proteins having leucine rich repeats such asLIG-1, ALS and decorin. Many efforts are focused on the screeningof mammalian recombinant DNA libraries to identify the codingsequences for novel secreted and membrane-bound proteins havingleucine rich repeats. Examples of screening methods and techniquesare described in the literature [see, for example, Klein et al.,Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We describe herein the identification and characterization of novelpolypeptides which have homology to proteins of the leucine richrepeat superfamily, designated herein as PRO335, PRO331 and PRO326polypeptides.

43. PRO332

Secreted proteins comprising a repeat characterized by anarrangement of conserved leucine residues (leucine-rich repeatmotif) have diverse biological roles. Certain proteoglycans, suchas biglycan, fibromodulin and decorin, are, for example,characterized by the presence of a leucine-rich repeat of about 24amino acids [Ruoslahti, Ann. Rev. Cell. Biol. 4 229-255 (1988);Oldberg et al., EMBO J. 8, 2601-2604 (1989)]. In general,proteoglycans are believed to play a role in regulatingextracellular matrix, cartilage or bone function. The proteoglycandecorin binds to collagen type I and II and affects the rate offibril formation. Fibromodulin also binds collagen and delaysfibril formation. Both fibromodulin and decorin inhibit theactivity of transforming growth factor beta (TGF-.beta.) (U.S. Pat.No. 5,583,103 issued Dec. 10, 1996). TGF-.beta. is known to play akey role in the induction of extracellular matrix and has beenimplicated in the development of fibrotic diseases, such as cancerand glomerulonephritis. Accordingly, proteoglycans have beenproposed for the treatment of fibrotic cancer, based upon theirability to inhibit TGF-.beta.'s growth stimulating activity on thecancer cell. Proteoglycans have also been described as potentiallyuseful in the treatment of other proliferative pathologies,including rheumatoid arthritis, arteriosclerosis, adult respiratorydistress syndrome, cirrhosis of the liver, fibrosis of the lungs,post-myocardial infarction, cardiac fibrosis, post-angioplastyrestenosis, renal interstitial fibrosis and certain dermal fibroticconditions, such as keloids and scarring, which might result fromburn injuries, other invasive skin injuries, or cosmetic orreconstructive surgery (U.S. Pat. No. 5,654,270, issued Aug. 5,1997).

We describe herein the identification and characterization of novelpolypeptides which have homology to proteins of the leucine richrepeat superfamily, designated herein as PRO332 polypeptides.

44. PRO334

Microfibril bundles and proteins found in association with thesebundles, particularly attachment molecules, are of interest in thefield of dermatology, particularly in the study of skin which hasbeen damaged from aging, injuries or the sun. Fibrillinmicrofibrils define the continuous elastic network of skin, and arepresent in dermis as microfibril bundles devoid of measurableelastin extending from the dermal-epithelial junction and ascomponents of the thick elastic fibres present in the deepreticular dermis. Moreover, Marfan syndrome has been linked tomutations which interfere with multimerization of fibrillinmonomers or other connective tissue elements.

Fibulin-1 is a modular glycoprotein with amino-terminalanaphlatoxin-like modules followed by nine epidermal growth factor(EGF)-like modules and, depending on alternative splicing, fourpossible carboxyl termini. Fibulin-2 is a novel extracellularmatrix protein frequently found in close association withmicrofibrils containing either fibronectin or fibrillin. Thus,fibrillin, fibulin, and molecules related thereto are of interest,particularly for the use of preventing skin from being damaged fromaging, injuries or the sun, or for restoring skin damaged fromsame. Moreover, these molecules are generally of interest in thestudy of connective tissue and attachment molecules and relatedmechanisms. Fibrillin, fibulin and related molecules are furtherdescribed in Adams, et al., J. Mol. Biol., 272(2):226-36 (1997);Kielty and Shuttleworth, Microsc. Res. Tech., 38(4):413-27 (1997);and Child, J. Card. Surg. 12(2Supp.):131-5 (1997).

Currently, efforts are being undertaken by both industry andacademia to identify new, native secreted and membrane-boundreceptor proteins, particularly secreted proteins which havehomology to fibulin and fibrillin. Many efforts are focused on thescreening of mammalian recombinant DNA libraries to identify thecoding sequences for novel secreted and membrane-bound receptorproteins. Examples of screening methods and techniques aredescribed in the literature [see, for example, Klein et al., Proc.Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No.5,536,637)].

We herein describe the identification and characterization of novelpolypeptides having homology to fibulin and fibrillin, designatedherein as PRO334 polypeptides.

45. PRO346

The widespread occurrence of cancer has prompted the devotion ofconsiderable resources and discovering new treatments of treatment.One particular method involves the creation of tumor or cancerspecific monoclonal antibodies (mAbs) which are specific to tumorantigens. Such mAbs, which can distinguish between normal andcancerous cells are useful in the diagnosis, prognosis andtreatment of the disease. Particular antigens are known to beassociated with neoplastic diseases, such as colorectal and breastcancer. Since colon cancer is a widespread disease, early diagnosisand treatment is an important medical goal. Diagnosis and treatmentof cancer can be implemented using monoclonal antibodies (mAbs)specific therefore having fluorescent, nuclear magnetic orradioactive tags. Radioactive genes, toxins and/or drug tagged mAbscan be used for treatment in situ with minimal patientdescription.

Carcinoembryonic antigen (CEA) is a glycoprotein found in humancolon cancer and the digestive organs of a 2-6 month human embryos.CEA is a known human tumor marker and is widely used in thediagnosis of neoplastic diseases, such as colon cancer. Forexample, when the serum levels of CEA are elevated in a patient, adrop of CEA levels after surgery would indicate the tumor resectionwas successful. On the other hand, a subsequent rise in serum CEAlevels after surgery would indicate that metastases of the originaltumor may have formed or that new primary tumors may have appeared.CEA may also be a target for mAb, antisense nucleotides

46. PRO268

Protein disulfide isomerase is an enzymatic protein which isinvolved in the promotion of correct refolding of proteins throughthe establishment of correct disulfide bond formation. Proteindisulfide isomerase was initially identified based upon its abilityto catalyze the renaturation of reduced denatured RNAse (Goldbergeret al., J. Biol. Chem. 239:1406-1410 (1964) and Epstein et al.,Cold Spring Harbor Symp. Quant. Biol. 28:439-449 (1963)). Proteindisulfide isomerase has been shown to be a resident enzyme of theendoplasmic reticulum which is retained in the endoplasmicreticulum via a -KDEL or -HDEL amino acid sequence at itsC-terminus.

Given the importance of disulfide bond-forming enzymes and theirpotential uses in a number of different applications, for examplein increasing the yield of correct refolding of recombinantlyproduced proteins, efforts are currently being undertaken by bothindustry and academia to identify new, native proteins havinghomology to protein disulfide isomerase. Many of these efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel protein disulfide isomerasehomologs. We herein describe a novel polypeptide having homology toprotein disulfide isomerase, designated herein as PRO268.

47. PRO330

Prolyl 4-hydroxylase is an enzyme which functions topost-translationally hydroxylate proline residues at the Y positionof the amino acid sequence Gly-X-Y, which is a repeating threeamino acid sequence found in both collagen and procollagen.Hydroxylation of proline residues at the Y position of the Gly-X-Yamino acid triplet to form 4-hydroxyproline residues at thosepositions is required before newly synthesized collagen polypeptidechains may fold into their proper three-dimensional triple-helicalconformation. If hydroxylation does not occur, synthesized collagenpolypeptides remain non-helical, are poorly secreted by cells andcannot assemble into stable functional collagen fibrils. Vuorio etal., Proc. Natl. Acad. Sci. USA 89:7467-7470 (1992). Prolyl4-hydroxylase is comprised of at least two different polypeptidesubunits, alpha and beta.

Efforts are being undertaken by both industry and academia toidentify new, native secreted and membrane-bound receptor proteins.Many efforts are focused on the screening of mammalian recombinantDNA libraries to identify the coding sequences for novel secretedand membrane-bound receptor proteins. Examples of screening methodsand techniques are described in the literature [see, for example,Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S.Pat. No. 5,536,637)]. Based upon these efforts, Applicants haveherein identified and describe a novel polypeptide having homologyto the alpha subunit of prolyl 4-hydroxylase, designated herein asPRO330.

48. PRO339 and PRO310

Fringe is a protein which specifically blocks serrate-mediatedactivation of notch in the dorsal compartment of the Drosophilawing imaginal disc. Fleming, et al., Development, 124(15):2973-81(1997). Therefore, fringe is of interest for both its role indevelopment as well as its ability to regulate serrate,particularly serrate's signaling abilities. Also of interest arenovel polypeptides which may have a role in development and/or theregulation of serrate-like molecules. Of particular interest arenovel polypeptides having homology to fringe as identified anddescribed herein, designated herein as PRO339 and PRO310polypeptides.

49. PRO244

Lectins are a class of proteins comprising a region that bindscarbohydrates specifically and non-covalently. Numerous lectinshave been identified in higher animals, both membrane-bound andsoluble, and have been implicated in a variety of cell-recognitionphenomena and tumor metastasis.

Most lectins can be classified as either C-type (calcium-dependent)or S-type (thiol-dependent).

Lectins are thought to play a role in regulating cellular eventsthat are initiated at the level of the plasma membrane. Forexample, plasma membrane associated molecules are involved in theactivation of various subsets of lymphoid cells, e.g.T-lymphocytes, and it is known that cell surface molecules areresponsible for activation of these cells and consequently theirresponse during an immune reaction.

A particular group of cell adhesion molecules, selecting, belong inthe superfamily of C-type lectins. This group includes L-selectin(peripheral lymph node homing receptor (pnHR), LEC-CAM-1, LAM-1,gp90.sup.MEL, gp100.sup.MEL, gp110.sup.MEL, MEL-14 antigen, Leu-8antigen, TQ-1 antigen, DREG antigen), E-selectin (LEC-CAM-2,LECAM-2, ELAM-1), and P-selectin (LEC-CAM-3, LECAM-3, GMP-140,PADGEM). The structure of selectins consists of a C-type lectin(carbohydrate binding) domain, an epidermal growth factor-like(EGF-like) motif, and variable numbers of complement regulatory(CR) motifs. Selectins are associated with leukocyte adhesion, e.g.the attachment of neutrophils to venular endothelial cells adjacentto inflammation (E-selectin), or with the trafficking oflymphocytes from blood to secondary lymphoid organs, e.g. lymphnodes and Peyer's patches (L-selectin).

Another exemplary lectin is the cell-associated macrophage antigen,Mac-2 that is believed to be involved in cell adhesion and immuneresponses. Macrophages also express a lectin that recognizes Tn Ag,a human carcinoma-associated epitope.

Another C-type lectin is CD95 (Fas antigen/APO-1) that is animportant mediator of immunologically relevant regulated orprogrammed cell death (apoptosis). "Apoptosis" is a non-necroticcell death that takes place in metazoan animal cells followingactivation of an intrinsic cell suicide program. The cloning of Fasantigen is described in PCT publication WO 91/10448, and Europeanpatent application EP510691. The mature Fas molecule consists of319 amino acids of which 157 are extracellular, 17 constitute thetransmembrane domain, and 145 are intracellular. Increased levelsof Fas expression at T cell surface have been associated with tumorcells and HIV-infected cells. Ligation of CD95 triggers apoptosisin the presence of interleukin-1 (IL-2).

C-type lectins also include receptors for oxidized low-densitylipoprotein (LDL). This suggests a possible role in thepathogenesis of atherosclerosis.

We herein describe the identification and characterization of novelpolypeptides having homology to C-type lectins, designated hereinas PRO244 polypeptides.

SUMMARY OF THE INVENTION

1. PRO211 and PRO217

Applicants have identified cDNA clones that encode novelpolypeptides having homology to EGF, designated in the presentapplication as "PRO211" and "PRO217" polypeptides.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO211 or PRO217 polypeptide. Inone aspect, the isolated nucleic acid comprises DNA encodingEGF-like homologue PRO211 and PRO217 polypeptides of FIG. 2 (SEQ IDNO:2) and/or 4 (SEQ ID NO:4) indicated in FIG. 1 (SEQ ID NO1)and/or FIG. 3 (SEQ ID NO:3), respectively, or is complementary tosuch encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions.

In another embodiment, the invention provides isolated PRO211 andPRO217 EGF-like homologue PRO211 and PRO217 polypeptides. Inparticular, the invention provides isolated native sequence PRO211and PRO217 EGF-like homologue polypeptides, which in oneembodiment, includes an amino acid sequence comprising residues: 1to 353 of FIG. 2 (SEQ ID NO:2) or (2) 1 to 379 of FIG. 4 (SEQ IDNO: 4).

2. PRO230

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO230".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO230 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO230polypeptide having amino acid residues 1 through 467 of FIG. 6 (SEQID NO:12), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO230polypeptide. In particular, the invention provides isolated nativesequence PRO230 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 through 467 of FIG. 6(SEQ ID NO:12).

In another embodiment, the invention provides an expressed sequencetag (EST) comprising the nucleotide sequence of SEQ ID NO:13 (FIG.7) which is herein designated as DNA20088.

3. PRO232

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO232".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO232 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO232polypeptide having amino acid residues 1 to 114 of FIG. 9 (SEQ IDNO:18), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO232polypeptide. In particular, the invention provides isolated nativesequence PRO232 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 114 of FIG. 9 (SEQ IDNO:18).

4. PRO187

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as "PRO187".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO187 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO187polypeptide of FIG. 11 (SEQ ID NO:23), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. In another aspect, the invention provides a nucleicacid comprising the coding sequence of FIG. 10 (SEQ ID NO:22) orits complement. In another aspect, the invention provides a nucleicacid of the full length protein of clone DNA27864-1155, depositedwith the ATCC under accession number ATCC 209375, alternatively thecoding sequence of clone DNA27864-1155, deposited under accessionnumber ATCC 209375.

In yet another embodiment, the invention provides isolated PRO187polypeptide. In particular, the invention provides isolated nativesequence PRO187 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 205 of FIG. 11 (SEQ IDNO:23). Alternatively, the invention provides a polypeptide encodedby the nucleic acid deposited under accession number ATCC209375.

5. PRO265

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO265".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO265 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO265polypeptide having amino acid residues 1 to 660 of FIG. 13 (SEQ IDNO:28), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO265polypeptide. In particular, the invention provides isolated nativesequence PRO265 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 660 of FIG. 13 (SEQ IDNO:28). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO265polypeptide.

6. PRO219

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO219".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO219 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO219polypeptide having amino acid residues 1 to 915 of FIG. 15 (SEQ IDNO:34), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO219polypeptide. In particular, the invention provides isolated nativesequence PRO219 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 915 of FIG. 15 (SEQ IDNO:34).

7. PRO246

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO246".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO246 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO246polypeptide having amino acid residues 1 to 390 of FIG. 17 (SEQ IDNO:39), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO246polypeptide. In particular, the invention provides isolated nativesequence PRO246 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 390 of FIG. 17 (SEQ IDNO:39). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO246polypeptide.

8. PRO228

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to CD97, EMR1 and latrophilin, whereinthe polypeptide is designated in the present application as"PRO228".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO228 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO228polypeptide having amino acid residues 1 to 690 of FIG. 19 (SEQ IDNO:49), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO228polypeptide. In particular, the invention provides isolated nativesequence PRO228 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 690 of FIG. 19 (SEQ IDNO:49). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO228polypeptide.

In another embodiment, the invention provides an expressed sequencetag (EST) comprising the nucleotide sequence of SEQ ID NO:50,designated herein as DNA21951.

9. PRO533

Applicants have identified a cDNA clone (DNA49435-1219) thatencodes a novel polypeptide, designated in the present applicationas PRO533.

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO533 polypeptide comprising the sequence ofamino acids 23 to 216 of FIG. 22 (SEQ ID NO:59), or (b) thecomplement of the DNA molecule of (a). The sequence identitypreferably is about 85%, more preferably about 90%, most preferablyabout 95%. In one aspect, the isolated nucleic acid has at leastabout 80%, preferably at least about 85%, more preferably at leastabout 90%, and most preferably at least about 95% sequence identitywith a polypeptide having amino acid residues 23 to 216 of FIG. 22(SEQ ID NO:59). Preferably, the highest degree of sequence identityoccurs within the secreted portion (amino acids 23 to 216 of FIG.22, SEQ ID NO:59). In a further embodiment, the isolated nucleicacid molecule comprises DNA encoding a PRO533 polypeptide havingamino acid residues 1 to 216 of FIG. 22 (SEQ ID NO:59), or iscomplementary to such encoding nucleic acid sequence, and remainsstably bound to it under at least moderate, and optionally, underhigh stringency conditions. In another aspect, the inventionprovides a nucleic acid of the full length protein of cloneDNA49435-1219, deposited with the ATCC under accession number ATCC209480.

In yet another embodiment, the invention provides isolated PRO533polypeptide. In particular, the invention provides isolated nativesequence PRO533 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 23 to 216 of FIG. 22 (SEQID NO:59). Native PRO533 polypeptides with or without the nativesignal sequence (amino acids 1 to 22 in FIG. 22 (SEQ ID NO:59)),and with or without the initiating methionine are specificallyincluded. Alternatively, the invention provides a PRO533polypeptide encoded by the nucleic acid deposited under accessionnumber ATCC 209480.

10. PRO245

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO245".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO245 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO245polypeptide having amino acid residues 1 to 312 of FIG. 24 (SEQ IDNO:64), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO245polypeptide. In particular, the invention provides isolated nativesequence PRO245 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 312 of FIG. 24 (SEQ IDNO:64).

11. PRO220, PRO221 and PRO227

Applicants have identified cDNA clones that each encode novelpolypeptides, all having leucine rich repeats. These polypeptidesare designated in the present application as PRO220, PRO221 andPRO227.

In one embodiment, the invention provides isolated nucleic acidmolecules comprising DNA respectively encoding PRO220, PRO221 andPRO227, respectively. In one aspect, provided herein is an isolatednucleic acid comprises DNA encoding the PRO220 polypeptide havingamino acid residues 1 through 708 of FIG. 26 (SEQ ID NO:69), or iscomplementary to such encoding nucleic acid sequence, and remainsstably bound to it under at least moderate, and optionally, underhigh stringency conditions. Also provided herein is an isolatednucleic acid comprises DNA encoding the PRO221 polypeptide havingamino acid residues 1 through 259 of FIG. 28 (SEQ ID NO:71), or iscomplementary to such encoding nucleic acid sequence, and remainsstably bound to it under at least moderate, and optionally, underhigh stringency conditions. Moreover, also provided herein is anisolated nucleic acid comprises DNA encoding the PRO227 polypeptidehaving amino acid residues 1 through 620 of FIG. 30 (SEQ ID NO:73),or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions.

In another embodiment, the invention provides isolated PRO220,PRO221 and PRO227 polypeptides. In particular, provided herein isthe isolated native sequence for the PRO220 polypeptide, which inone embodiment, includes an amino acid sequence comprising residues1 to 708 of FIG. 26 (SEQ ID NO:69). Additionally provided herein isthe isolated native sequence for the PRO221 polypeptide, which inone embodiment, includes an amino acid sequence comprising residues1 to 259 of FIG. 28 (SEQ ID NO:71). Moreover, provided herein isthe isolated native sequence for the PRO227 polypeptide, which inone embodiment, includes an amino acid sequence comprising residues1 to 620 of FIG. 30 (SEQ ID NO:73).

12. PRO258

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to CRTAM and poliovirus receptorprecursors, wherein the polypeptide is designated in the presentapplication as "PRO258".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO258 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO258polypeptide having amino acid residues 1 to 398 of FIG. 32 (SEQ IDNO:84), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO258polypeptide. In particular, the invention provides isolated nativesequence PRO258 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 398 of FIG. 32 (SEQ IDNO:84). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO258polypeptide.

13. PRO266

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO266".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO266 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO266polypeptide having amino acid residues 1 to 696 of FIG. 34 (SEQ IDNO:91), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO266polypeptide. In particular, the invention provides isolated nativesequence PRO266 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 696 of FIG. 34 (SEQ IDNO:91).

14. PRO269

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as PRO269.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO269 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO269polypeptide having amino acid residues 1 to 490 of FIG. 36 (SEQ IDNO:96), or is complementary to such encoding nucleic acid sequence,and remains stably bound to it under at least moderate, andoptionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO269polypeptide. In particular, the invention provides isolated nativesequence PRO269 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 490 of FIG. 36 (SEQ IDNO:96). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO269polypeptide.

15. PRO287

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO287".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO287 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO287polypeptide having amino acid residues 1 to 415 of FIG. 38 (SEQ IDNO:104), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO287polypeptide. In particular, the invention provides isolated nativesequence PRO287 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 415 of FIG. 38 (SEQ IDNO:104).

16. PRO214

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as "PRO214".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO214 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO214polypeptide of FIG. 40 (SEQ ID NO:109), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. In another aspect, the invention provides a nucleicacid comprising the coding sequence of FIG. 39 (SEQ ID NO:108) orits complement. In another aspect, the invention provides a nucleicacid of the full length protein of clone DNA32286-1191, depositedwith ATCC under accession number ATCC 209385.

In yet another embodiment, the invention provides isolated PRO214polypeptide. In particular, the invention provides isolated nativesequence PRO214 polypeptide, which in one embodiment, includes anamino acid sequence comprising the residues of FIG. 40 (SEQ IDNO:109). Alternatively, the invention provides a polypeptideencoded by the nucleic acid deposited under accession number ATCC209385.

17. PRO317

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as "PRO317".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO317 polypeptide. In one aspect,the isolated nucleic acid comprises DNA (SEQ ID NO:113) encodingPRO317 polypeptide having amino acid residues 1 to 366 of FIG. 42,or is complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions.

In another embodiment, the invention provides isolated PRO317polypeptide. In particular, the invention provides isolatednative-sequence PRO317 polypeptide, which in one embodiment,includes an amino acid sequence comprising residues 1 to 366 ofFIG. 42 (SEQ ID NO:114).

In yet another embodiment, the invention supplies a method ofdetecting the presence of PRO317 in a sample, the methodcomprising:

a) contacting a detectable anti-PRO317 antibody with a samplesuspected of containing PRO317; and

b) detecting binding of the antibody to the sample; wherein thesample is selected from the group consisting of a body fluid, atissue sample, a cell extract, and a cell culture medium.

In a still further embodiment a method is provided for determiningthe presence of PRO317 mRNA in a sample, the method comprising:

a) contacting a sample suspected of containing PRO317 mRNA with adetectable nucleic acid probe that hybridizes under moderate tostringent conditions to PRO317 mRNA; and

b) detecting hybridization of the probe to the sample.

Preferably, in this method the sample is a tissue sample and thedetecting step is by in situ hybridization, or the sample is a cellextract and detection is by Northern analysis.

Further, the invention provides a method for treating aPRO317-associated disorder comprising administering to a mammal aneffective amount of the PRO317 polypeptide or a composition thereofcontaining a carrier, or with an effective amount of a PRO317agonist or PRO317 antagonist, such as an antibody which bindsspecifically to PRO317.

18. PRO301

Applicants have identified a cDNA clone (DNA40628-1216) thatencodes a novel polypeptide, designated in the present applicationas "PRO301".

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO301 polypeptide comprising the sequence ofamino acids 28 to 258 of FIG. 44 (SEQ ID NO:119), or (b) thecomplement of the DNA molecule of (a). The sequence identitypreferably is about 85%, more preferably about 90%, most preferablyabout 95%. In one aspect, the isolated nucleic acid has at leastabout 80%, preferably at least about 85%, more preferably at leastabout 90%, and most preferably at least about 95% sequence identitywith a polypeptide having amino acid residues 28 to 258 of FIG. 44(SEQ ID NO:119). Preferably, the highest degree of sequenceidentity occurs within the extracellular domains (amino acids 28 to258 of FIG. 44, SEQ ID NO:119). In a further embodiment, theisolated nucleic acid molecule comprises DNA encoding a PRO301polypeptide having amino acid residues 28 to 299 of FIG. 44 (SEQ IDNO:119), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. In anotheraspect, the invention provides a nucleic acid of the full lengthprotein of clone DNA40628-1216, deposited with the ATCC underaccession number ATCC 209432, alternatively the coding sequence ofclone DNA40628-1216, deposited under accession number ATCC209432.

In yet another embodiment, the invention provides isolated PRO301polypeptide. In particular, the invention provides isolated nativesequence PRO301 polypeptide, which in one embodiment, includes anamino acid sequence comprising the extracellular domain residues 28to 258 of FIG. 44 (SEQ ID NO:119). Native PRO301 polypeptides withor without the native signal sequence (amino acids 1 to 27 in FIG.44 (SEQ ID NO:119), and with or without the initiating methionineare specifically included. Additionally, the sequences of theinvention may also comprise the transmembrane domain (residues 236to about 258 in FIG. 44; SEQ ID NO:119) and/or the intracellulardomain (about residue 259 to 299 in FIG. 44; SEQ ID NO:119).Alternatively, the invention provides a PRO301 polypeptide encodedby the nucleic acid deposited under accession number ATCC209432.

19. PRO224

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO224".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO224 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO224polypeptide having amino acid residues 1 to 282 of FIG. 46 (SEQ IDNO:127), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO224polypeptide. In particular, the invention provides isolated nativesequence PRO224 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 282 of FIG. 46 (SEQ IDNO:127).

20. PRO222

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO222".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO222 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO222polypeptide having amino acid residues 1 to 490 of FIG. 48 (SEQ IDNO:132), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO222polypeptide. In particular, the invention provides isolated nativesequence PRO222 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 490 of FIG. 48 (SEQ IDNO:132).

21. PRO234

Applicants have identified a cDNA clone that encodes a novel lectinpolypeptide molecule, designated in the present application as"PRO234".

In one embodiment, the invention provides an isolated nucleic acidencoding a novel lectin comprising DNA encoding a PRO234polypeptide. In one aspect, the isolated nucleic acid comprises theDNA encoding PRO234 polypeptides having amino acid residues 1 to382 of FIG. 50 (SEQ ID NO:137), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. In another aspect, the invention provides an isolatednucleic acid molecule comprising the nucleotide sequence of FIG. 49(SEQ ID NO:136).

In another embodiment, the invention provides isolated novel PRO234polypeptides. In particular, the invention provides isolated nativesequence PRO234 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 382 of FIG. 50 (SEQ IDNO:137).

In yet another embodiment, the invention provides oligonucleotideprobes useful for isolating genomic and cDNA nucleotidesequences.

22. PRO231

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to a putative acid phosphatase, whereinthe polypeptide is designated in the present application as"PRO231".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO231 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO231polypeptide having amino acid residues 1 to 428 of FIG. 52 (SEQ IDNO:142), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO231polypeptide. In particular, the invention provides isolated nativesequence PRO231 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 428 of FIG. 52 (SEQ IDNO:142).

23. PRO229

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to scavenger receptors wherein thepolypeptide is designated in the present application as"PRO229".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO229 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO229polypeptide having amino acid residues 1 to 347 of FIG. 54 (SEQ IDNO:148), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO229polypeptide. In particular, the invention provides isolated nativesequence PRO229 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 347 of FIG. 54 (SEQ IDNO:148).

24. PRO238

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to reductase, wherein the polypeptideis designated in the present application as "PRO238".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO238 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO238polypeptide having amino acid residues 1 to 310 of FIG. 56 (SEQ IDNO:153), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO238polypeptide. In particular, the invention provides isolated nativesequence PRO238 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 310 of FIG. 56 (SEQ IDNO:153).

25. PRO233

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO233".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO233 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO233polypeptide having amino acid residues 1 to 300 of FIG. 58 (SEQ IDNO:159), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO233polypeptide. In particular, the invention provides isolated nativesequence PRO233 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 300 of FIG. 58 (SEQ IDNO:159).

26. PRO223

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to serine carboxypeptidasepolypeptides, wherein the polypeptide is designated in the presentapplication as "PRO223".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO223 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO223polypeptide having amino acid residues 1 to 476 of FIG. 60 (SEQ IDNO:164), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO223polypeptide. In particular, the invention provides isolated nativesequence PRO223 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 476 of FIG. 60 (SEQ IDNO:164).

27. PRO235

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO235".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO235 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO235polypeptide having amino acid residues 1 to 552 of FIG. 62 (SEQ IDNO:170), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO235polypeptide. In particular, the invention provides isolated nativesequence PRO235 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 552 of FIG. 62 (SEQ IDNO:170).

28. PRO236 and PRO262

Applicants have identified cDNA clones that encode novelpolypeptides having homology to .beta.-galactosidase, wherein thosepolypeptides are designated in the present application as "PRO236"and "PRO262".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO236 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO236polypeptide having amino acid residues 1 to 636 of FIG. 64 (SEQ IDNO:175), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO262 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO262polypeptide having amino acid residues 1 to 654 of FIG. 66 (SEQ IDNO:177), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO236polypeptide. In particular, the invention provides isolated nativesequence PRO236 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 636 of FIG. 64 (SEQ IDNO:175).

In another embodiment, the invention provides isolated PRO262polypeptide. In particular, the invention provides isolated nativesequence PRO262 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 654 of FIG. 66 (SEQ IDNO:177).

29. PRO239

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO239".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO239 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO239polypeptide having amino acid residues 1 to 501 of FIG. 68 (SEQ IDNO:185), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO239polypeptide. In particular, the invention provides isolated nativesequence PRO239 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 501 of FIG. 68 (SEQ IDNO:185).

30. PRO257

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO257".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO257 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO257polypeptide having amino acid residues 1 to 607 of FIG. 70 (SEQ IDNO:190), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO257polypeptide. In particular, the invention provides isolated nativesequence PRO257 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 607 of FIG. 70 (SEQ IDNO:190). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO257polypeptide.

31. PRO260

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO260".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO260 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO260polypeptide having amino acid residues 1 to 467 of FIG. 72 (SEQ IDNO:195), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO260polypeptide. In particular, the invention provides isolated nativesequence PRO260 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 467 of FIG. 72 (SEQ IDNO:195).

32. PRO263

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to CD44 antigen, wherein thepolypeptide is designated in the present application as"PRO263".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO263 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO263polypeptide having amino acid residues 1 to 322 of FIG. 74 (SEQ IDNO:201), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO263polypeptide. In particular, the invention provides isolated nativesequence PRO263 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 322 of FIG. 74 (SEQ IDNO:201). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO263polypeptide.

33. PRO270

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO270".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO270 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA which includes thesequence encoding the PRO270 polypeptide having amino acid residues1 to 296 of FIG. 76 (SEQ ID NO:207), or is complementary to suchencoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions.

In another embodiment, the invention provides isolated PRO270polypeptide. In particular, the invention provides isolated nativesequence PRO270 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 296 of FIG. 76 (SEQ IDNO:207).

34. PRO271

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the proteoglycan link protein,wherein the polypeptide is designated in the present application as"PRO271".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO271 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO271polypeptide having amino acid residues 1 to 360 of FIG. 78 (SEQ IDNO:213), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO271polypeptide. In particular, the invention provides isolated nativesequence PRO271 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 360 of FIG. 78 (SEQ IDNO:213).

35. PRO272

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO272".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO272 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO272polypeptide having amino acid residues 1 to 328 of FIG. 80 (SEQ IDNO:221), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO272polypeptide. In particular, the invention provides isolated nativesequence PRO272 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 328 of FIG. 80 (SEQ IDNO:211).

36. PRO294

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO294".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO294 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO294polypeptide having amino acid residues 1 to 550 of FIG. 82 (SEQ IDNO:227), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO294polypeptide. In particular, the invention provides isolated nativesequence PRO294 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 550 of FIG. 82 (SEQ IDNO:227).

37. PRO295

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO295".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO295 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO295polypeptide having amino acid residues 1 to 350 of FIG. 84 (SEQ IDNO:236), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO295polypeptide. In particular, the invention provides isolated nativesequence PRO295 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 350 of FIG. 84 (SEQ IDNO:236).

38. PRO293

Applicants have identified a cDNA clone that encodes a novel humanneuronal leucine rich repeat polypeptide, wherein the polypeptideis designated in the present application as "PRO293".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO293 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO293polypeptide having amino acid residues 1 to 713 of FIG. 86 (SEQ IDNO:245), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO293polypeptide. In particular, the invention provides isolated nativesequence PRO293 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 713 of FIG. 86 (SEQ IDNO:245). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO293polypeptide.

39. PRO247

Applicants have identified a cDNA clone that encodes a novelpolypeptide having leucine rich repeats wherein the polypeptide isdesignated in the present application as "PRO247".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO247 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO247polypeptide having amino acid residues 1 to 546 of FIG. 88 (SEQ IDNO:250), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO247polypeptide. In particular, the invention provides isolated nativesequence PRO247 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 546 of FIG. 88 (SEQ IDNO:250). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO247polypeptide.

40. PRO302, PRO303, PRO304, PRO307 and PRO343

Applicants have identified cDNA clones that encode novelpolypeptides having homology to various proteases, wherein thosepolypeptide are designated in the present application as "PRO302","PRO303", "PRO304", "PRO307" and "PRO343" polypeptides.

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO302 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO302polypeptide having amino acid residues 1 to 452 of FIG. 90 (SEQ IDNO:255), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO303 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO303polypeptide having amino acid residues 1 to 314 of FIG. 92 (SEQ IDNO:257), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In yet another embodiment, the invention provides an isolatednucleic acid molecule comprising DNA encoding a PRO304 polypeptide.In one aspect, the isolated nucleic acid comprises DNA encoding thePRO304 polypeptide having amino acid residues 1 to 556 of FIG. 94(SEQ ID NO:259), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO307 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO307polypeptide having amino acid residues 1 to 383 of FIG. 96 (SEQ IDNO:261), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleicacid molecule comprising DNA encoding a PRO343 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO343polypeptide having amino acid residues 1 to 317 of FIG. 98 (SEQ IDNO:263), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO302polypeptide. In particular, the invention provides isolated nativesequence PRO302 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 452 of FIG. 90 (SEQ IDNO:255).

In another embodiment, the invention provides isolated PRO303polypeptide. In particular, the invention provides isolated nativesequence PRO303 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 314 of FIG. 92 (SEQ IDNO:257).

In another embodiment, the invention provides isolated PRO304polypeptide. In particular, the invention provides isolated nativesequence PRO304 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 556 of FIG. 94 (SEQ IDNO:259).

In another embodiment, the invention provides isolated PRO307polypeptide. In particular, the invention provides isolated nativesequence PRO307 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 383 of FIG. 96 (SEQ IDNO:261).

In another embodiment, the invention provides isolated PRO343polypeptide. In particular, the invention provides isolated nativesequence PRO343 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 317 of FIG. 98 (SEQ IDNO:263).

41. PRO328

Applicants have identified a cDNA clone that encodes a novelpolypeptide, wherein the polypeptide is designated in the presentapplication as "PRO328".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO328 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO328polypeptide having amino acid residues 1 to 463 of FIG. 100 (SEQ IDNO:285), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO328polypeptide. In particular, the invention provides isolated nativesequence PRO328 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 463 of FIG. 100 (SEQID NO:285). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO306polypeptide.

42. PRO335, PRO331 and PRO326

Applicants have identified three cDNA clones that respectivelyencode three novel polypeptides, each having leucine rich repeatsand homology to LIG-1 and ALS. These polypeptides are designated inthe present application as PRO335, PRO331 and PRO326,respectively.

In one embodiment, the invention provides three isolated nucleicacid molecules comprising DNA respectively encoding PRO335, PRO331and PRO326, respectively. In one aspect, herein is provided anisolated nucleic acid comprising DNA encoding the PRO335polypeptide having amino acid residues 1 through 1059 of FIG. 102(SEQ ID NO:290), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions. Also providedherein is an isolated nucleic acid comprises DNA encoding thePRO331 polypeptide having amino acid residues 1 through 640 of FIG.104 (SEQ ID NO:292), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at leastmoderate, and optionally, under high stringency conditions.Additionally provided herein is an isolated nucleic acid comprisesDNA encoding the PRO326 polypeptide having amino acid residues 1through 1119 of FIG. 106 (SEQ ID NO:294), or is complementary tosuch encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions.

In another embodiment, the invention provides isolated PRO335,PRO331 and PRO326 polypeptides or extracellular domains thereof. Inparticular, the invention provides isolated native sequence for thePRO335 polypeptide, which in one embodiment, includes an amino acidsequence comprising residues 1 through 1059 of FIG. 102 (SEQ IDNO:290). Also provided herein is the isolated native sequence forthe PRO331 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 through 640 of FIG. 104 (SEQ IDNO:292). Also provided herein is the isolated native sequence forthe PRO326 polypeptide, which in one embodiment, includes an aminoacid sequence comprising residues 1 through 1119 of FIG. 106 (SEQID NO:294).

43. PRO332

Applicants have identified a cDNA clone (DNA40982-1235) thatencodes a novel polypeptide, designated in the present applicationas "PRO332."

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA having at least about 80% sequence identityto (a) a DNA molecule encoding a PRO358 polypeptide comprising thesequence of amino acids 49 to 642 of FIG. 108 (SEQ ID NO:310), or(b) the complement of the DNA molecule of (a). The sequenceidentity preferably is about 85%, more preferably about 90%, mostpreferably about 95%. In one aspect, the isolated nucleic acid hasat least about 80%, preferably at least about 85%, more preferablyat least about 90%, and most preferably at least about 95% sequenceidentity with a polypeptide having amino acid residues 1 to 642 ofFIG. 108 (SEQ ID NO:310). Preferably, the highest degree ofsequence identity occurs within the leucine-rich repeat domains(amino acids 116 to 624 of FIG. 108, SEQ ID NO:310). In a furtherembodiment, the isolated nucleic acid molecule comprises DNAencoding a PRO332 polypeptide having amino acid residues 49 to 642of FIG. 108 (SEQ ID NO:310), or is complementary to such encodingnucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringencyconditions.

In another embodiment, the invention provides isolated PRO332polypeptides. In particular, the invention provides isolated nativesequence PRO332 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 49 to 624 of FIG. 108 (SEQID NO:310). Native PRO332 polypeptides with or without the nativesignal sequence (amino acids 1 to 48 in FIG. 108, SEQ ID NO:310),and with or without the initiating methionine are specificallyincluded.

44. PRO334

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to fibulin and fibrillin, wherein thepolypeptide is designated in the present application as"PRO334".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO334 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO334polypeptide having amino acid residues 1 to 509 of FIG. 110 (SEQ IDNO:315), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO334polypeptide. In particular, the invention provides isolated nativesequence PRO334 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 509 of FIG. 110 (SEQID NO:315).

45. PRO346

Applicants have identified a cDNA clone (DNA44167-1243) thatencodes a novel polypeptide, designated in the present applicationas "PRO346."

In one embodiment, the invention provides an isolated nucleic acidmolecule having at least about 80% sequence identity to (a) a DNAmolecule encoding a PRO346 polypeptide comprising the sequence ofamino acids 19 to 339 of FIG. 112 (SEQ ID NO: 320), or (b) thecomplement of the DNA molecule of (a). The sequence identitypreferably is about 85%, more preferably about 90%, most preferablyabout 95%. In one aspect, the isolated nucleic acid has at leastabout 80%, preferably at least about 85%, more preferably at leastabout 90%, and most preferably at least about 95% sequence identitywith a polypeptide having amino acid residues 19 to 339 of FIG. 112(SEQ ID NO:320). Preferably, the highest degree of sequenceidentity occurs within the extracellular domains (amino acids 19 to339 of FIG. 112, SEQ ID NO:320). In alternative embodiments, thepolypeptide by which the homology is measured comprises theresidues 1-339, 19-360 or 19-450 of FIG. 112, SEQ ID NO:320). In afurther embodiment, the isolated nucleic acid molecule comprisesDNA encoding a PRO346 polypeptide having amino acid residues 19 to339 of FIG. 112 (SEQ ID NO:320), alternatively residues 1-339,19-360 or 19-450 of FIG. 112 (SEQ ID NO:320) or is complementary tosuch encoding nucleic acid sequence, and remains stably bound to itunder at least moderate, and optionally, under high stringencyconditions. In another aspect, the invention provides a nucleicacid of the full length protein of clone DNA44167-1243, depositedwith the ATCC under accession number ATCC 209434, alternatively thecoding sequence of clone DNA44167-1243, deposited under accessionnumber ATCC 209434.

In yet another embodiment, the invention provides isolated PRO346polypeptide. In particular, the invention provides isolated nativesequence PRO346 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 19 to 339 of FIG. 112 (SEQID NO:320). Native PRO346 polypeptides with or without the nativesignal sequence (residues 1 to 18 in FIG. 112 (SEQ ID NO:320), withor without the initiating methionine, with or without thetransmembrane domain (residues 340 to 360) and with or without theintracellular domain (residues 361 to 450) are specificallyincluded. Alternatively, the invention provides a PRO346polypeptide encoded by the nucleic acid deposited under accessionnumber ATCC 209434.

46. PRO268

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to protein disulfide isomerase, whereinthe polypeptide is designated in the present application as"PRO268".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO268 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO268polypeptide having amino acid residues 1 to 280 of FIG. 114 (SEQ IDNO:325), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO268polypeptide. In particular, the invention provides isolated nativesequence PRO268 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 280 of FIG. 114 (SEQID NO:325). An additional embodiment of the present invention isdirected to an isolated extracellular domain of a PRO268polypeptide.

47. PRO330

Applicants have identified a cDNA clone that encodes a novelpolypeptide having homology to the alpha subunit of prolyl4-hydroxylase, wherein the polypeptide is designated in the presentapplication as "PRO330".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding a PRO330 polypeptide. In oneaspect, the isolated nucleic acid comprises DNA encoding the PRO330polypeptide having amino acid residues 1 to 533 of FIG. 116 (SEQ IDNO:332), or is complementary to such encoding nucleic acidsequence, and remains stably bound to it under at least moderate,and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO330polypeptide. In particular, the invention provides isolated nativesequence PRO330 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 533 of FIG. 116 (SEQID NO:332).

48. PRO339 and PRO310

Applicants have identified two cDNA clones wherein each cloneencodes a novel polypeptide having homology to fringe, wherein thepolypeptides are designated in the present application as "PRO339"and "PRO310".

In one embodiment, the invention provides isolated nucleic acidmolecules comprising DNA encoding a PRO339 and/or a PRO310polypeptide. In one aspect, the isolated nucleic acid comprises DNAencoding the PRO339 polypeptide having amino acid residues 1 to 772of FIG. 118 (SEQ ID NO:339), or is complementary to such encodingnucleic acid sequence, and remains stably bound to it under atleast moderate, and optionally, under high stringency conditions.In another aspect, the isolated nucleic acid comprises DNA encodingthe PRO310 polypeptide having amino acid residues 1 to 318 of FIG.120 (SEQ ID NO:341), or is complementary to such encoding nucleicacid sequence, and remains stably bound to it under at leastmoderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO339 aswell as isolated PRO310 polypeptides. In particular, the inventionprovides isolated native sequence PRO339 polypeptide, which in oneembodiment, includes an amino acid sequence comprising residues 1to 772 of FIG. 118 (SEQ ID NO:339). The invention further providesisolated native sequence PRO310 polypeptide, which in oneembodiment, includes an amino acid sequence comprising residues 1to 318 of FIG. 120 (SEQ ID NO:341).

49. PRO244

Applicants have identified a cDNA clone that encodes a novelpolypeptide, designated in the present application as "PRO244".

In one embodiment, the invention provides an isolated nucleic acidmolecule comprising DNA encoding PRO244 polypeptide. In one aspect,the isolated nucleic acid comprises DNA encoding PRO244 polypeptidehaving amino acid residues 1 to 219 of FIG. 122 (SEQ ID NO:377), oris complementary to such encoding nucleic acid sequence, andremains stably bound to it under at least moderate, and optionally,under high stringency conditions.

In another embodiment, the invention provides isolated PRO244polypeptide. In particular, the invention provides isolated nativesequence PRO244 polypeptide, which in one embodiment, includes anamino acid sequence comprising residues 1 to 219 of FIG. 122 (SEQID NO:377).

50. Additional Embodiments

In other embodiments of the present invention, the inventionprovides vectors comprising DNA encoding any of the hereindescribed polypeptides. Host cell comprising any such vector arealso provided. By way of example, the host cells may be CHO cells,E. coli, or yeast. A process for producing any of the hereindescribed polypeptides is further provided and comprises culturinghost cells under conditions suitable for expression of the desiredpolypeptide and recovering the desired polypeptide from the cellculture.

In other embodiments, the invention provides chimeric moleculescomprising any of the herein described polypeptides fused to aheterologous polypeptide or amino acid sequence. Example of suchchimeric molecules comprise any of the herein describedpolypeptides fused to an epitope tag sequence or a Fc region of animmunoglobulin.

In another embodiment, the invention provides an antibody whichspecifically binds to any of the above or below describedpolypeptides. Optionally, the antibody is a monoclonal antibody,humanized antibody, antibody fragment or single-chain antibody.

In yet other embodiments, the invention provides oligonucleotideprobes useful for isolating genomic and cDNA nucleotide sequences,wherein those probes may be derived from any of the above or belowdescribed nucleotide sequences.

In other embodiments, the invention provides an isolated nucleicacid molecule comprising a nucleotide sequence that encodes a PROpolypeptide.

In one aspect, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% sequence identity,preferably at least about 81% sequence identity, more preferably atleast about 82% sequence identity, yet more preferably at leastabout 83% sequence identity, yet more preferably at least about 84%sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity,yet more preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet morepreferably at least about 89% sequence identity, yet morepreferably at least about 90% sequence identity, yet morepreferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet morepreferably at least about 95% sequence identity, yet morepreferably at least about 96% sequence identity, yet morepreferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to (a) a DNAmolecule encoding a PRO polypeptide having a full-length amino acidsequence as disclosed herein, an amino acid sequence lacking thesignal peptide as disclosed herein or an extracellular domain of atransmembrane protein, with or without the signal peptide, asdisclosed herein, or (b) the complement of the DNA molecule of(a).

In other aspects, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% sequence identity,preferably at least about 81% sequence identity, more preferably atleast about 82% sequence identity, yet more preferably at leastabout 83% sequence identity, yet more preferably at least about 84%sequence identity, yet more preferably at least about 85% sequenceidentity, yet more preferably at least about 86% sequence identity,yet more preferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet morepreferably at least about 89% sequence identity, yet morepreferably at least about 90% sequence identity, yet morepreferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet morepreferably at least about 95% sequence identity, yet morepreferably at least about 96% sequence identity, yet morepreferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to (a) a DNAmolecule comprising the coding sequence of a full-length PROpolypeptide cDNA as disclosed herein, the coding sequence of a PROpolypeptide lacking the signal peptide as disclosed herein or thecoding sequence of an extracellular domain of a transmembrane PROpolypeptide, with or without the signal peptide, as disclosedherein, or (b) the complement of the DNA molecule of (a).

In a further aspect, the invention concerns an isolated nucleicacid molecule comprising a nucleotide sequence having at leastabout 80% sequence identity, preferably at least about 81% sequenceidentity, more preferably at least about 82% sequence identity, yetmore preferably at least about 83% sequence identity, yet morepreferably at least about 84% sequence identity, yet morepreferably at least about 85% sequence identity, yet morepreferably at least about 86% sequence identity, yet morepreferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet morepreferably at least about 89% sequence identity, yet morepreferably at least about 90% sequence identity, yet morepreferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet morepreferably at least about 95% sequence identity, yet morepreferably at least about 96% sequence identity, yet morepreferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to (a) a DNAmolecule that encodes the same mature polypeptide encoded by any ofthe human protein cDNAs deposited with the ATCC as disclosedherein, or (b) the complement of the DNA molecule of (a).

Another aspect the invention provides an isolated nucleic acidmolecule comprising a nucleotide sequence encoding a PROpolypeptide which is either transmembrane domain-deleted ortransmembrane domain-inactivated, or is complementary to suchencoding nucleotide sequence, wherein the transmembrane domain(s)of such polypeptide are disclosed herein. Therefore, solubleextracellular domains of the herein described PRO polypeptides arecontemplated.

Another embodiment is directed to fragments of a PRO polypeptidecoding sequence, or the complement thereof, that may find use as,for example, hybridization probes or for encoding fragments of aPRO polypeptide that may optionally encode a polypeptide comprisinga binding site for an anti-PRO antibody. Such nucleic acidfragments are usually at least about 20 nucleotides in length,preferably at least about 30 nucleotides in length, more preferablyat least about 40 nucleotides in length, yet more preferably atleast about 50 nucleotides in length, yet more preferably at leastabout 60 nucleotides in length, yet more preferably at least about70 nucleotides in length, yet more preferably at least about 80nucleotides in length, yet more preferably at least about 90nucleotides in length, yet more preferably at least about 100nucleotides in length, yet more preferably at least about 110nucleotides in length, yet more preferably at least about 120nucleotides in length, yet more preferably at least about 130nucleotides in length, yet more preferably at least about 140nucleotides in length, yet more preferably at least about 150nucleotides in length, yet more preferably at least about 160nucleotides in length, yet more preferably at least about 170nucleotides in length, yet more preferably at least about 180nucleotides in length, yet more preferably at least about 190nucleotides in length, yet more preferably at least about 200nucleotides in length, yet more preferably at least about 250nucleotides in length, yet more preferably at least about 300nucleotides in length, yet more preferably at least about 350nucleotides in length, yet more preferably at least about 400nucleotides in length, yet more preferably at least about 450nucleotides in length, yet more preferably at least about 500nucleotides in length, yet more preferably at least about 600nucleotides in length, yet more preferably at least about 700nucleotides in length, yet more preferably at least about 800nucleotides in length, yet more preferably at least about 900nucleotides in length and yet more preferably at least about 1000nucleotides in length, wherein in this context the term "about"means the referenced nucleotide sequence length plus or minus 10%of that referenced length. It is noted that novel fragments of aPRO polypeptide-encoding nucleotide sequence may be determined in aroutine manner by aligning the PRO polypeptide-encoding nucleotidesequence with other known nucleotide sequences using any of anumber of well known sequence alignment programs and determiningwhich PRO polypeptide-encoding nucleotide sequence fragment(s) arenovel. All of such PRO polypeptide-encoding nucleotide sequencesare contemplated herein. Also contemplated are the PRO polypeptidefragments encoded by these nucleotide molecule fragments,preferably those PRO polypeptide fragments that comprise a bindingsite for an anti-PRO antibody.

In another embodiment, the invention provides isolated PROpolypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

In a certain aspect, the invention concerns an isolated PROpolypeptide, comprising an amino acid sequence having at leastabout 80% sequence identity, preferably at least about 81% sequenceidentity, more preferably at least about 82% sequence identity, yetmore preferably at least about 83% sequence identity, yet morepreferably at least about 84% sequence identity, yet morepreferably at least about 85% sequence identity, yet morepreferably at least about 86% sequence identity, yet morepreferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet morepreferably at least about 89% sequence identity, yet morepreferably at least about 90% sequence identity, yet morepreferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet morepreferably at least about 95% sequence identity, yet morepreferably at least about 96% sequence identity, yet morepreferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to a PROpolypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide asdisclosed herein or an extracellular domain of a transmembraneprotein, with or without the signal peptide, as disclosedherein.

In a further aspect, the invention concerns an isolated PROpolypeptide comprising an amino acid sequence having at least about80% sequence identity, preferably at least about 81% sequenceidentity, more preferably at least about 82% sequence identity, yetmore preferably at least about 83% sequence identity, yet morepreferably at least about 84% sequence identity, yet morepreferably at least about 85% sequence identity, yet morepreferably at least about 86% sequence identity, yet morepreferably at least about 87% sequence identity, yet morepreferably at least about 88% sequence identity, yet morepreferably at least about 89% sequence identity, yet morepreferably at least about 90% sequence identity, yet morepreferably at least about 91% sequence identity, yet morepreferably at least about 92% sequence identity, yet morepreferably at least about 93% sequence identity, yet morepreferably at least about 94% sequence identity, yet morepreferably at least about 95% sequence identity, yet morepreferably at least about 96% sequence identity, yet morepreferably at least about 97% sequence identity, yet morepreferably at least about 98% sequence identity and yet morepreferably at least about 99% sequence identity to an amino acidsequence encoded by any of the human protein cDNAs deposited withthe ATCC as disclosed herein.

In a further aspect, the invention concerns an isolated PROpolypeptide comprising an amino acid sequence scoring at leastabout 80% positives, preferably at least about 81% positives, morepreferably at least about 82% positives, yet more preferably atleast about 83% positives, yet more preferably at least about 84%positives, yet more preferably at least about 85% positives, yetmore preferably at least about 86% positives, yet more preferablyat least about 87% positives, yet more preferably at least about88% positives, yet more preferably at least about 89% positives,yet more preferably at least about 90% positives, yet morepreferably at least about 91% positives, yet more preferably atleast about 92% positives, yet more preferably at least about 93%positives, yet more preferably at least about 94% positives, yetmore preferably at least about 95% positives, yet more preferablyat least about 96% positives, yet more preferably at least about97% positives, yet more preferably at least about 98% positives andyet more preferably at least about 99% positives when compared withthe amino acid sequence of a PRO polypeptide having a full-lengthamino acid sequence as disclosed herein, an amino acid sequencelacking the signal peptide as disclosed herein or an extracellulardomain of a transmembrane protein, with or without the signalpeptide, as disclosed herein.

In a specific aspect, the invention provides an isolated PROpolypeptide without the N-terminal signal sequence and/or theinitiating methionine and is encoded by a nucleotide sequence thatencodes such an amino acid sequence as hereinbefore described.Processes for producing the same are also herein described, whereinthose processes comprise culturing a host cell comprising a vectorwhich comprises the appropriate encoding nucleic acid moleculeunder conditions suitable for expression of the PRO polypeptide andrecovering the PRO polypeptide from the cell culture.

Another aspect the invention provides an isolated PRO polypeptidewhich is either transmembrane domain-deleted or transmembranedomain-inactivated. Processes for producing the same are alsoherein described, wherein those processes comprise culturing a hostcell comprising a vector which comprises the appropriate encodingnucleic acid molecule under conditions suitable for expression ofthe PRO polypeptide and recovering the PRO polypeptide from thecell culture.

In yet another embodiment, the invention concerns agonists andantagonists of a native PRO polypeptide as defined herein. In aparticular embodiment, the agonist or antagonist is an anti-PROantibody or a small molecule.

In a further embodiment, the invention concerns a method ofidentifying agonists or antagonists to a PRO polypeptide whichcomprise contacting the PRO polypeptide with a candidate moleculeand monitoring a biological activity mediated by said PROpolypeptide. Preferably, the PRO polypeptide is a native PROpolypeptide.

In a still further embodiment, the invention concerns a compositionof matter comprising a PRO polypeptide, or an agonist or antagonistof a PRO polypeptide as herein described, or an anti-PRO antibody,in combination with a carrier. Optionally, the carrier is apharmaceutically acceptable carrier.

Another embodiment of the present invention is directed to the useof a PRO polypeptide, or an agonist or antagonist thereof ashereinbefore described, or an anti-PRO antibody, for thepreparation of a medicament useful in the treatment of a conditionwhich is responsive to the PRO polypeptide, an agonist orantagonist thereof or an anti-PRO antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a nativesequence PRO211 cDNA, wherein SEQ ID NO:1 is a clone designatedherein as "DNA32292-1131".

FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived from thecoding sequence of SEQ ID NO:1 shown in FIG. 1.

FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a nativesequence PRO217 cDNA, wherein SEQ ID NO:3 is a clone designatedherein as "DNA33094-1131".

FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived from thecoding sequence of SEQ ID NO:3 shown in FIG. 3.

FIG. 5 shows a nucleotide sequence (SEQ ID NO:11) of a nativesequence PRO230 cDNA, wherein SEQ ID NO:11 is a clone designatedherein as "DNA33223-1136".

FIG. 6 shows the amino acid sequence (SEQ ID NO:12) derived fromthe coding sequence of SEQ ID NO:11 shown in FIG. 5.

FIG. 7 shows a nucleotide sequence designated herein as DNA20088(SEQ ID NO:13).

FIG. 8 shows a nucleotide sequence (SEQ ID NO:17) of a nativesequence PRO232 cDNA, wherein SEQ ID NO:17 is a clone designatedherein as "DNA34435-1140".

FIG. 9 shows the amino acid sequence (SEQ ID NO:18) derived fromthe coding sequence of SEQ ID NO:17 shown in FIG. 8.

FIG. 10 shows a nucleotide sequence (SEQ ID NO:22) of a nativesequence PRO187 cDNA, wherein SEQ ID NO:22 is a clone designatedherein as "DNA27864-1155".

FIG. 11 shows the amino acid sequence (SEQ ID NO:23) derived fromthe coding sequence of SEQ ID NO:22 shown in FIG. 10.

FIG. 12 shows a nucleotide sequence (SEQ ID NO:27) of a nativesequence PRO265 cDNA, wherein SEQ ID NO:27 is a clone designatedherein as "DNA36350-1158".

FIG. 13 shows the amino acid sequence (SEQ ID NO:28) derived fromthe coding sequence of SEQ ID NO:27 shown in FIG. 12.

FIG. 14 shows a nucleotide sequence (SEQ ID NO:33) of a nativesequence PRO219 cDNA, wherein SEQ ID NO:33 is a clone designatedherein as "DNA32290-1164".

FIG. 15 shows the amino acid sequence (SEQ ID NO:34) derived fromthe coding sequence of SEQ ID NO:33 shown in FIG. 14.

FIG. 16 shows a nucleotide sequence (SEQ ID NO:38) of a nativesequence PRO246 cDNA, wherein SEQ ID NO:38 is a clone designatedherein as "DNA35639-1172".

FIG. 17 shows the amino acid sequence (SEQ ID NO:39) derived fromthe coding sequence of SEQ ID NO:38 shown in FIG. 16.

FIG. 18 shows a nucleotide sequence (SEQ ID NO:48) of a nativesequence PRO228 cDNA, wherein SEQ ID NO:48 is a clone designatedherein as "DNA33092-1202".

FIG. 19 shows the amino acid sequence (SEQ ID NO:49) derived fromthe coding sequence of SEQ ID NO:48 shown in FIG. 18.

FIG. 20 shows a nucleotide sequence designated herein as DNA21951(SEQ ID NO:50).

FIG. 21 shows a nucleotide sequence (SEQ ID NO:58) of a nativesequence PRO533 cDNA, wherein SEQ ID NO:58 is a clone designatedherein as "DNA49435-1219".

FIG. 22 shows the amino acid sequence (SEQ ID NO:59) derived fromthe coding sequence of SEQ ID NO:58 shown in FIG. 21.

FIG. 23 shows a nucleotide sequence (SEQ ID NO:63) of a nativesequence PRO245 cDNA, wherein SEQ ID NO:63 is a clone designatedherein as "DNA35638-1141".

FIG. 24 shows the amino acid sequence (SEQ ID NO:64) derived fromthe coding sequence of SEQ ID NO:63 shown in FIG. 23.

FIG. 25 shows a nucleotide sequence (SEQ ID NO:68) of a nativesequence PRO220 cDNA, wherein SEQ ID NO:68 is a clone designatedherein as "DNA32298-1132".

FIG. 26 shows the amino acid sequence (SEQ ID NO:69) derived fromthe coding sequence of SEQ ID NO:68 shown in FIG. 25.

FIG. 27 shows a nucleotide sequence (SEQ ID NO:70) of a nativesequence PRO221 cDNA, wherein SEQ ID NO:70 is a clone designatedherein as "DNA33089-1132".

FIG. 28 shows the amino acid sequence (SEQ ID NO:71) derived fromthe coding sequence of SEQ ID NO:70 shown in FIG. 27.

FIG. 29 shows a nucleotide sequence (SEQ ID NO:72) of a nativesequence PRO227 cDNA, wherein SEQ ID NO:72 is a clone designatedherein as "DNA33786-1132".

FIG. 30 shows the amino acid sequence (SEQ ID NO:73) derived fromthe coding sequence of SEQ ID NO:72 shown in FIG. 29.

FIG. 31 shows a nucleotide sequence (SEQ ID NO:83) of a nativesequence PRO258 cDNA, wherein SEQ ID NO:83 is a clone designatedherein as "DNA35918-1174".

FIG. 32 shows the amino acid sequence (SEQ ID NO:84) derived fromthe coding sequence of SEQ ID NO:83 shown in FIG. 31.

FIG. 33 shows a nucleotide sequence (SEQ ID NO:90) of a nativesequence PRO266 cDNA, wherein SEQ ID NO:90 is a clone designatedherein as "DNA37150-1178".

FIG. 34 shows the amino acid sequence (SEQ ID NO:91) derived fromthe coding sequence of SEQ ID NO:90 shown in FIG. 33.

FIG. 35 shows a nucleotide sequence (SEQ ID NO:95) of a nativesequence PRO269 cDNA, wherein SEQ ID NO:95 is a clone designatedherein as "DNA38260-1180".

FIG. 36 shows the amino acid sequence (SEQ ID NO:96) derived fromthe coding sequence of SEQ ID NO:95 shown in FIG. 35.

FIG. 37 shows a nucleotide sequence (SEQ ID NO:103) of a nativesequence PRO287 cDNA, wherein SEQ ID NO:103 is a clone designatedherein as "DNA39969-1185".

FIG. 38 shows the amino acid sequence (SEQ ID NO:104) derived fromthe coding sequence of SEQ ID NO:103 shown in FIG. 37.

FIG. 39 shows a nucleotide sequence (SEQ ID NO:108) of a nativesequence PRO214 cDNA, wherein SEQ ID NO:108 is a clone designatedherein as "DNA32286-1191".

FIG. 40 shows the amino acid sequence (SEQ ID NO:109) derived fromthe coding sequence of SEQ ID NO:108 shown in FIG. 39.

FIG. 41 shows a nucleotide sequence (SEQ ID NO:113) of a nativesequence PRO317 cDNA, wherein SEQ ID NO:113 is a clone designatedherein as "DNA33461-1199".

FIG. 42 shows the amino acid sequence (SEQ ID NO:114) derived fromthe coding sequence of SEQ ID NO:113 shown in FIG. 41.

FIG. 43 shows a nucleotide sequence (SEQ ID NO:118) of a nativesequence PRO301 cDNA, wherein SEQ ID NO:118 is a clone designatedherein as "DNA40628-1216".

FIG. 44 shows the amino acid sequence (SEQ ID NO:119) derived fromthe coding sequence of SEQ ID NO:118 shown in FIG. 43.

FIG. 45 shows a nucleotide sequence (SEQ ID NO:126) of a nativesequence PRO224 cDNA, wherein SEQ ID NO:126 is a clone designatedherein as "DNA33221-1133".

FIG. 46 shows the amino acid sequence (SEQ ID NO:127) derived fromthe coding sequence of SEQ ID NO:126 shown in FIG. 45.

FIG. 47 shows a nucleotide sequence (SEQ ID NO:131) of a nativesequence PRO222 cDNA, wherein SEQ ID NO:131 is a clone designatedherein as "DNA33107-1135".

FIG. 48 shows the amino acid sequence (SEQ ID NO:132) derived fromthe coding sequence of SEQ ID NO:131 shown in FIG. 47.

FIG. 49 shows a nucleotide sequence (SEQ ID NO:136) of a nativesequence PRO234 cDNA, wherein SEQ ID NO:136 is a clone designatedherein as "DNA35557-1137".

FIG. 50 shows the amino acid sequence (SEQ ID NO:137) derived fromthe coding sequence of SEQ ID NO:136 shown in FIG. 49.

FIG. 51 shows a nucleotide sequence (SEQ ID NO:141) of a nativesequence PRO231 cDNA, wherein SEQ ID NO:141 is a clone designatedherein as "DNA34434-1139".

FIG. 52 shows the amino acid sequence (SEQ ID NO:142) derived fromthe coding sequence of SEQ ID NO:141 shown in FIG. 51.

FIG. 53 shows a nucleotide sequence (SEQ ID NO:147) of a nativesequence PRO229 cDNA, wherein SEQ ID NO:147 is a clone designatedherein as "DNA33100-1159".

FIG. 54 shows the amino acid sequence (SEQ ID NO:148) derived fromthe coding sequence of SEQ ID NO:147 shown in FIG. 53.

FIG. 55 shows a nucleotide sequence (SEQ ID NO:152) of a nativesequence PRO238 cDNA, wherein SEQ ID NO:152 is a clone designatedherein as "DNA35600-1162".

FIG. 56 shows the amino acid sequence (SEQ ID NO:153) derived fromthe coding sequence of SEQ ID NO:152 shown in FIG. 55.

FIG. 57 shows a nucleotide sequence (SEQ ID NO:158) of a nativesequence PRO233 cDNA, wherein SEQ ID NO:158 is a clone designatedherein as "DNA34436-1238".

FIG. 58 shows the amino acid sequence (SEQ ID NO:159) derived fromthe coding sequence of SEQ ID NO:158 shown in FIG. 57.

FIG. 59 shows a nucleotide sequence (SEQ ID NO:163) of a nativesequence PRO223 cDNA, wherein SEQ ID NO:163 is a clone designatedherein as "DNA33206-1165".

FIG. 60 shows the amino acid sequence (SEQ ID NO:164) derived fromthe coding sequence of SEQ ID NO:163 shown in FIG. 59.

FIG. 61 shows a nucleotide sequence (SEQ ID NO:169) of a nativesequence PRO235 cDNA, wherein SEQ ID NO:169 is a clone designatedherein as "DNA35558-1167".

FIG. 62 shows the amino acid sequence (SEQ ID NO:170) derived fromthe coding sequence of SEQ ID NO:169 shown in FIG. 61.

FIG. 63 shows a nucleotide sequence (SEQ ID NO:174) of a nativesequence PRO236 cDNA, wherein SEQ ID NO:174 is a clone designatedherein as "DNA35599-1168".

FIG. 64 shows the amino acid sequence (SEQ ID NO:175) derived fromthe coding sequence of SEQ ID NO:174 shown in FIG. 63.

FIG. 65 shows a nucleotide sequence (SEQ ID NO:176) of a nativesequence PRO262 cDNA, wherein SEQ ID NO:176 is a clone designatedherein as "DNA36992-1168".

FIG. 66 shows the amino acid sequence (SEQ ID NO:177) derived fromthe coding sequence of SEQ ID NO:176 shown in FIG. 65.

FIG. 67 shows a nucleotide sequence (SEQ ID NO:184) of a nativesequence PRO239 cDNA, wherein SEQ ID NO:184 is a clone designatedherein as "DNA34407-1169".

FIG. 68 shows the amino acid sequence (SEQ ID NO:185) derived fromthe coding sequence of SEQ ID NO:184 shown in FIG. 67.

FIG. 69 shows a nucleotide sequence (SEQ ID NO:189) of a nativesequence PRO257 cDNA, wherein SEQ ID NO:189 is a clone designatedherein as "DNA35841-1173".

FIG. 70 shows the amino acid sequence (SEQ ID NO:190) derived fromthe coding sequence of SEQ ID NO:189 shown in FIG. 69.

FIG. 71 shows a nucleotide sequence (SEQ ID NO:194) of a nativesequence PRO260 cDNA, wherein SEQ ID NO:194 is a clone designatedherein as "DNA33470-1175".

FIG. 72 shows the amino acid sequence (SEQ ID NO:195) derived fromthe coding sequence of SEQ ID NO:194 shown in FIG. 71.

FIG. 73 shows a nucleotide sequence (SEQ ID NO:200) of a nativesequence PRO263 cDNA, wherein SEQ ID NO:200 is a clone designatedherein as "DNA34431-1177".

FIG. 74 shows the amino acid sequence (SEQ ID NO:201) derived fromthe coding sequence of SEQ ID NO:200 shown in FIG. 73.

FIG. 75 shows a nucleotide sequence (SEQ ID NO:206) of a nativesequence PRO270 cDNA, wherein SEQ ID NO:206 is a clone designatedherein as "DNA39510-1181".

FIG. 76 shows the amino acid sequence (SEQ ID NO:207) derived fromthe coding sequence of SEQ ID NO:206 shown in FIG. 75.

FIG. 77 shows a nucleotide sequence (SEQ ID NO:212) of a nativesequence PRO271 cDNA, wherein SEQ ID NO:212 is a clone designatedherein as "DNA39423-1182".

FIG. 78 shows the amino acid sequence (SEQ ID NO:213) derived fromthe coding sequence of SEQ ID NO:212 shown in FIG. 77.

FIG. 79 shows a nucleotide sequence (SEQ ID NO:220) of a nativesequence PRO272 cDNA, wherein SEQ ID NO:220 is a clone designatedherein as "DNA40620-1183".

FIG. 80 shows the amino acid sequence (SEQ ID NO:221) derived fromthe coding sequence of SEQ ID NO:220 shown in FIG. 79.

FIG. 81 shows a nucleotide sequence (SEQ ID NO:226) of a nativesequence PRO294 cDNA, wherein SEQ ID NO:226 is a clone designatedherein as "DNA40604-1187".

FIG. 82 shows the amino acid sequence (SEQ ID NO:227) derived fromthe coding sequence of SEQ ID NO:226 shown in FIG. 81.

FIG. 83 shows a nucleotide sequence (SEQ ID NO:235) of a nativesequence PRO295 cDNA, wherein SEQ ID NO:235 is a clone designatedherein as "DNA38268-1188".

FIG. 84 shows the amino acid sequence (SEQ ID NO:236) derived fromthe coding sequence of SEQ ID NO:235 shown in FIG. 83.

FIG. 85 shows a nucleotide sequence (SEQ ID NO:244) of a nativesequence PRO293 cDNA, wherein SEQ ID NO:244 is a clone designatedherein as "DNA37151-1193".

FIG. 86 shows the amino acid sequence (SEQ ID NO:245) derived fromthe coding sequence of SEQ ID NO:244 shown in FIG. 85.

FIG. 87 shows a nucleotide sequence (SEQ ID NO:249) of a nativesequence PRO247 cDNA, wherein SEQ ID NO:249 is a clone designatedherein as "DNA35673-1201".

FIG. 88 shows the amino acid sequence (SEQ ID NO:250) derived fromthe coding sequence of SEQ ID NO:249 shown in FIG. 87.

FIG. 89 shows a nucleotide sequence (SEQ ID NO:254) of a nativesequence PRO302 cDNA, wherein SEQ ID NO:254 is a clone designatedherein as "DNA40370-1217".

FIG. 90 shows the amino acid sequence (SEQ ID NO:255) derived fromthe coding sequence of SEQ ID NO:254 shown in FIG. 89.

FIG. 91 shows a nucleotide sequence (SEQ ID NO:256) of a nativesequence PRO303 cDNA, wherein SEQ ID NO:256 is a clone designatedherein as "DNA42551-1217".

FIG. 92 shows the amino acid sequence (SEQ ID NO:257) derived fromthe coding sequence of SEQ ID NO:256 shown in FIG. 91.

FIG. 93 shows a nucleotide sequence (SEQ ID NO:258) of a nativesequence PRO304 cDNA, wherein SEQ ID NO:258 is a clone designatedherein as "DNA39520-1217".

FIG. 94 shows the amino acid sequence (SEQ ID NO:259) derived fromthe coding sequence of SEQ ID NO:258 shown in FIG. 93.

FIG. 95 shows a nucleotide sequence (SEQ ID NO:260) of a nativesequence PRO307 cDNA, wherein SEQ ID NO:260 is a clone designatedherein as "DNA41225-1217".

FIG. 96 shows the amino acid sequence (SEQ ID NO:261) derived fromthe coding sequence of SEQ ID NO:260 shown in FIG. 95.

FIG. 97 shows a nucleotide sequence (SEQ ID NO:262) of a nativesequence PRO343 cDNA, wherein SEQ ID NO:262 is a clone designatedherein as "DNA43318-1217".

FIG. 98 shows the amino acid sequence (SEQ ID NO:263) derived fromthe coding sequence of SEQ ID NO:262 shown in FIG. 97.

FIG. 99 shows a nucleotide sequence (SEQ ID NO:284) of a nativesequence PRO328 cDNA, wherein SEQ ID NO:284 is a clone designatedherein as "DNA40587-1231".

FIG. 100 shows the amino acid sequence (SEQ ID NO:285) derived fromthe coding sequence of SEQ ID NO:284 shown in FIG. 99.

FIG. 101 shows a nucleotide sequence (SEQ ID NO:289) of a nativesequence PRO335 cDNA, wherein SEQ ID NO:289 is a clone designatedherein as "DNA41388-1234".

FIG. 102 shows the amino acid sequence (SEQ ID NO:290) derived fromthe coding sequence of SEQ ID NO:289 shown in FIG. 101.

FIG. 103 shows a nucleotide sequence (SEQ ID NO:291) of a nativesequence PRO331 cDNA, wherein SEQ ID NO:291 is a clone designatedherein as "DNA40981-1234".

FIG. 104 shows the amino acid sequence (SEQ ID NO:292) derived fromthe coding sequence of SEQ ID NO:291 shown in FIG. 103.

FIG. 105 shows a nucleotide sequence (SEQ ID NO:293) of a nativesequence PRO326 cDNA, wherein SEQ ID NO:293 is a clone designatedherein as "DNA37140-1234".

FIG. 106 shows the amino acid sequence (SEQ ID NO:294) derived fromthe coding sequence of SEQ ID NO:293 shown in FIG. 105.

FIG. 107 shows a nucleotide sequence (SEQ ID NO:309) of a nativesequence PRO332 cDNA, wherein SEQ ID NO:309 is a clone designatedherein as "DNA40982-1235".

FIG. 108 shows the amino acid sequence (SEQ ID NO:310) derived fromthe coding sequence of SEQ ID NO:309 shown in FIG. 107.

FIG. 109 shows a nucleotide sequence (SEQ ID NO:314) of a nativesequence PRO334 cDNA, wherein SEQ ID NO:314 is a clone designatedherein as "DNA41379-1236".

FIG. 110 shows the amino acid sequence (SEQ ID NO:315) derived fromthe coding sequence of SEQ ID NO:314 shown in FIG. 109.

FIG. 111 shows a nucleotide sequence (SEQ ID NO:319) of a nativesequence PRO346 cDNA, wherein SEQ ID NO:319 is a clone designatedherein as "DNA44167-1243".

FIG. 112 shows the amino acid sequence (SEQ ID NO:320) derived fromthe coding sequence of SEQ ID NO:319 shown in FIG. 111.

FIG. 113 shows a nucleotide sequence (SEQ ID NO:324) of a nativesequence PRO268 cDNA, wherein SEQ ID NO:324 is a clone designatedherein as "DNA39427-1179".

FIG. 114 shows the amino acid sequence (SEQ ID NO:325) derived fromthe coding sequence of SEQ ID NO:324 shown in FIG. 113.

FIG. 115 shows a nucleotide sequence (SEQ ID NO:331) of a nativesequence PRO330 cDNA, wherein SEQ ID NO:331 is a clone designatedherein as "DNA40603-1232".

FIG. 116 shows the amino acid sequence (SEQ ID NO:332) derived fromthe coding sequence of SEQ ID NO:331 shown in FIG. 115.

FIG. 117 shows a nucleotide sequence (SEQ ID NO:338) of a nativesequence PRO339 cDNA, wherein SEQ ID NO:338 is a clone designatedherein as "DNA43466-1225".

FIG. 118 shows the amino acid sequence (SEQ ID NO:339) derived fromthe coding sequence of SEQ ID NO:338 shown in FIG. 117.

FIG. 119 shows a nucleotide sequence (SEQ ID NO:340) of a nativesequence PRO310 cDNA, wherein SEQ ID NO:340 is a clone designatedherein as "DNA43046-1225".

FIG. 120 shows the amino acid sequence (SEQ ID NO:341) derived fromthe coding sequence of SEQ ID NO:340 shown in FIG. 119.

FIG. 121 shows a nucleotide sequence (SEQ ID NO:376) of a nativesequence PRO244 cDNA, wherein SEQ ID NO:376 is a clone designatedherein as "DNA35668-1171".

FIG. 122 shows the amino acid sequence (SEQ ID NO:377) derived fromthe coding sequence of SEQ ID NO:376 shown in FIG. 121.

FIG. 123 shows a nucleotide sequence (SEQ ID NO:422) of a nativesequence PRO1868 cDNA, wherein SEQ ID NO:422 is a clone designatedherein as "DNA77624-2515".

FIG. 124 shows the amino acid sequence (SEQ ID NO:423) derived fromthe coding sequence of SEQ ID NO:422 shown in FIG. 123.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

The terms "PRO polypeptide" and "PRO" as used herein and whenimmediately followed by a numerical designation refer to variouspolypeptides, wherein the complete designation (i.e., PRO/number)refers to specific polypeptide sequences as described herein. Theterms "PRO/number polypeptide" and "PRO/number" wherein the term"number" is provided as an actual numerical designation as usedherein encompass native sequence polypeptides and polypeptidevariants (which are further defined herein). The PRO polypeptidesdescribed herein may be isolated from a variety of sources, such asfrom human tissue types or from another source, or prepared byrecombinant or synthetic methods.

A "native sequence PRO polypeptide" comprises a polypeptide havingthe same amino acid sequence as the corresponding PRO polypeptidederived from nature. Such native sequence PRO polypeptides can beisolated from nature or can be produced by recombinant or syntheticmeans. The term "native sequence PRO polypeptide" specificallyencompasses naturally-occurring truncated or secreted forms of thespecific PRO polypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively splicedforms) and naturally-occurring allelic variants of the polypeptide.In various embodiments of the invention, the native sequence PROpolypeptides disclosed herein are mature or full-length nativesequence polypeptides comprising the full-length amino acidssequences shown in the accompanying figures. Start and stop codonsare shown in bold font and underlined in the figures. However,while the PRO polypeptide disclosed in the accompanying figures areshown to begin with methionine residues designated herein as aminoacid position 1 in the figures, it is conceivable and possible thatother methionine residues located either upstream or downstreamfrom the amino acid position 1 in the figures may be employed asthe starting amino acid residue for the PRO polypeptides.

The PRO polypeptide "extracellular domain" or "ECD" refers to aform of the PRO polypeptide which is essentially free of thetransmembrane and cytoplasmic domains. Ordinarily, a PROpolypeptide ECD will have less than 1% of such transmembrane and/orcytoplasmic domains and preferably, will have less than 0.5% ofsuch domains. It will be understood that any transmembrane domainsidentified for the PRO polypeptides of the present invention areidentified pursuant to criteria routinely employed in the art foridentifying that type of hydrophobic domain. The exact boundariesof a transmembrane domain may vary but most likely by no more thanabout 5 amino acids at either end of the domain as initiallyidentified herein. Optionally, therefore, an extracellular domainof a PRO polypeptide may contain from about 5 or fewer amino acidson either side of the transmembrane domain/extracellular domainboundary as identified in the Examples or specification and suchpolypeptides, with or without the associated signal peptide, andnucleic acid encoding them, are comtemplated by the presentinvention.

The approximate location of the "signal peptides" of the variousPRO polypeptides disclosed herein are shown in the presentspecification and/or the accompanying figures. It is noted,however, that the C-terminal boundary of a signal peptide may vary,but most likely by no more than about 5 amino acids on either sideof the signal peptide C-terminal boundary as initially identifiedherein, wherein the C-terminal boundary of the signal peptide maybe identified pursuant to criteria routinely employed in the artfor identifying that type of amino acid sequence element (e.g.,Nielsen et al., Prot. Eng. 10: 1-6 (1997) and von Heinje et al.,Nucl. Acids. Res. 14:4683-4690 (1986)). Moreover, it is alsorecognized that, in some cases, cleavage of a signal sequence froma secreted polypeptide is not entirely uniform, resulting in morethan one secreted species. These mature polypeptides, where thesignal peptide is cleaved within no more than about 5 amino acidson either side of the C-terminal boundary of the signal peptide asidentified herein, and the polynucleotides encoding them, arecontemplated by the present invention.

"PRO polypeptide variant" means an active PRO polypeptide asdefined above or below having at least about 80% amino acidsequence identity with a full-length native sequence PROpolypeptide sequence as disclosed herein, a PRO polypeptidesequence lacking the signal peptide as disclosed herein, anextracellular domain of a PRO polypeptide, with or without thesignal peptide, as disclosed herein or any other fragment of afull-length PRO polypeptide sequence as disclosed herein. Such PROpolypeptide variants include, for instance, PRO polypeptideswherein one or more amino acid residues are added, or deleted, atthe N- or C-terminus of the full-length native amino acid sequence.Ordinarily, a PRO polypeptide variant will have at least about 80%amino acid sequence identity, preferably at least about 81% aminoacid sequence identity, more preferably at least about 82% aminoacid sequence identity, more preferably at least about 83% aminoacid sequence identity, more preferably at least about 84% aminoacid sequence identity, more preferably at least about 85% aminoacid sequence identity, more preferably at least about 86% aminoacid sequence identity, more preferably at least about 87% aminoacid sequence identity, more preferably at least about 88% aminoacid sequence identity, more preferably at least about 89% aminoacid sequence identity, more preferably at least about 90% aminoacid sequence identity, more preferably at least about 91% aminoacid sequence identity, more preferably at least about 92% aminoacid sequence identity, more preferably at least about 93% aminoacid sequence identity, more preferably at least about 94% aminoacid sequence identity, more preferably at least about 95% aminoacid sequence identity, more preferably at least about 96% aminoacid sequence identity, more preferably at least about 97% aminoacid sequence identity, more preferably at least about 98% aminoacid sequence identity and most preferably at least about 99% aminoacid sequence identity with a full-length native sequence PROpolypeptide sequence as disclosed herein, a PRO polypeptidesequence lacking the signal peptide as disclosed herein, anextracellular domain of a PRO polypeptide, with or without thesignal peptide, as disclosed herein or any other specificallydefined fragment of a full-length PRO polypeptide sequence asdisclosed herein. Ordinarily, PRO variant polypeptides are at leastabout 10 amino acids in length, often at least about 20 amino acidsin length, more often at least about 30 amino acids in length, moreoften at least about 40 amino acids in length, more often at leastabout 50 amino acids in length, more often at least about 60 aminoacids in length, more often at least about 70 amino acids inlength, more often at least about 80 amino acids in length, moreoften at least about 90 amino acids in length, more often at leastabout 100 amino acids in length, more often at least about 150amino acids in length, more often at least about 200 amino acids inlength, more often at least about 300 amino acids in length, ormore.

"Percent (%) amino acid sequence identity" with respect to the PROpolypeptide sequence s identified herein is defined as thepercentage of amino acid residues in a candidate sequence that areidentical with the amino acid residues in the specific PROpolypeptide sequence, after aligning the sequences and introducinggaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as partof the sequence identity. Alignment for purposes of determiningpercent amino acid sequence identity can be achieved in variousways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGNor Megalign (DNASTAR) software. Those skilled in the art candetermine appropriate parameters for measuring alignment, includingany algorithms needed to achieve maximal alignment over the fulllength of the sequences being compared. For purposes herein,however, % amino acid sequence identity values are generated usingthe sequence comparison computer program ALIGN-2, wherein thecomplete source code for the ALIGN-2 program is provided in Table 1below. The ALIGN-2 sequence comparison computer program wasauthored by Genentech, Inc. and the source code shown in Table 1below has been filed with user documentation in the U.S. CopyrightOffice, Washington D.C., 20559, where it is registered under U.S.Copyright Registration No. TXU510087. The ALIGN-2 program ispublicly available through Genentech, Inc., South San Francisco,Calif. or may be compiled from the source code provided in Table 1below. The ALIGN-2 program should be compiled for use on a UNIXoperating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do notvary.

In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given aminoacid sequence A to, with, or against a given amino acid sequence B(which can alternatively be phrased as a given amino acid sequenceA that has or comprises a certain % amino acid sequence identityto, with, or against a given amino acid sequence B) is calculatedas follows: 100 times the fraction X/Y where X is the number ofamino acid residues scored as identical matches by the sequencealignment program ALIGN-2 in that program's alignment of A and B,and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence Ais not equal to the length of amino acid sequence B, the % aminoacid sequence identity of A to B will not equal the % amino acidsequence identity of B to A. As examples of % amino acid sequenceidentity calculations using this method, Tables 2 and 3 demonstratehow to calculate the % amino acid sequence identity of the aminoacid sequence designated "Comparison Protein" to the amino acidsequence designated "PRO", wherein "PRO" represents the amino acidsequence of a hypothetical PRO polypeptide of interest, "ComparisonProtein" represents the amino acid sequence of a polypeptideagainst which the "PRO" polypeptide of interest is being compared,and "X, "Y" and "Z" each represent different hypothetical aminoacid residues.

Unless specifically stated otherwise, all % amino acid sequenceidentity values used herein are obtained as described in theimmediately preceding paragraph using the ALIGN-2 computer program.However, % amino acid sequence identity values may also be obtainedas described below by using the WU-BLAST-2 computer program(Altschul et al., Methods in Enzymology 266:460-480 (1996)). Mostof the WU-BLAST-2 search parameters are set to the default values.Those not set to default values, i.e., the adjustable parameters,are set with the following values: overlap span=1, overlapfraction=0.125, word threshold (T)=11, and scoring matrix=BLOSUM62.When WU-BLAST-2 is employed, a % amino acid sequence identity valueis determined by dividing (a) the number of matching identicalamino acid residues between the amino acid sequence of the PROpolypeptide of interest having a sequence derived from the nativePRO polypeptide and the comparison amino acid sequence of interest(i.e., the sequence against which the PRO polypeptide of interestis being compared which may be a PRO variant polypeptide) asdetermined by WU-BLAST-2 by (b) the total number of amino acidresidues of the PRO polypeptide of interest. For example, in thestatement "a polypeptide comprising an the amino acid sequence Awhich has or having at least 80% amino acid sequence identity tothe amino acid sequence B", the amino acid sequence A is thecomparison amino acid sequence of interest and the amino acidsequence B is the amino acid sequence of the PRO polypeptide ofinterest.

Percent amino acid sequence identity may also be determined usingthe sequence comparison program NCBI-BLAST2 (Altschul et al.,Nucleic Acids Res. 25:3389-3402 (1997)). NCBI-BLAST2 uses severalsearch parameters, wherein all of those search parameters are setto default values including, for example, unmask=yes, strand=all,expected occurrences=10, minimum low complexity length=15/5,multi-pass e-value=0.01, constant for multi-pass=25, dropoff forfinal gapped alignment=25 and scoring matrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given aminoacid sequence A to, with, or against a given amino acid sequence B(which can alternatively be phrased as a given amino acid sequenceA that has or comprises a certain % amino acid sequence identityto, with, or against a given amino acid sequence B) is calculatedas follows: 100 times the fraction X/Y where X is the number ofamino acid residues scored as identical matches by the sequencealignment program NCBI-BLAST2 in that program's alignment of A andB, and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence Ais not equal to the length of amino acid sequence B, the % aminoacid sequence identity of A to B will not equal the % amino acidsequence identity of B to A.

"PRO variant polynucleotide" or "PRO variant nucleic acid sequence"means a nucleic acid molecule which encodes an active PROpolypeptide as defined below and which has at least about 80%nucleic acid sequence identity with a nucleotide acid sequenceencoding a full-length native sequence PRO polypeptide sequence asdisclosed herein, a full-length native sequence PRO polypeptidesequence lacking the signal peptide as disclosed herein, anextracellular domain of a PRO polypeptide, with or without thesignal peptide, as disclosed herein or any other fragment of afull-length PRO polypeptide sequence as disclosed herein.Ordinarily, a PRO variant polynucleotide will have at least about80% nucleic acid sequence identity, more preferably at least about81% nucleic acid sequence identity, more preferably at least about82% nucleic acid sequence identity, more preferably at least about83% nucleic acid sequence identity, more preferably at least about84% nucleic acid sequence identity, more preferably at least about85% nucleic acid sequence identity, more preferably at least about86% nucleic acid sequence identity, more preferably at least about87% nucleic acid sequence identity, more preferably at least about88% nucleic acid sequence identity, more preferably at least about89% nucleic acid sequence identity, more preferably at least about90% nucleic acid sequence identity, more preferably at least about91% nucleic acid sequence identity, more preferably at least about92% nucleic acid sequence identity, more preferably at least about93% nucleic acid sequence identity, more preferably at least about94% nucleic acid sequence identity, more preferably at least about95% nucleic acid sequence identity, more preferably at least about96% nucleic acid sequence identity, more preferably at least about97% nucleic acid sequence identity, more preferably at least about98% nucleic acid sequence identity and yet more preferably at leastabout 99% nucleic acid sequence identity with a nucleic acidsequence encoding a full-length native sequence PRO polypeptidesequence as disclosed herein, a full-length native sequence PROpolypeptide sequence lacking the signal peptide as disclosedherein, an extracellular domain of a PRO polypeptide, with orwithout the signal sequence, as disclosed herein or any otherfragment of a full-length PRO polypeptide sequence as disclosedherein. Variants do not encompass the native nucleotidesequence.

Ordinarily, PRO variant polynucleotides are at least about 30nucleotides in length, often at least about 60 nucleotides inlength, more often at least about 90 nucleotides in length, moreoften at least about 120 nucleotides in length, more often at leastabout 150 nucleotides in length, more often at least about 180nucleotides in length, more often at least about 210 nucleotides inlength, more often at least about 240 nucleotides in length, moreoften at least about 270 nucleotides in length, more often at leastabout 300 nucleotides in length, more often at least about 450nucleotides in length, more often at least about 600 nucleotides inlength, more often at least about 900 nucleotides in length, ormore.

"Percent (%) nucleic acid sequence identity" with respect toPRO-encoding nucleic acid sequences identified herein is defined asthe percentage of nucleotides in a candidate sequence that areidentical with the nucleotides in the PRO nucleic acid sequence ofinterest, after aligning the sequences and introducing gaps, ifnecessary, to achieve the maximum percent sequence identity.Alignment for purposes of determining percent nucleic acid sequenceidentity can be achieved in various ways that are within the skillin the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR)software. For purposes herein, however, % nucleic acid sequenceidentity values are generated using the sequence comparisoncomputer program ALIGN-2, wherein the complete source code for theALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequencecomparison computer program was authored by Genentech, Inc. and thesource code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No.TXU510087. The ALIGN-2 program is publicly available throughGenentech, Inc., South San Francisco, Calif. or may be compiledfrom the source code provided in Table 1 below. The ALIGN-2 programshould be compiled for use on a UNIX operating system, preferablydigital UNIX V4.0D. All sequence comparison parameters are set bythe ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for nucleic acid sequencecomparisons, the % nucleic acid sequence identity of a givennucleic acid sequence C to, with, or against a given nucleic acidsequence D (which can alternatively be phrased as a given nucleicacid sequence C that has or comprises a certain % nucleic acidsequence identity to, with, or against a given nucleic acidsequence D) is calculated as follows: 100 times the fraction W/Zwhere W is the number of nucleotides scored as identical matches bythe sequence alignment program ALIGN-2 in that program's alignmentof C and D, and where Z is the total number of nucleotides in D. Itwill be appreciated that where the length of nucleic acid sequenceC is not equal to the length of nucleic acid sequence D, the %nucleic acid sequence identity of C to D will not equal the %nucleic acid sequence identity of D to C. As examples of % nucleicacid sequence identity calculations, Tables 4 and 5, demonstratehow to calculate the % nucleic acid sequence identity of thenucleic acid sequence designated "Comparison DNA" to the nucleicacid sequence designated "PRO-DNA", wherein "PRO-DNA" represents ahypothetical PRO-encoding nucleic acid sequence of interest,"Comparison DNA" represents the nucleotide sequence of a nucleicacid molecule against which the "PRO-DNA" nucleic acid molecule ofinterest is being compared, and "N", "L" and "V" each representdifferent hypothetical nucleotides.

Unless specifically stated otherwise, all % nucleic acid sequenceidentity values used herein are obtained as described in theimmediately preceding paragraph using the ALIGN-2 computer program.However, % nucleic acid sequence identity values may also beobtained as described below by using the WU-BLAST-2 computerprogram (Altschul et al., Methods in Enzymology 266:460-480(1996)). Most of the WU-BLAST-2 search parameters are set to thedefault values. Those not set to default values, i.e., theadjustable parameters, are set with the following values: overlapspan=1, overlap fraction=0.125, word threshold (T)=11, and scoringmatrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleic acidsequence identity value is determined by dividing (a) the number ofmatching identical nucleotides between the nucleic acid sequence ofthe PRO polypeptide-encoding nucleic acid molecule of interesthaving a sequence derived from the native sequence PROpolypeptide-encoding nucleic acid and the comparison nucleic acidmolecule of interest (i.e., the sequence against which the PROpolypeptide-encoding nucleic acid molecule of interest is beingcompared which may be a variant PRO polynucleotide) as determinedby WU-BLAST-2 by (b) the total number of nucleotides of the PROpolypeptide-encoding nucleic acid molecule of interest. Forexample, in the statement "an isolated nucleic acid moleculecomprising a nucleic acid sequence A which has or having at least80% nucleic acid sequence identity to the nucleic acid sequence B",the nucleic acid sequence A is the comparison nucleic acid moleculeof interest and the nucleic acid sequence B is the nucleic acidsequence of the PRO polypeptide-encoding nucleic acid molecule ofinterest.

Percent nucleic acid sequence identity may also be determined usingthe sequence comparison program NCBI-BLAST2 (Altschul et al.,Nucleic Acids Res. 25:3389-3402 (1997)). NCBI-BLAST2 uses severalsearch parameters, wherein all of those search parameters are setto default values including, for example, unmask=yes, strand=all,expected occurrences=10, minimum low complexity length=15/5,multi-pass e-value=0.01, constant for multi-pass=25, dropoff forfinal gapped alignment=25 and scoring matrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for sequencecomparisons, the % nucleic acid sequence identity of a givennucleic acid sequence C to, with, or against a given nucleic acidsequence D (which can alternatively be phrased as a given nucleicacid sequence C that has or comprises a certain % nucleic acidsequence identity to, with, or against a given nucleic acidsequence D) is calculated as follows: 100 times the fraction W/Zwhere W is the number of nucleotides scored as identical matches bythe sequence alignment program NCBI-BLAST2 in that program'salignment of C and D, and where Z is the total number ofnucleotides in D. It will be appreciated that where the length ofnucleic acid sequence C is not equal to the length of nucleic acidsequence D, the % nucleic acid sequence identity of C to D will notequal the % nucleic acid sequence identity of D to C.

In other embodiments, PRO variant polynucleotides are nucleic acidmolecules that encode an active PRO polypeptide and which arecapable of hybridizing, preferably under stringent hybridizationand wash conditions, to nucleotide sequences encoding a full-lengthPRO polypeptide as disclosed herein. PRO variant polypeptides maybe those that are encoded by a PRO variant polynucleotide.

The term "positives", in the context of sequence comparisonperformed as described above, includes residues in the sequencescompared that are not identical but have similar properties (e.g.as a result of conservative substitutions, see Table 6 below). Forpurposes herein, the % value of positives is determined by dividing(a) the number of amino acid residues scoring a positive valuebetween the PRO polypeptide amino acid sequence of interest havinga sequence derived from the native PRO polypeptide sequence and thecomparison amino acid sequence of interest (i.e., the amino acidsequence against which the PRO polypeptide sequence is beingcompared) as determined in the BLOSUM62 matrix of WU-BLAST-2 by (b)the total number of amino acid residues of the PRO polypeptide ofinterest.

Unless specifically stated otherwise, the % value of positives iscalculated as described in the immediately preceding paragraph.However, in the context of the amino acid sequence identitycomparisons performed as described for ALIGN-2 and NCBI-BLAST-2above, includes amino acid residues in the sequences compared thatare not only identical, but also those that have similarproperties. Amino acid residues that score a positive value to anamino acid residue of interest are those that are either identicalto the amino acid residue of interest or are a preferredsubstitution (as defined in Table 6 below) of the amino acidresidue of interest.

For amino acid sequence comparisons using ALIGN-2 or NCBI-BLAST2,the % value of positives of a given amino acid sequence A to, with,or against a given amino acid sequence B (which can alternativelybe phrased as a given amino acid sequence A that has or comprises acertain % positives to, with, or against a given amino acidsequence B) is calculated as follows: 100 times the fraction X/Ywhere X is the number of amino acid residues scoring a positivevalue as defined above by the sequence alignment program ALIGN-2 orNCBI-BLAST2 in that program's alignment of A and B, and where Y isthe total number of amino acid residues in B. It will beappreciated that where the length of amino acid sequence A is notequal to the length of amino acid sequence B, the % positives of Ato B will not equal the % positives of B to A.

"Isolated," when used to describe the various polypeptidesdisclosed herein, means polypeptide that has been identified andseparated and/or recovered from a component of its naturalenvironment. Contaminant components of its natural environment arematerials that would typically interfere with diagnostic ortherapeutic uses for the polypeptide, and may include enzymes,hormones, and other proteinaceous or non-proteinaceous solutes. Inpreferred embodiments, the polypeptide will be purified (1) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator,or (2) to homogeneity by SDS-PAGE under non-reducing or reducingconditions using Coomassie blue or, preferably, silver stain.Isolated polypeptide includes polypeptide in situ withinrecombinant cells, since at least one component of the PROpolypeptide natural environment will not be present. Ordinarily,however, isolated polypeptide will be prepared by at least onepurification step.

An "isolated" PRO polypeptide-encoding nucleic acid or otherpolypeptide-encoding nucleic acid is a nucleic acid molecule thatis identified and separated from at least one contaminant nucleicacid molecule with which it is ordinarily associated in the naturalsource of the polypeptide-encoding nucleic acid. An isolatedpolypeptide-encoding nucleic acid molecule is other than in theform or setting in which it is found in nature. Isolatedpolypeptide-encoding nucleic acid molecules therefore aredistinguished from the specific polypeptide-encoding nucleic acidmolecule as it exists in natural cells. However, an isolatedpolypeptide-encoding nucleic acid molecule includespolypeptide-encoding nucleic acid molecules contained in cells thatordinarily express the polypeptide where, for example, the nucleicacid molecule is in a chromosomal location different from that ofnatural cells.

The term "control sequences" refers to DNA sequences necessary forthe expression of an operably linked coding sequence in aparticular host organism. The control sequences that are suitablefor prokaryotes, for example, include a promoter, optionally anoperator sequence, and a ribosome binding site. Eukaryotic cellsare known to utilize promoters, polyadenylation signals, andenhancers.

Nucleic acid is "operably linked" when it is placed into afunctional relationship with another nucleic acid sequence. Forexample, DNA for a presequence or secretory leader is operablylinked to DNA for a polypeptide if it is expressed as a preproteinthat participates in the secretion of the polypeptide; a promoteror enhancer is operably linked to a coding sequence if it affectsthe transcription of the sequence; or a ribosome binding site isoperably linked to a coding sequence if it is positioned so as tofacilitate translation. Generally, "operably linked" means that theDNA sequences being linked are contiguous, and, in the case of asecretory leader, contiguous and in reading phase. However,enhancers do not have to be contiguous. Linking is accomplished byligation at convenient restriction sites. If such sites do notexist, the synthetic oligonucleotide adaptors or linkers are usedin accordance with conventional practice.

The term "antibody" is used in the broadest sense and specificallycovers, for example, single anti-PRO monoclonal antibodies(including agonist, antagonist, and neutralizing antibodies),anti-PRO antibody compositions with polyepitopic specificity,single chain anti-PRO antibodies, and fragments of anti-PROantibodies (see below). The term "monoclonal antibody" as usedherein refers to an antibody obtained from a population ofsubstantially homogeneous antibodies, i.e., the individualantibodies comprising the population are identical except forpossible naturally-occurring mutations that may be present in minoramounts.

"Stringency" of hybridization reactions is readily determinable byone of ordinary skill in the art, and generally is an empiricalcalculation dependent upon probe length, washing temperature, andsalt concentration. In general, longer probes require highertemperatures for proper annealing, while shorter probes need lowertemperatures. Hybridization generally depends on the ability ofdenatured DNA to reanneal when complementary strands are present inan environment below their melting temperature. The higher thedegree of desired homology between the probe and hybridizablesequence, the higher the relative temperature which can be used. Asa result, it follows that higher relative temperatures would tendto make the reaction conditions more stringent, while lowertemperatures less so. For additional details and explanation ofstringency of hybridization reactions, see Ausubel et al., CurrentProtocols in Molecular Biology, Wiley Interscience Publishers,(1995).

"Stringent conditions" or "high stringency conditions", as definedherein, may be identified by those that: (1) employ low ionicstrength and high temperature for washing, for example 0.015 Msodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfateat 50.degree. C.; (2) employ during hybridization a denaturingagent, such as formamide, for example, 50% (v/v) formamide with0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50mM sodiumphosphate buffer at pH 6.5 with 750 mM sodium chloride, 75mM sodium citrate at 42.degree. C.; or (3) employ 50% formamide,5.times. SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodiumphosphate (pH 6.8), 0.1% sodium pyrophosphate, 5.times. Denhardt'ssolution, sonicated salmon sperm DNA (50 .mu.g/ml), 0.1% SDS, and10% dextran sulfate at 42.degree. C., with washes at 42.degree. C.in 0.2.times. SSC (sodium chloride/sodium citrate) and 50%formamide at 55.degree. C., followed by a high-stringency washconsisting of 0.1.times. SSC containing EDTA at 55.degree. C.

"Moderately stringent conditions" may be identified as described bySambrook et al., Molecular Cloning: A Laboratory Manual, New York:Cold Spring Harbor Press, 1989, and include the use of washingsolution and hybridization conditions (e.g., temperature, ionicstrength and %SDS) less stringent that those described above. Anexample of moderately stringent conditions is overnight incubationat 37.degree. C. in a solution comprising: 20% formamide, 5.times.SSC (150 mM NaCl, 15 mM trisodiumcitrate), 50 mM sodiumphosphate(pH 7.6), 5.times. Denhardt's solution, 10% dextran sulfate, and 20mg/ml denatured sheared salmon sperm DNA, followed by washing thefilters in 1.times. SSC at about 37-50.degree. C. The skilledartisan will recognize how to adjust the temperature, ionicstrength, etc. as necessary to accommodate factors such as probelength and the like.

The term "epitope tagged" when used herein refers to a chimericpolypeptide comprising a PRO polypeptide fused to a "tagpolypeptide". The tag polypeptide has enough residues to provide anepitope against which an antibody can be made, yet is short enoughsuch that it does not interfere with activity of the polypeptide towhich it is fused. The tag polypeptide preferably also is fairlyunique so that the antibody does not substantially cross-react withother epitopes. Suitable tag polypeptides generally have at leastsix amino acid residues and usually between about 8 and 50 aminoacid residues (preferably, between about 10 and 20 amino acidresidues).

As used herein, the term "immunoadhesin" designates antibody-likemolecules which combine the binding specificity of a heterologousprotein (an "adhesin") with the effector functions ofimmunoglobulin constant domains. Structurally, the immunoadhesinscomprise a fusion of an amino acid sequence with the desiredbinding specificity which is other than the antigen recognition andbinding site of an antibody (i.e., is "heterologous"), and animmunoglobulin constant domain sequence. The adhesin part of animmunoadhesin molecule typically is a contiguous amino acidsequence comprising at least the binding site of a receptor or aligand. The immunoglobulin constant domain sequence in theimmunoadhesin may be obtained from any immunoglobulin, such asIgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 andIgA-2), IgE, IgD or IgM.

"Active" or "activity" for the purposes herein refers to form(s) ofa PRO polypeptide which retain a biological and/or an immunologicalactivity of native or naturally-occurring PRO, wherein "biological"activity refers to a biological function (either inhibitory orstimulatory) caused by a native or naturally-occurring PRO otherthan the ability to induce the production of an antibody against anantigenic epitope possessed by a native or naturally-occurring PROand an "immunological" activity refers to the ability to induce theproduction of an antibody against an antigenic epitope possessed bya native or naturally-occurring PRO.

The term "antagonist" is used in the broadest sense, and includesany molecule that partially or fully blocks, inhibits, orneutralizes a biological activity of a native PRO polypeptidedisclosed herein. In a similar manner, the term "agonist" is usedin the broadest sense and includes any molecule that mimics abiological activity of a native PRO polypeptide disclosed herein.Suitable agonist or antagonist molecules specifically includeagonist or antagonist antibodies or antibody fragments, fragmentsor amino acid sequence variants of native PRO polypeptides,peptides, antisense oligonucleotides, small organic molecules, etc.Methods for identifying agonists or antagonists of a PROpolypeptide may comprise contacting a PRO polypeptide with acandidate agonist or antagonist molecule and measuring a detectablechange in one or more biological activities normally associatedwith the PRO polypeptide.

"Treatment" refers to both therapeutic treatment and prophylacticor preventative measures, wherein the object is to prevent or slowdown (lessen) the targeted pathologic condition or disorder. Thosein need of treatment include those already with the disorder aswell as those prone to have the disorder or those in whom thedisorder is to be prevented.

"Chronic" administration refers to administration of the agent(s)in a continuous mode as opposed to an acute mode, so as to maintainthe initial therapeutic effect (activity) for an extended period oftime. "Intermittent" administration is treatment that is notconsecutively done without interruption, but rather is cyclic innature.

"Mammal" for purposes of treatment refers to any animal classifiedas a mammal, including humans, domestic and farm animals, and zoo,sports, or pet animals, such as dogs, cats, cattle, horses, sheep,pigs, goats, rabbits, etc. Preferably, the mammal is human.

Administration "in combination with" one or more furthertherapeutic agents includes simultaneous (concurrent) andconsecutive administration in any order.

"Carriers" as used herein include pharmaceutically acceptablecarriers, excipients, or stabilizers which are nontoxic to the cellor mammal being exposed thereto at the dosages and concentrationsemployed. Often the physiologically acceptable carrier is anaqueous pH buffered solution. Examples of physiologicallyacceptable carriers include buffers such as phosphate, citrate, andother organic acids; antioxidants including ascorbic acid; lowmolecular weight (less than about 10 residues) polypeptide;proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids suchas glycine, glutamine, asparagine, arginine or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugaralcohols such as mannitol or sorbitol; salt-forming counterionssuch as sodium; and/or nonionic surfactants such as TWEEN.TM.,polyethylene glycol (PEG), and PLURONICS.TM..

"Antibody fragments" comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab',F(ab').sub.2, and Fv fragments; diabodies; linear antibodies(Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chainantibody molecules; and multispecific antibodies formed fromantibody fragments.

Papain digestion of antibodies produces two identicalantigen-binding fragments, called "Fab" fragments, each with asingle antigen-binding site, and a residual "Fc" fragment, adesignation reflecting the ability to crystallize readily. Pepsintreatment yields an F(ab').sub.2 fragment that has twoantigen-combining sites and is still capable of cross-linkingantigen.

"Fv" is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This region consists of adimer of one heavy- and one light-chain variable domain in tight,non-covalent association. It is in this configuration that thethree CDRs of each variable domain interact to define anantigen-binding site on the surface of the V.sub.H-V.sub.L dimer.Collectively, the six CDRs confer antigen-binding specificity tothe antibody. However, even a single variable domain (or half of anFv comprising only three CDRs specific for an antigen) has theability to recognize and bind antigen, although at a lower affinitythan the entire binding site.

The Fab fragment also contains the constant domain of the lightchain and the first constant domain (CH1) of the heavy chain. Fabfragments differ from Fab' fragments by the addition of a fewresidues at the carboxy terminus of the heavy chain CH1 domainincluding one or more cysteines from the antibody hinge region.Fab'-SH is the designation herein for Fab' in which the cysteineresidue(s) of the constant domains bear a free thiol group.F(ab').sub.2 antibody fragments originally were produced as pairsof Fab' fragments which have hinge cysteines between them. Otherchemical couplings of antibody fragments are also known.

The "light chains" of antibodies (immunoglobulins) from anyvertebrate species can be assigned to one of two clearly distincttypes, called kappa and lambda, based on the amino acid sequencesof their constant domains.

Depending on the amino acid sequence of the constant domain oftheir heavy chains, immunoglobulins can be assigned to differentclasses. There are five major classes of immunoglobulins: IgA, IgD,IgE, IgG, and IgM, and several of these may be further divided intosubclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, andIgA2.

"Single-chain Fv" or "sFv" antibody fragments comprise the V.sub.Hand V.sub.L domains of antibody, wherein these domains are presentin a single polypeptide chain. Preferably, the Fv polypeptidefurther comprises a polypeptide linker between the V.sub.H andV.sub.L domains which enables the sFv to form the desired structurefor antigen binding. For a review of sFv, see Pluckthun in ThePharmacology of Monoclonal Antibodies, vol. 113, Rosenburg andMoore eds., Springer-Verlag, New York, pp. 269-315 (1994).

The term "diabodies" refers to small antibody fragments with twoantigen-binding sites, which fragments comprise a heavy-chainvariable domain (V.sub.H) connected to a light-chain variabledomain (V.sub.L) in the same polypeptide chain (V.sub.H-V.sub.L).By using a linker that is too short to allow pairing between thetwo domains on the same chain, the domains are forced to pair withthe complementary domains of another chain and create twoantigen-binding sites. Diabodies are described more fully in, forexample, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl.Acad. Sci. USA, 90:6444-6448 (1993).

An "isolated" antibody is one which has been identified andseparated and/or recovered from a component of its naturalenvironment. Contaninant components of its natural environment arematerials which would interfere with diagnostic or therapeutic usesfor the antibody, and may include enzymes, hormones, and otherproteinaceous or nonproteinaceous solutes. In preferredembodiments, the antibody will be purified (1) to greater than 95%by weight of antibody as determined by the Lowry method, and mostpreferably more than 99% by weight, (2) to a degree sufficient toobtain at least 15 residues of N-terminal or internal amino acidsequence by use of a spinning cup sequenator, or (3) to homogeneityby SDS-PAGE under reducing or nonreducing conditions usingCoomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since atleast one component of the antibody's natural environment will notbe present. Ordinarily, however, isolated antibody will be preparedby at least one purification step.

The word "label" when used herein refers to a detectable compoundor composition which is conjugated directly or indirectly to theantibody so as to generate a "labeled" antibody. The label may bedetectable by itself (e.g. radioisotope labels or fluorescentlabels) or, in the case of an enzymatic label, may catalyzechemical alteration of a substrate compound or composition which isdetectable.

By "solid phase" is meant a non-aqueous matrix to which theantibody of the present invention can adhere. Examples of solidphases encompassed herein include those formed partially orentirely of glass (e.g., controlled pore glass), polysaccharides(e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcoholand silicones. In certain embodiments, depending on the context,the solid phase can comprise the well of an assay plate; in othersit is a purification column (e.g., an affinity chromatographycolumn). This term also includes a discontinuous solid phase ofdiscrete particles, such as those described in U.S. Pat. No.4,275,149.

A "liposome" is a small vesicle composed of various types oflipids, phospholipids and/or surfactant which is useful fordelivery of a drug (such as a PRO polypeptide or antibody thereto)to a mammal. The components of the liposome are commonly arrangedin a bilayer formation, similar to the lipid arrangement ofbiological membranes.

A "small molecule" is defined herein to have a molecular weightbelow about 500 Daltons.

"PRO317-associated disorder" refers to a pathological condition ordisease wherein PRO317 is over- or underexpressed. Such disordersinclude diseases of the female genital tract or of the endometriumof a mammal, including hyperplasia, endometritis, endometriosis,wherein the patient is at risk for infertility due to endometrialfactor, endometrioma, and endometrial cancer, especially thosediseases involving abnormal bleeding such as a gynecologicaldisease. They also include diseases involving angiogenesis, whereinthe angiogenesis results in a pathological condition, such ascancer involving solid tumors (the therapy for the disorder wouldresult in decreased vascularization and a decline in growth andmetastasis of a variety of tumors). Alternatively, the angiogenesismay be beneficial, such as for ischemia, especially coronaryischemia. Hence, these disorders include those found in patientswhose hearts are functioning but who have a blocked blood supplydue to atherosclerotic coronary artery disease, and those with afunctioning but underperfused heart, including patients withcoronary arterial disease who are not optimal candidates forangioplasty and coronary artery by-pass surgery. The disorders alsoinclude diseases involving the kidney or originating from thekidney tissue, such as polycystic kidney disease and chronic andacute renal failure.

TABLE-US-00001 TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 aminoacids) Comparison XXXXXYYYYYYY (Length = 12 amino acids) Protein %amino acid sequence identity = (the number of identically matchingamino acid residues between the two polypeptide sequences asdetermined by ALIGN-2) divided by (the total number of amino acidresidues of the PRO polypeptide) = 5 divided by 15 = 33.3%

TABLE-US-00002 TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids)Comparison XXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein %amino acid sequence identity = (the number of identically matchingamino acid residues between the two polypeptide sequences asdetermined by ALIGN-2) divided by (the total number of amino acidresidues of the PRO polypeptide) = 5 divided by 10 = 50%

TABLE-US-00003 TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14nucleotides) Comparison NNNNNNLLLLLLLLLL (Length = 16 nucleotides)DNA % nucleic acid sequence identity = (the number of identicallymatching nucleotides between the two nucleic acid sequences asdetermined by ALIGN-2) divided by (the total number of nucleotidesof the PRO-DNA nucleic acid sequence) = 6 divided by 14 = 42.9%

TABLE-US-00004 TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12nucleotides) Comparison NNNNLLLVV (Length = 9 nucleotides) DNA %nucleic acid sequence identity = (the number of identicallymatching nucleotides between the two nucleic acid sequences asdetermined by ALIGN-2) divided by (the total number of nucleotidesof the PRO-DNA nucleic acid sequence) = 4 divided by 12 = 33.3%

II. Compositions and Methods of the Invention

A. Full-length PRO Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO polypeptides. In particular, cDNAsencoding various PRO polypeptides have been identified andisolated, as disclosed in further detail in the Examples below. Itis noted that proteins produced in separate expression rounds maybe given different PRO numbers but the UNQ number is unique for anygiven DNA and the encoded protein, and will not be changed.However, for sake of simplicity, in the present specification theprotein encoded by the full length native nucleic acid moleculesdisclosed herein as well as all further native homologues andvariants included in the foregoing definition of PRO, will bereferred to as "PRO/number", regardless of their origin or mode ofpreparation.

As disclosed in the Examples below, various cDNA clones have beendeposited with the ATCC. The actual nucleotide sequences of thoseclones can readily be determined by the skilled artisan bysequencing of the deposited clone using routine methods in the art.The predicted amino acid sequence can be determined from thenucleotide sequence using routine skill. For the PRO polypeptidesand encoding nucleic acids described herein, Applicants haveidentified what is believed to be the reading frame bestidentifiable with the sequence information available at thetime.

1. Full-length PRO211 and PRO217 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO211 and PRO217. In particular, Applicantshave identified and isolated cDNA encoding PRO211 and PRO217polypeptides, as disclosed in further detail in the Examples below.Using BLAST (FastA format) sequence alignment computer programs,Applicants found that cDNA sequences encoding full-length nativesequence PRO211 and PRO217 have homologies to known proteins havingEGF-like domains. Specifically, the cDNA sequence DNA32292-1131(FIG. 1, SEQ ID NO:1) has certain identify and a Blast score of 209with PAC6_RAT and certain identify and a Blast score of 206 withFibulin-1, isoform c precursor. The cDNA sequence DNA33094-1131(FIG. 3, SEQ ID NO:3) has 36% identity and a Blast score of 336with eastern newt tenascin, and 37% identity and a Blast score of331 with human tenascin-X precursor. Accordingly, it is presentlybelieved that PRO211 and PRO217 polypeptides disclosed in thepresent application are newly identified members of the EGF-likefamily and possesses properties typical of the EGF-like proteinfamily.

2. Full-length PRO230 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO230. In particular, Applicants haveidentified and isolated cDNA encoding a PRO230 polypeptide, asdisclosed in further detail in the Examples below. Using knownprograms such as BLAST and FastA sequence alignment computerprograms, Applicants found that a cDNA sequence encodingfull-length native sequence PRO230 has 48% amino acid identity withthe rabbit tubulointerstitial nephritis antigen precursor.Accordingly, it is presently believed that PRO230 polypeptidedisclosed in the present application is a newly identified memberof the tubulointerstitial nephritis antigen family and possessesthe ability to be recognized by human autoantibodies in certainforms of tubulointerstitial nephritis.

3. Full-length PRO232 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO232. In particular, Applicants haveidentified and isolated cDNA encoding a PRO232 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that aportion of the full-length native sequence PRO232 (shown in FIG. 9and SEQ ID NO:18) has 35% sequence identity with a stem cellsurface antigen from Gallus gallus. Accordingly, it is presentlybelieved that the PRO232 polypeptide disclosed in the presentapplication may be a newly identified stem cell antigen.

4. Full-length PRO187 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO187. In particular, Applicants haveidentified and isolated cDNA encoding a PRO187 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that afull-length native sequence PRO187 (shown in FIG. 15) has 74% aminoacid sequence identity and BLAST score of 310 with variousandrogen-induced growth factors and FGF-8. Accordingly, it ispresently believed that PRO187 polypeptide disclosed in the presentapplication is a newly identified member of the FGF-8 proteinfamily and may possess identify activity or property typical of theFGF-8-like protein family.

5. Full-length PRO265 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO265. In particular, Applicants haveidentified and isolated cDNA encoding a PRO265 polypeptide, asdisclosed in further detail in the Examples below. Using programssuch as BLAST and FastA sequence alignment computer programs,Applicants found that various portions of the PRO265 polypeptidehave significant homology with the fibromodulin protein andfibromodulin precursor protein. Applicants have also found that theDNA encoding the PRO265 polypeptide has significant homology withplatelet glycoprotein V, a member of the leucine rich relatedprotein family involved in skin and wound repair. Accordingly, itis presently believed that PRO265 polypeptide disclosed in thepresent application is a newly identified member of the leucinerich repeat family and possesses protein protein bindingcapabilities, as well as be involved in skin and wound repair astypical of this family.

6. Full-length PRO219 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO219. In particular, Applicants haveidentified and isolated cDNA encoding a PRO219 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO219 polypeptide have significanthomology with the mouse and human matrilin-2 precursorpolypeptides. Accordingly, it is presently believed that PRO219polypeptide disclosed in the present application is related to thematrilin-2 precursor polypeptide.

7. Full-length PRO246 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO246. In particular, Applicants haveidentified and isolated cDNA encoding a PRO246 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that aportion of the PRO246 polypeptide has significant homology with thehuman cell surface protein HCAR. Accordingly, it is presentlybelieved that PRO246 polypeptide disclosed in the presentapplication may be a newly identified membrane-bound virus receptoror tumor cell-specific antigen.

8. Full-length PRO228 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO228. In particular, Applicants haveidentified and isolated cDNA encoding a PRO228 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO228 polypeptide have significanthomology with the EMR1 protein. Applicants have also found that theDNA encoding the PRO228 polypeptide has significant homology withlatrophilin, macrophage-restricted cell surface glycoprotein,B0457.1 and leucocyte antigen CD97 precursor. Accordingly, it ispresently believed that PRO228 polypeptide disclosed in the presentapplication is a newly identified member of the seven transmembranesuperfamily and possesses characteristics and functional propertiestypical of this family. In particular, it is believed that PRO228is a new member of the subgroup within this family to which CD97and EMR1 belong.

9. Full-length PRO533 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO533. In particular, Applicants haveidentified and isolated cDNA encoding a PRO533 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST-2and FastA sequence alignment computer programs, Applicants foundthat a full-length native sequence PRO533 (shown in FIG. 22 and SEQID NO:59) has a Blast score of 509 and 53% amino acid sequenceidentity with fibroblast growth factor (FGF). Accordingly, it ispresently believed that PRO533 disclosed in the present applicationis a newly identified member of the fibroblast growth factor familyand may possess activity typical of such polypeptides.

10. Full-length PRO245 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO245. In particular, Applicants haveidentified and isolated cDNA encoding a PRO245 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that aportion of the amino acid sequence of the PRO245 polypeptide has60% amino acid identity with the human c-myb protein. Accordingly,it is presently believed that the PRO245 polypeptide disclosed inthe present application may be a newly identified member of thetransmembrane protein tyrosine kinase family.

11. Full-length PRO220, PRO221 and PRO227 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO220, PRO221 and PRO227. In particular,Applicants have identified and isolated cDNAs encoding a PRO220,PRO221 and PRO227 polypeptide, respectively, as disclosed infurther detail in the Examples below. Using BLAST and FastAsequence alignment computer programs, PRO220 has amino acididentity with the amino acid sequence of a leucine rich proteinwherein the identity is 87%. PRO220 additionally has amino acididentity with the neuronal leucine rich protein wherein theidentity is 55%. The neuronal leucine rich protein is furtherdescribed in Taguchi, et al., Mol. Brain Res., 35:31-40 (1996).

PRO221 has amino acid identity with the SLIT protein precursor,wherein different portions of these two proteins have therespective percent identities of 39%, 38%, 34%, 31%, and 30%.

PRO227 has amino acid identity with the amino acid sequence ofplatelet glycoprotein V precursor. The same results were obtainedfor human glycoprotein V. Different portions of these two proteinsshow the following percent identities of 30%, 28%, 28%, 31%, 35%,39% and 27%.

Accordingly, it is presently believed that PRO220, PRO221 andPRO227 polypeptides disclosed in the present application are newlyidentified members of the leucine rich repeat protein superfamilyand that each possesses protein-protein binding capabilitiestypical of the leucine rich repeat protein superfamily. It is alsobelieved that they have capabilities similar to those of SLIT, theleucine rich repeat protein and human glycoprotein V.

12. Full-length PRO258 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO258. In particular, Applicants haveidentified and isolated cDNA encoding a PRO258 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO258 polypeptide have significanthomology with the CRTAM and poliovirus receptors. Accordingly, itis presently believed that PRO258 polypeptide disclosed in thepresent application is a newly identified member of the Igsuperfamily and possesses virus receptor capabilities or regulatesimmune function as typical of this family.

13. Full-length PRO266 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO266. In particular, Applicants haveidentified and isolated cDNA encoding a PRO266 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO266 polypeptide have significanthomology with the SLIT protein from Drosophilia. Accordingly, it ispresently believed that PRO266 polypeptide disclosed in the presentapplication is a newly identified member of the leucine rich repeatfamily and possesses ligand-ligand binding activity and neuronaldevelopment typical of this family. SLIT has been shown to beuseful in the study and treatment of Alzheimer's disease, supra,and thus, PRO266 may have involvement in the study and cure of thisdisease.

14. Full-length PRO269 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO269. In particular, Applicants haveidentified and isolated cDNA encoding a PRO269 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST,FastA and sequence alignment computer programs, Applicants foundthat the amino acid sequence encoded by nucleotides 314 to 1783 ofthe full-length native sequence PRO269 (shown in FIG. 35 and SEQ IDNO:95) has significant homology to human urinary thrombomodulin andvarious thrombomodulin analogues respectively, to which it wasaligned. Accordingly, it is presently believed that PRO269polypeptide disclosed in the present application is a newlyidentified member of the thrombomodulin family.

15. Full-length PRO287 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO287. In particular, Applicants haveidentified and isolated cDNA encoding a PRO287 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO287 polypeptide have significanthomology with the type 1 procollagen C-proteinase enhancer proteinprecursor and type 1 procollagen C-proteinase enhancer protein.Accordingly, it is presently believed that PRO287 polypeptidedisclosed in the present application is a newly identified memberof the C-proteinase enhancer protein family.

16. Full-length PRO214 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO214. In particular, Applicants haveidentified and isolated cDNA encoding a PRO214 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that afull-length native sequence PRO214 polypeptide (shown in FIG. 40and SEQ ID NO:109) has 49% amino acid sequence identity with HTprotein, a known member of the EGF-family. The comparison resultedin a BLAST score of 920, with 150 matching nucleotides.Accordingly, it is presently believed that the PRO214 polypeptidedisclosed in the present application is a newly identified memberof the family comprising EGF domains and may possess activities orproperties typical of the EGF-domain containing family.

17. Full-length PRO317 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO317. In particular, cDNA encoding aPRO317 polypeptide has been identified and isolated, as disclosedin further detail in the Examples below. Using BLAST.TM. andFastA.TM. sequence alignment computer programs, it was found that afull-length native-sequence PRO317 (shown in FIG. 42 and SEQ IDNO:114) has 92% amino acid sequence identity with EBAF-1. Further,it is closely aligned with many other members of theTGF-superfamily.

Accordingly, it is presently believed that PRO317 disclosed in thepresent application is a newly identified member of theTGF-superfamily and may possess properties that are therapeuticallyuseful in conditions of uterine bleeding, etc. Hence, PRO317 may beuseful in diagnosing or treating abnormal bleeding involved ingynecological diseases, for example, to avoid or lessen the needfor a hysterectomy. PRO317 may also be useful as an agent thataffects angiogenesis in general, so PRO317 may be useful inanti-tumor indications, or conversely, in treating coronaryischemic conditions.

Library sources reveal that ESTs used to obtain the consensus DNAfor generating PRO317 primers and probes were found in normaltissues (uterus, prostate, colon, and pancreas), in several tumors(colon, brain (twice), pancreas, and mullerian cell), and in aheart with ischemia. PRO317 has shown up in several tissues aswell, but it does look to have a greater concentration in uterus.Hence, PRO317 may have a broader use by the body than EBAF-1. It iscontemplated that, at least for some indications, PRO317 may haveopposite effects from EBAF-1.

18. Full-length PRO301 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO301. In particular, Applicants haveidentified and isolated cDNA encoding a PRO301 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that afull-length native sequence PRO301 (shown in FIG. 44 and SEQ IDNO:119) has a Blast score of 246 corresponding to 30% amino acidsequence identity with human A33 antigen precursor. Accordingly, itis presently believed that PRO301 disclosed in the presentapplication is a newly identified member of the A33 antigen proteinfamily and may be expressed in human neoplastic diseases such ascolorectal cancer.

19. Full-length PRO224 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO224. In particular, Applicants haveidentified and isolated cDNA encoding a PRO224 polypeptide, asdisclosed in further detail in the Examples below. Using knownprograms such as BLAST and FastA sequence alignment computerprograms, Applicants found that full-length native PRO224 (FIG. 46,SEQ ID NO:127) has amino acid identity with apolipoprotein Ereceptor 2906 from homo sapiens. The alignments of differentportions of these two polypeptides show amino acid identities of37%, 36%, 30%, 44%, 44% and 28% respectively. Full-length nativePRO224 (FIG. 46, SEQ ID NO:127) also has amino acid identity withvery low-density lipoprotein receptor precursor from gall. Thealignments of different portions of these two polypeptides showamino acid identities of 38%, 37%, 42%, 33%, and 37% respectively.Additionally, full-length native PRO224 (FIG. 46, SEQ ID NO:127)has amino acid identity with the chicken oocyte receptor P95 fromGallus gallus. The alignments of different portions of these twopolypeptides show amino acid identities of 38%, 37%, 42%, 33%, and37% respectively. Moreover, full-length native PRO224 (FIG. 46, SEQID NO:127) has amino acid identity with very low densitylipoprotein receptor short form precursor from humans. Thealignments of different portions of these two polypeptides showamino acid identities of 32%, 38%, 34%, 45%, and 31%, respectively.Accordingly, it is presently believed that PRO224 polypeptidedisclosed in the present application is a newly identified memberof the low density lipoprotein receptor family and possesses thestructural characteristics required to have the functional abilityto recognize and endocytose low density lipoproteins typical of thelow density lipoprotein receptor family. (The alignments describedabove used the following scoring parameters: T=7, S+65, S2=36,Matrix: BLOSUM62.)

20. Full-length PRO222 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO222. In particular, Applicants haveidentified and isolated cDNA encoding a PRO222 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that asequence encoding full-length native sequence PRO222 (shown in FIG.48 and SEQ ID NO:132) has 25-26% amino acid identity with mousecomplement factor h precursor, has 27-29% amino acid identity withcomplement receptor, has 25-47% amino acid identity with mousecomplement C3b receptor type 2 long form precursor, has 40% aminoacid identity with human hypothetical protein kiaa0247.Accordingly, it is presently believed that PRO222 polypeptidedisclosed in the present application is a newly identified memberof the complement receptor family and possesses activity typical ofthe complement receptor family.

21. Full-length PRO234 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO234. In particular, Applicants haveidentified and isolated cDNA encoding a PRO234 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST(FastA-format) sequence alignment computer programs, Applicantsfound that a cDNA sequence encoding full-length native sequencePRO234 has 31% identity and Blast score of 134 with E-selectinprecursor. Accordingly, it is presently believed that the PRO234polypeptides disclosed in the present application are newlyidentified members of the lectin/selectin family and possessactivity typical of the lectin/selectin family.

22. Full-length PRO231 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO231. In particular, Applicants haveidentified and isolated cDNA encoding a PRO231 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatthe full-length native sequence PRO231 polypeptide (shown in FIG.52 and SEQ ID NO:142) has 30% and 31% amino acid identity withhuman and rat prostatic acid phosphatase precursor proteins,respectively. Accordingly, it is presently believed that the PRO231polypeptide disclosed in the present application may be a newlyidentified member of the acid phosphatase protein family.

23. Full-length PRO229 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO229. In particular, Applicants haveidentified and isolated cDNA encoding a PRO229 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO229 polypeptide have significanthomology with antigen wc1.1, M130 antigen, T cell surfaceglycoprotein CD6 and CD6. It also is related to Sp-alpha.Accordingly, it is presently believed that PRO229 polypeptidedisclosed in the present application is a newly identified memberof the family containing scavenger receptor homology, a sequencemotif found in a number of proteins involved in immune function andthus possesses immune function and/or segments which resistdegradation, typical of this family.

24. Full-length PRO238 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO238. In particular, Applicants haveidentified and isolated cDNA encoding a PRO238 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO238 polypeptide have significanthomology with reductases, including oxidoreductase and fattyacyl-CoA reductase. Accordingly, it is presently believed thatPRO238 polypeptide disclosed in the present application is a newlyidentified member of the reductase family and possesses reducingactivity typical of the reductase family.

25. Full-length PRO233 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO233. In particular, Applicants haveidentified and isolated cDNA encoding a PRO233 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO233 polypeptide have significanthomology with the reductase protein. Applicants have also foundthat the DNA encoding the PRO233 polypeptide has significanthomology with proteins from Caenorhabditis elegans. Accordingly, itis presently believed that PRO233 polypeptide disclosed in thepresent application is a newly identified member of the reductasefamily and possesses the ability to effect the redox state of thecell typical of the reductase family.

26. Full-length PRO223 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO223. In particular, Applicants haveidentified and isolated cDNA encoding a PRO223 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatthe PRO223 polypeptide has significant homology with various serinecarboxypeptidase polypeptides. Accordingly, it is presentlybelieved that PRO223 polypeptide disclosed in the presentapplication is a newly identified serine carboxypeptidase.

27. Full-length PRO235 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO235. In particular, Applicants haveidentified and isolated cDNA encoding a PRO235 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO235 polypeptide have significanthomology with the various plexin proteins. Accordingly, it ispresently believed that PRO235 polypeptide disclosed in the presentapplication is a newly identified member of the plexin family andpossesses cell adhesion properties typical of the plexinfamily.

28. Full-length PRO236 and PRO262 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO236 and PRO262. In particular, Applicantshave identified and isolated cDNA encoding PRO236 and PRO262polypeptides, as disclosed in further detail in the Examples below.Using BLAST and FastA sequence alignment computer programs,Applicants found that various portions of the PRO236 and PRO262polypeptides have significant homology with various.beta.-galactosidase and .beta.-galactosidase precursorpolypeptides. Accordingly, it is presently believed that the PRO236and PRO262 polypeptides disclosed in the present application arenewly identified .beta.-galactosidase homologs.

29. Full-length PRO239 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO239. In particular, Applicants haveidentified and isolated cDNA encoding a PRO239 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO239 polypeptide have significanthomology with densin proteins. Accordingly, it is presentlybelieved that PRO239 polypeptide disclosed in the presentapplication is a newly identified member of the densin family andpossesses cell adhesion and the ability to effect synapticprocesses as is typical of the densin family.

30. Full-length PRO257 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO257. In particular, Applicants haveidentified and isolated cDNA encoding a PRO257 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO257 polypeptide have significanthomology with the ebnerin precursor and ebnerin protein.Accordingly, it is presently believed that PRO257 polypeptidedisclosed in the present application is a newly identified proteinmember which is related to the ebnerin protein.

31. Full-length PRO260 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO260. In particular, Applicants haveidentified and isolated cDNA encoding a PRO260 polypeptide, asdisclosed in further detail in the Examples below. Using programssuch as BLAST and FastA sequence alignment computer programs,Applicants found that various portions of the PRO260 polypeptidehave significant homology with the alpha-1-fucosidase precursor.Accordingly, it is presently believed that PRO260 polypeptidedisclosed in the present application is a newly identified memberof the fucosidase family and possesses enzymatic activity relatedto fucose residues typical of the fucosidase family.

32. Full-length PRO263 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO263. In particular, Applicants haveidentified and isolated cDNA encoding a PRO263 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO263 polypeptide have significanthomology with the CD44 antigen and related proteins. Accordingly,it is presently believed that PRO263 polypeptide disclosed in thepresent application is a newly identified member of the CD44antigen family and possesses at least one of the propertiesassociated with these antigens, i.e., cancer and HIV marker,cell-cell or cell-matrix interactions, regulating cell traffic,lymph node homing, transmission of growth signals, and presentationof chemokines and growth facors to traveling cells.

33. Full-length PRO270 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO270. In particular, Applicants haveidentified and isolated cDNA encoding a PRO270 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST,FastA and sequence alignment computer programs, Applicants foundthat that various portions of the PRO270 polypeptide havesignificant homology with various thioredoxin proteins.Accordingly, it is presently believed that PRO270 polypeptidedisclosed in the present application is a newly identified memberof the thioredoxin family and possesses the ability to effectreduction-oxidation (redox) state typical of the thioredoxinfamily.

34. Full-length PRO271 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO271. In particular, Applicants haveidentified and isolated cDNA encoding a PRO271 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatthe PRO271 polypeptide has significant homology with various linkproteins and precursors thereof. Accordingly, it is presentlybelieved that PRO271 polypeptide disclosed in the presentapplication is a newly identified link protein homolog.

35. Full-length PRO272 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO272. In particular, Applicants haveidentified and isolated cDNA encoding a PRO272 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO272 polypeptide have significanthomology with the human reticulocalbin protein and its precursors.Applicants have also found that the DNA encoding the PRO272polypeptide has significant homology with the mouse reticulocalbinprecursor protein. Accordingly, it is presently believed thatPRO272 polypeptide disclosed in the present application is a newlyidentified member of the reticulocalbin family and possesses theability to bind calcium typical of the reticulocalbin family.

36. Full-length PRO294 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO294. In particular, Applicants haveidentified and isolated cDNA encoding a PRO294 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO294 polypeptide have significanthomology with the various portions of a number of collagenproteins. Accordingly, it is presently believed that PRO294polypeptide disclosed in the present application is a newlyidentified member of the collagen family.

37. Full-length PRO295 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO295. In particular, Applicants haveidentified and isolated cDNA encoding a PRO295 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO295 polypeptide have significanthomology with integrin proteins. Accordingly, it is presentlybelieved that PRO295 polypeptide disclosed in the presentapplication is a newly identified member of the integrin family andpossesses cell adhesion typical of the integrin family.

38. Full-length PRO293 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO293. In particular, Applicants haveidentified and isolated cDNA encoding a PRO293 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatportions of the PRO293 polypeptide have significant homology withthe neuronal leucine rich repeat proteins 1 and 2, (NLRR-1 andNLRR-2), particularly NLRR-2. Accordingly, it is presently believedthat PRO293 polypeptide disclosed in the present application is anewly identified member of the neuronal leucine rich repeat proteinfamily and possesses ligand-ligand binding activity typical of theNRLL protein family.

39. Full-length PRO247 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO247. In particular, Applicants haveidentified and isolated cDNA encoding a PRO247 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO247 polypeptide have significanthomology with densin. Applicants have also found that the DNAencoding the PRO247 polypeptide has significant homology with anumber of other proteins, including KIAA0231. Accordingly, it ispresently believed that PRO247 polypeptide disclosed in the presentapplication is a newly identified member of the leucine rich repeatfamily and possesses ligand binding abilities typical of thisfamily.

40. Full-length PRO302, PRO303, PRO304, PRO307 and PRO343Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO302, PRO303, PRO304, PRO307 and PRO343.In particular, Applicants have identified and isolated cDNAencoding PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO302, PRO303, PRO304, PRO307 and PRO343polypeptides have significant homology with various proteaseproteins. Accordingly, it is presently believed that the PRO302,PRO303, PRO304, PRO307 and PRO343 polypeptides disclosed in thepresent application are newly identified protease proteins.

41. Full-length PRO328 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO328. In particular, Applicants haveidentified and isolated cDNA encoding a PRO328 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO328 polypeptide have significanthomology with the human glioblastoma protein ("GLIP"). Further,Applicants found that various portions of the PRO328 polypeptidehave significant homology with the cysteine rich secretory protein("CRISP") as identified by BLAST homology [ECCRISP3.sub.--1,S68683, and CRS3_HUMAN]. Accordingly, it is presently believed thatPRO328 polypeptide disclosed in the present application is a newlyidentified member of the GLIP or CRISP families and possessestranscriptional regulatory activity typical of the GLIP or CRISPfamilies.

42. Full-length PRO335, PRO331 and PRO326 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO335, PRO331 or PRO326. In particular,Applicants have identified and isolated cDNA encoding a PRO335,PRO331 or PRO326 polypeptide, as disclosed in further detail in theExamples below. Using BLAST and FastA sequence alignment computerprograms, Applicants found that various portions of the PRO335,PRO331 or PRO326 polypeptide have significant homology with LIG-1,ALS and in the case of PRO331, additionally, decorin. Accordingly,it is presently believed that the PRO335, PRO331 and PRO326polypeptides disclosed in the present application are newlyidentified members of the leucine rich repeat superfamily, andparticularly, are related to LIG-1 and possess the biologicalfunctions of this family as discussed and referenced herein.

43. Full-length PRO332 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO332. In particular, Applicants haveidentified and isolated cDNA encoding PRO332 polypeptides, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that afull-length native sequence PRO332 (shown in FIG. 108 and SEQ IDNO:310) has about 30-40% amino acid sequence identity with a seriesof known proteoglycan sequences, including, for example,fibromodulin and fibromodulin precursor sequences of variousspecies (FMOD_BOVIN, FMOD_CHICK, FMOD_RAT, FMOD_MOUSE, FMOD_HUMAN,P_R36773), osteomodulin sequences (AB000114.sub.--1,AB007848.sub.--1), decorin sequences (CFU83141.sub.--1,OCU03394.sub.--1, P R42266, P_R42267, P_R42260, P R89439), keratansulfate proteoglycans (BTU48360.sub.--1, AF022890.sub.--1), cornealproteoglycan (AF022256.sub.--1), and bone/cartilage proteoglycansand proteoglycane precursors (PGS1_BOVIN, PGS2_MOUSE, PGS2_HUMAN).Accordingly, it is presently believed that PRO332 disclosed in thepresent application is a new proteoglycan-type molecule, and mayplay a role in regulating extracellular matrix, cartilage, and/orbone function.

44. Full-length PRO334 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO334. In particular, Applicants haveidentified and isolated cDNA encoding a PRO334 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO334 polypeptide have significanthomology with fibulin and fibrillin. Accordingly, it is presentlybelieved that PRO334 polypeptide disclosed in the presentapplication is a newly identified member of the epidermal growthfactor family and possesses properties and activities typical ofthis family.

45. Full-length PRO346 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO346. In particular, Applicants haveidentified and isolated cDNA encoding a PRO346 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that afull-length native sequence PRO346 (shown in FIG. 112 and SEQ IDNO:320) has 28% amino acid sequence identity with carcinoembryonicantigen. Accordingly, it is presently believed that PRO346disclosed in the present application is a newly identified memberof the carcinoembryonic protein family and may be expressed inassociation with neoplastic tissue disorders.

46. Full-length PRO268 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO268. In particular, Applicants haveidentified and isolated cDNA encoding a PRO268 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatportions of the PRO268 polypeptide have significant homology withthe various protein disulfide isomerase proteins. Accordingly, itis presently believed that PRO268 polypeptide disclosed in thepresent application is a homolog of the protein disulfide isomerasep5 protein.

47. Full-length PRO330 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO330. In particular, Applicants haveidentified and isolated cDNA encoding a PRO330 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO330 polypeptide have significanthomology with the murine prolyl 4-hydroxylase alpha-II subunitprotein. Accordingly, it is presently believed that PRO330polypeptide disclosed in the present application is a novel prolyl4-hydroxylase subunit polypeptide.

48. Full-length PRO339 and PRO310 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in thepresent application as PRO339 and PRO310. In particular, Applicantshave identified and isolated cDNA encoding a PRO339 polypeptide, asdisclosed in further detail in the Examples below. Applicants havealso identified and isolated cDNA encoding a PRO310 polypeptide, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found thatvarious portions of the PRO339 and PRO310 polypeptides havesignificant homology with small secreted proteins from C. elegansand are distantly related to fringe. PRO339 also shows homology tocollagen-like polymers. Sequences which were used to identifyPRO310, designated herein as DNA40533 and DNA42267, also showhomology to proteins from C. elegans. Accordingly, it is presentlybelieved that the PRO339 and PRO310 polypeptides disclosed in thepresent application are newly identified member of the family ofproteins involved in development, and which may have regulatoryabilities similar to the capability of fringe to regulateserrate.

49. Full-length PRO244 Polypeptides

The present invention provides newly identified and isolatednucleotide sequences encoding C-type lectins referred to in thepresent application as PRO244. In particular, applicants haveidentified and isolated cDNA encoding PRO244 polypeptides, asdisclosed in further detail in the Examples below. Using BLAST andFastA sequence alignment computer programs, Applicants found that afull-length native sequence PRO244 (shown in FIG. 122 and SEQ IDNO:377) has 43% amino acid sequence identity with the hepaticlectin gallus gallus (LECH-CHICK), and 42% amino acid sequenceidentity with an HIV gp120 binding C-type lectin (A46274).Accordingly, it is presently believed that PRO244 disclosed in thepresent application is a newly identified member of the C-lectinsuperfamily and may play a role in immune function, apoptosis, orin the pathogenesis of atherosclerosis. In addition, PRO244 may beuseful in identifying tumor-associated epitopes.

B. PRO Polypeptide Variants

In addition to the full-length native sequence PRO polypeptidesdescribed herein, it is contemplated that PRO variants can beprepared. PRO variants can be prepared by introducing appropriatenucleotide changes into the PRO DNA, and/or by synthesis of thedesired PRO polypeptide. Those skilled in the art will appreciatethat amino acid changes may alter post-translational processes ofthe PRO, such as changing the number or position of glycosylationsites or altering the membrane anchoring characteristics.

Variations in the native full-length sequence PRO or in variousdomains of the PRO described herein, can be made, for example,using any of the techniques and guidelines for conservative andnon-conservative mutations set forth, for instance, in U.S. Pat.No. 5,364,934. Variations may be a substitution, deletion orinsertion of one or more codons encoding the PRO that results in achange in the amino acid sequence of the PRO as compared with thenative sequence PRO. Optionally the variation is by substitution ofat least one amino acid with any other amino acid in one or more ofthe domains of the PRO. Guidance in determining which amino acidresidue may be inserted, substituted or deleted without adverselyaffecting the desired activity may be found by comparing thesequence of the PRO with that of homologous known protein moleculesand minimizing the number of amino acid sequence changes made inregions of high homology. Amino acid substitutions can be theresult of replacing one amino acid with another amino acid havingsimilar structural and/or chemical properties, such as thereplacement of a leucine with a serine, i.e., conservative aminoacid replacements. Insertions or deletions may optionally be in therange of about 1 to 5 amino acids. The variation allowed may bedetermined by systematically making insertions, deletions orsubstitutions of amino acids in the sequence and testing theresulting variants for activity exhibited by the full-length ormature native sequence.

PRO polypeptide fragments are provided herein. Such fragments maybe truncated at the N-terminus or C-terminus, or may lack internalresidues, for example, when compared with a full length nativeprotein. Certain fragments lack amino acid residues that are notessential for a desired biological activity of the PROpolypeptide.

PRO fragments may be prepared by any of a number of conventionaltechniques. Desired peptide fragments may be chemicallysynthesized. An alternative approach involves generating PROfragments by enzymatic digestion, e.g., by treating the proteinwith an enzyme known to cleave proteins at sites defined byparticular amino acid residues, or by digesting the DNA withsuitable restriction enzymes and isolating the desired fragment.Yet another suitable technique involves isolating and amplifying aDNA fragment encoding a desired polypeptide fragment, by polymerasechain reaction (PCR). Oligonucleotides that define the desiredtermini of the DNA fragment are employed at the 5' and 3' primersin the PCR. Preferably, PRO polypeptide fragments share at leastone biological and/or immunological activity with the native PROpolypeptide disclosed herein.

In particular embodiments, conservative substitutions of interestare shown in Table 6 under the heading of preferred substitutions.If such substitutions result in a change in biological activity,then more substantial changes, denominated exemplary substitutionsin Table 6, or as further described below in reference to aminoacid classes, are introduced and the products screened.

TABLE-US-00005 TABLE 6 Original Exemplary Preferred ResidueSubstitutions Substitutions Ala (A) val; leu; ile val Arg (R) lys;gln; asn lys Asn (N) gln; his; lys; arg gln Asp (D) glu glu Cys (C)ser ser Gln (Q) asn asn Glu (E) asp asp Gly (G) pro; ala ala His(H) asn; gln; lys; arg arg Ile (I) leu; val; met; leu ala; phe;norleucine Leu (L) norleucine; ile; val; ile met; ala; phe Lys (K)arg; gln; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile;leu ala; tyr Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp(W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile; leu;met; phe; leu ala; norleucine

Substantial modifications in function or immunological identity ofthe PRO polypeptide are accomplished by selecting substitutionsthat differ significantly in their effect on maintaining (a) thestructure of the polypeptide backbone in the area of thesubstitution, for example, as a sheet or helical conformation, (b)the charge or hydrophobicity of the molecule at the target site, or(c) the bulk of the side chain. Naturally occurring residues aredivided into groups based on common side-chain properties: (1)hydrophobic: norleucine, met, ala, val, leu, ile; (2) neutralhydrophilic: cys, ser, thr; (3) acidic: asp, glu; (4) basic: asn,gln, his, lys, arg; (5) residues that influence chain orientation:gly, pro; and (6) aromatic: trp, tyr, phe.

Non-conservative substitutions will entail exchanging a member ofone of these classes for another class. Such substituted residuesalso may be introduced into the conservative substitution sites or,more preferably, into the remaining (non-conserved) sites.

The variations can be made using methods known in the art such asoligonucleotide-mediated (site-directed) mutagenesis, alaninescanning, and PCR mutagenesis. Site-directed mutagenesis [Carter etal., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. AcidsRes., 10:6487 (1987)], cassette mutagenesis [Wells et al., Gene,34:315 (1985)], restriction selection mutagenesis [Wells et al.,Philos. Trans. R. Soc. London SerA, 317:415 (1986)] or other knowntechniques can be performed on the cloned DNA to produce the PROvariant DNA.

Scanning amino acid analysis can also be employed to identify oneor more amino acids along a contiguous sequence. Among thepreferred scanning amino acids are relatively small, neutral aminoacids. Such amino acids include alanine, glycine, serine, andcysteine. Alanine is typically a preferred scanning amino acidamong this group because it eliminates the side-chain beyond thebeta-carbon and is less likely to alter the main-chain conformationof the variant [Cunningham and Wells, Science, 244: 1081-1085(1989)]. Alanine is also typically preferred because it is the mostcommon amino acid. Further, it is frequently found in both buriedand exposed positions [Creighton, The Proteins, (W. H. Freeman& Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. If alaninesubstitution does not yield adequate amounts of variant, anisoteric amino acid can be used.

C. Modifications of PRO

Covalent modifications of PRO are included within the scope of thisinvention. One type of covalent modification includes reactingtargeted amino acid residues of a PRO polypeptide with an organicderivatizing agent that is capable of reacting with selected sidechains or the N- or C-terminal residues of the PRO. Derivatizationwith bifunctional agents is useful, for instance, for crosslinkingPRO to a water-insoluble support matrix or surface for use in themethod for purifying anti-PRO antibodies, and vice-versa. Commonlyused crosslinking agents include, e.g.,1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde,N-hydroxysuccinimide esters, for example, esters with4-azidosalicylic acid, homobifunctional imidoesters, includingdisuccinimidyl esters such as3,3'-dithiobis(succinimidylpropionate), bifunctional maleimidessuch as bis-N-maleimido-1,8-octane and agents such asmethyl-3-[(p-azidophenyl)dithio]propioimidate.

Other modifications include deamidation of glutaminyl andasparaginyl residues to the corresponding glutamyl and aspartylresidues, respectively, hydroxylation of proline and lysine,phosphorylation of hydroxyl groups of seryl or threonyl residues,methylation of the .alpha.-amino groups of lysine, arginine, andhistidine side chains [T. E. Creighton, Proteins: Structure andMolecular Properties, W. H. Freeman & Co., San Francisco, pp.79-86 (1983)], acetylation of the N-terminal amine, and amidationof any C-terminal carboxyl group.

Another type of covalent modification of the PRO polypeptideincluded within the scope of this invention comprises altering thenative glycosylation pattern of the polypeptide. "Altering thenative glycosylation pattern" is intended for purposes herein tomean deleting one or more carbohydrate moieties found in nativesequence PRO (either by removing the underlying glycosylation siteor by deleting the glycosylation by chemical and/or enzymaticmeans), and/or adding one or more glycosylation sites that are notpresent in the native sequence PRO. In addition, the phraseincludes qualitative changes in the glycosylation of the nativeproteins, involving a change in the nature and proportions of thevarious carbohydrate moieties present.

Addition of glycosylation sites to the PRO polypeptide may beaccomplished by altering the amino acid sequence. The alterationmay be made, for example, by the addition of, or substitution by,one or more serine or threonine residues to the native sequence PRO(for O-linked glycosylation sites). The PRO amino acid sequence mayoptionally be altered through changes at the DNA level,particularly by mutating the DNA encoding the PRO polypeptide atpreselected bases such that codons are generated that willtranslate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties onthe PRO polypeptide is by chemical or enzymatic coupling ofglycosides to the polypeptide. Such methods are described in theart, e.g., in WO 87/05330 published 11 Sep. 1987, and in Aplin andWriston, CRC Crit. Rev. Biochem., pp. 259-306 (1981).

Removal of carbohydrate moieties present on the PRO polypeptide maybe accomplished chemically or enzymatically or by mutationalsubstitution of codons encoding for amino acid residues that serveas targets for glycosylation. Chemical deglycosylation techniquesare known in the art and described, for instance, by Hakimuddin, etal., Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al.,Anal. Biochem., 118:131 (1981). Enzymatic cleavage of carbohydratemoieties on polypeptides can be achieved by the use of a variety ofendo- and exo-glycosidases as described by Thotakura et al., Meth.Enzymol., 138:350 (1987).

Another type of covalent modification of PRO comprises linking thePRO polypeptide to one of a variety of nonproteinaceous polymers,e.g., polyethylene glycol (PEG), polypropylene glycol, orpolyoxyalkylenes, in the manner set forth in U.S. Pat. Nos.4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or4,179,337.

The PRO of the present invention may also be modified in a way toform a chimeric molecule comprising PRO fused to another,heterologous polypeptide or amino acid sequence.

In one embodiment, such a chimeric molecule comprises a fusion ofthe PRO with a tag polypeptide which provides an epitope to whichan anti-tag antibody can selectively bind. The epitope tag isgenerally placed at the amino- or carboxyl-terminus of the PRO. Thepresence of such epitope-tagged forms of the PRO can be detectedusing an antibody against the tag polypeptide. Also, provision ofthe epitope tag enables the PRO to be readily purified by affinitypurification using an anti-tag antibody or another type of affinitymatrix that binds to the epitope tag. Various tag polypeptides andtheir respective antibodies are well known in the art. Examplesinclude poly-histidine (poly-his) or poly-histidine-glycine(poly-his-gly) tags; the flu HA tag polypeptide and its antibody12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165 (1988)]; thec-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodiesthereto [Evan et al., Molecular and Cellular Biology, 5:3610-3616(1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag andits antibody [Paborsky et al., Protein Engineering, 3(6):547-553(1990)]. Other tag polypeptides include the Flag-peptide [Hopp etal., BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide[Martin et al., Science 255:192-194 (1992)]; an .alpha.-tubulinepitope peptide [Skinner et al., J. Biol. Chem., 266:15163-15166(1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth etal., Proc. Natl. Acad. Sci. USA, 87:6393-6397 (1990)].

In an alternative embodiment, the chimeric molecule may comprise afusion of the PRO with an immunoglobulin or a particular region ofan immunoglobulin. For a bivalent form of the chimeric molecule(also referred to as an "immunoadhesin"), such a fusion could be tothe Fc region of an IgG molecule. The Ig fusions preferably includethe substitution of a soluble (transmembrane domain deleted orinactivated) form of a PRO polypeptide in place of at least onevariable region within an Ig molecule. In a particularly preferredembodiment, the immunoglobulin fusion includes the hinge, CH2 andCH3, or the hinge, CH1, CH2 and CH3 regions of an IgG1 molecule.For the production of immunoglobulin fusions see also U.S. Pat. No.5,428,130 issued Jun. 27, 1995.

D. Preparation of PRO

The description below relates primarily to production of PRO byculturing cells transformed or transfected with a vector containingPRO nucleic acid. It is, of course, contemplated that alternativemethods, which are well known in the art, may be employed toprepare PRO. For instance, the PRO sequence, or portions thereof,may be produced by direct peptide synthesis using solid-phasetechniques [see, e.g., Stewart et al., Solid-Phase PeptideSynthesis, W. H. Freeman Co., San Francisco, Calif. (1969);Merrifield, J. Am. Chem. Soc., 85:2149-2154 (1963)]. In vitroprotein synthesis may be performed using manual techniques or byautomation. Automated synthesis may be accomplished, for instance,using an Applied Biosystems Peptide Synthesizer (Foster City,Calif.) using manufacturer's instructions. Various portions of thePRO may be chemically synthesized separately and combined usingchemical or enzymatic methods to produce the full-length PRO.

1. Isolation of DNA Encoding PRO

DNA encoding PRO may be obtained from a cDNA library prepared fromtissue believed to possess the PRO mRNA and to express it at adetectable level. Accordingly, human PRO DNA can be convenientlyobtained from a cDNA library prepared from human tissue, such asdescribed in the Examples. The PRO-encoding gene may also beobtained from a genomic library or by known synthetic procedures(e.g., automated nucleic acid synthesis).

Libraries can be screened with probes (such as antibodies to thePRO or oligonucleotides of at least about 20-80 bases) designed toidentify the gene of interest or the protein encoded by it.Screening the cDNA or genomic library with the selected probe maybe conducted using standard procedures, such as described inSambrook et al., Molecular Cloning: A Laboratory Manual (New York:Cold Spring Harbor Laboratory Press, 1989). An alternative means toisolate the gene encoding PRO is to use PCR methodology [Sambrooket al., supra; Dieffenbach et al., PCR Primer: A Laboratory Manual(Cold Spring Harbor Laboratory Press, 1995)].

The Examples below describe techniques for screening a cDNAlibrary. The oligonucleotide sequences selected as probes should beof sufficient length and sufficiently unambiguous that falsepositives are minimized. The oligonucleotide is preferably labeledsuch that it can be detected upon hybridization to DNA in thelibrary being screened. Methods of labeling are well known in theart, and include the use of radiolabels like .sup.32P-labeled ATP,biotinylation or enzyme labeling. Hybridization conditions,including moderate stringency and high stringency, are provided inSambrook et al., supra.

Sequences identified in such library screening methods can becompared and aligned to other known sequences deposited andavailable in public databases such as GenBank or other privatesequence databases. Sequence identity (at either the amino acid ornucleotide level) within defined regions of the molecule or acrossthe full-length sequence can be determined using methods known inthe art and as described herein.

Nucleic acid having protein coding sequence may be obtained byscreening selected cDNA or genomic libraries using the deducedamino acid sequence disclosed herein for the first time, and, ifnecessary, using conventional primer extension procedures asdescribed in Sambrook et al., supra, to detect precursors andprocessing intermediates of mRNA that may not have beenreverse-transcribed into cDNA.

2. Selection and Transformation of Host Cells

Host cells are transfected or transformed with expression orcloning vectors described herein for PRO production and cultured inconventional nutrient media modified as appropriate for inducingpromoters, selecting transformants, or amplifying the genesencoding the desired sequences. The culture conditions, such asmedia, temperature, pH and the like, can be selected by the skilledartisan without undue experimentation. In general, principles,protocols, and practical techniques for maximizing the productivityof cell cultures can be found in Mammalian Cell Biotechnology: aPractical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrooket al., supra.

Methods of eukaryotic cell transfection and prokaryotic celltransformation are known to the ordinarily skilled artisan, forexample, CaCl.sub.2, CaPO.sub.4, liposome-mediated andelectroporation. Depending on the host cell used, transformation isperformed using standard techniques appropriate to such cells. Thecalcium treatment employing calcium chloride, as described inSambrook et al., supra, or electroporation is generally used forprokaryotes. Infection with Agrobacterium tumefaciens is used fortransformation of certain plant cells, as described by Shaw et al.,Gene, 23:315 (1983) and WO 89/05859 published 29 Jun. 1989. Formammalian cells without such cell walls, the calcium phosphateprecipitation method of Graham and van der Eb, Virology, 52:456-457(1978) can be employed. General aspects of mammalian cell hostsystem transfections have been described in U.S. Pat. No.4,399,216. Transformations into yeast are typically carried outaccording to the method of Van Solingen et al., J. Bact., 130:946(1977) and Hsiao et al., Proc. Natl. Acad. Sci. (USA), 76:3829(1979). However, other methods for introducing DNA into cells, suchas by nuclear microinjection, electroporation, bacterial protoplastfusion with intact cells, or polycations, e.g., polybrene,polyornithine, may also be used. For various techniques fortransforming mammalian cells, see Keown et al., Methods inEnzymology, 185:527-537 (1990) and Mansour et al., Nature,336:348-352 (1988).

Suitable host cells for cloning or expressing the DNA in thevectors herein include prokaryote, yeast, or higher eukaryotecells. Suitable prokaryotes include but are not limited toeubacteria, such as Gram-negative or Gram-positive organisms, forexample, Enterobacteriaceae such as E. coli. Various E. colistrains are publicly available, such as E. coli K12 strain MM294(ATCC 31,446); E. coli X1776 (ATCC 31,537); E. coli strain W3110(ATCC 27,325) and K5 772 (ATCC 53,635). Other suitable prokaryotichost cells include Enterobacteriaceae such as Escherichia, e.g., E.coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g.,Salmonella typhimurium, Serratia, e.g., Serratia marcescans, andShigella, as well as Bacilli such as B. subtilis and B.licheniformis (e.g., B. licheniformis 41P disclosed in DD 266,710published 12 Apr. 1989), Pseudomonas such as P. aeruginosa, andStreptomyces. These examples are illustrative rather than limiting.Strain W3110 is one particularly preferred host or parent hostbecause it is a common host strain for recombinant DNA productfermentations. Preferably, the host cell secretes minimal amountsof proteolytic enzymes. For example, strain W3110 may be modifiedto effect a genetic mutation in the genes encoding proteinsendogenous to the host, with examples of such hosts including E.coli W3110 strain 1A2, which has the complete genotype tonA; E.coli W3110 strain 9E4, which has the complete genotype tonA ptr3;E. coli W3110 strain 27C7 (ATCC 55,244), which has the completegenotype tonA ptr3phoA E15 (argF-lac)169 degP ompT kan.sup.r; E.coli W3110 strain 37D6, which has the complete genotype tonA ptr3phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan.sup.r; E. coli W3110strain 40B4, which is strain 37D6 with a non-kanamycin resistantdegP deletion mutation; and an E. coli strain having mutantperiplasmic protease disclosedin U.S. Pat. No. 4,946,783 issued 7Aug. 1990. Alternatively, in vitro methods of cloning, e.g., PCR orother nucleic acid polymerase reactions, are suitable.

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are suitable cloning or expression hosts forPRO-encoding vectors. Saccharomyces cerevisiae is a commonly usedlower eukaryotic host microorganism. Others includeSchizosaccharomyces pombe (Beach and Nurse, Nature, 290: 140[1981]; EP 139,383 published 2 May 1985); Kluyveromyces hosts (U.S.Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991))such as, e.g., K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt etal., J. Bacteriol., 737 [1983]), K. fragilis (ATCC 12,424), K.bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii(ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al.,Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus;yarrowia EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna etal., J. Basic Microbiol., 28:265-278 [1988]); Candida; Trichodernareesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl.Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such asSchwannionyces occidentalis (EP 394,538 published 31 Oct. 1990);and filamentous fungi such as, e.g., Neurospora, Penicillium,Tolypocladium (WO 91/00357 published 10 Jan. 1991), and Aspergillushosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res.Commun., 112:284-289 [1983]; Tilburn et al., Gene, 26:205-221[1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81: 1470-1474[1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479 [1985]).Methylotropic yeasts are suitable herein and include, but are notlimited to, yeast capable of growth on methanol selected from thegenera consisting of Hansenula, Candida, Kloeckera, Pichia,Saccharomyces, Torulopsis, and Rhodotorula. A list of specificspecies that are exemplary of this class of yeasts may be found inC. Anthony, The Biochemistry of Methylotrophs, 269 (1982).

Suitable host cells for the expression of glycosylated PRO arederived from multicellular organisms. Examples of invertebratecells include insect cells such as Drosophila S2 and SpodopteraSf9, as well as plant cells. Examples of useful mammalian host celllines include Chinese hamster ovary (CHO) and COS cells. Morespecific examples include monkey kidney CV1 line transformed bySV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or293 cells subcloned for growth in suspension culture, Graham etal., J. Gen Virol., 36:59 (1977)); Chinese hamster ovarycells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci. USA,77:4216(1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod.,23:243-251(1980)); human lung cells (W138, ATCC CCL 75); humanliver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562,ATCC CCL51). The selection of the appropriate host cell is deemedto be within the skill in the art.

3. Selection and Use of a Replicable Vector

The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may beinserted into a replicable vector for cloning (amplification of theDNA) or for expression. Various vectors are publicly available. Thevector may, for example, be in the form of a plasmid, cosmid, viralparticle, or phage. The appropriate nucleic acid sequence may beinserted into the vector by a variety of procedures. In general,DNA is inserted into an appropriate restriction endonucleasesite(s) using techniques known in the art. Vector componentsgenerally include, but are not limited to, one or more of a signalsequence, an origin of replication, one or more marker genes, anenhancer element, a promoter, and a transcription terminationsequence. Construction of suitable vectors containing one or moreof these components employs standard ligation techniques which areknown to the skilled artisan.

The PRO may be produced recombinantly not only directly, but alsoas a fusion polypeptide with a heterologous polypeptide, which maybe a signal sequence or other polypeptide having a specificcleavage site at the N-terminus of the mature protein orpolypeptide. In general, the signal sequence may be a component ofthe vector, or it may be a part of the PRO-encoding DNA that isinserted into the vector. The signal sequence may be a prokaryoticsignal sequence selected, for example, from the group of thealkaline phosphatase, penicillinase, lpp, or heat-stableenterotoxin II leaders. For yeast secretion the signal sequence maybe, e.g., the yeast invertase leader, alpha factor leader(including Saccharomyces and Kluyveromyces .alpha.-factor leaders,the latter described in U.S. Pat. No. 5,010,182), or acidphosphatase leader, the C. albicans glucoamylase leader (EP 362,179published 4 Apr. 1990), or the signal described in WO 90/13646published 15 Nov. 1990. In mammalian cell expression, mammaliansignal sequences may be used to direct secretion of the protein,such as signal sequences from secreted polypeptides of the same orrelated species, as well as viral secretory leaders.

Both expression and cloning vectors contain a nucleic acid sequencethat enables the vector to replicate in one or more selected hostcells. Such sequences are well known for a variety of bacteria,yeast, and viruses. The origin of replication from the plasmidpBR322 is suitable for most Grain-negative bacteria, the 2 .mu.plasmid origin is suitable for yeast, and various viral origins(SV40, polyoma, adenovirus, VSV or BPV) are useful for cloningvectors in mammalian cells.

Expression and cloning vectors will typically contain a selectiongene, also termed a selectable marker. Typical selection genesencode proteins that (a) confer resistance to antibiotics or othertoxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline,(b) complement auxotrophic deficiencies, or (c) supply criticalnutrients not available from complex media, e.g., the gene encodingD-alanine racemase for Bacilli.

An example of suitable selectable markers for mammalian cells arethose that enable the identification of cells competent to take upthe PRO-encoding nucleic acid, such as DHFR or thymidine kinase. Anappropriate host cell when wild-type DHFR is employed is the CHOcell line deficient in DHFR activity, prepared and propagated asdescribed by Urlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216(1980). A suitable selection gene for use in yeast is the trp1 genepresent in the yeast plasmid YRp7 [Stinchcomb et al., Nature,282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper etal., Gene, 10:157 (1980)]. The trp1 gene provides a selectionmarker for a mutant strain of yeast lacking the ability to grow intryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics,85:12 (1977)].

Expression and cloning vectors usually contain a promoter operablylinked to the PRO-encoding nucleic acid sequence to direct mRNAsynthesis. Promoters recognized by a variety of potential hostcells are well known. Promoters suitable for use with prokaryotichosts include the .beta.-lactamase and lactose promoter systems[Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature,281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promotersystem [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], andhybrid promoters such as the tac promoter [deBoer et al., Proc.Natl. Acad. Sci. USA, 80:21-25 (1983)]. Promoters for use inbacterial systems also will contain a Shine-Dalgarno (S.D.)sequence operably linked to the DNA encoding PRO.

Examples of suitable promoting sequences for use with yeast hostsinclude the promoters for 3-phosphoglycerate kinase [Hitzeman etal., J. Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes[Hess et al., J. Adv. Enzyme Reg., 7:149 (1968); Holland,Biochemistry, 17:4900 (1978)], such as enolase,glyceraldehyde-3-phosphate dehydrogenase, hexolinase, pyruvatedecarboxylase, phosphofructokinase, glucose-6-phosphate isomerase,3-phosphoglycerate mutase, pyruvate kinase, triosephosphateisomerase, phosphoglucose isomerase, and glucokinase.

Other yeast promoters, which are inducible promoters having theadditional advantage of transcription controlled by growthconditions, are the promoter regions for alcohol dehydrogenase 2,isocytochrome C, acid phosphatase, degradative enzymes associatedwith nitrogen metabolism, metallothionein,glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsiblefor maltose and galactose utilization. Suitable vectors andpromoters for use in yeast expression are further described in EP73,657.

PRO transcription from vectors in mammalian host cells iscontrolled, for example, by promoters obtained from the genomes ofviruses such as polyoma virus, fowlpox virus (UK 2,211,504published 5 Jul. 1989), adenovirus (such as Adenovirus 2), bovinepapilloma virus, avian sarcoma virus, cytomegalovirus, aretrovirus, hepatitis-B virus and Simian Virus 40 (SV40), fromheterologous mammalian promoters, e.g., the actin promoter or animmunoglobulin promoter, and from heat-shock promoters, providedsuch promoters are compatible with the host cell systems.

Transcription of a DNA encoding the PRO by higher eukaryotes may beincreased by inserting an enhancer sequence into the vector.Enhancers are cis-acting elements of DNA, usually about from 10 to300 bp, that act on a promoter to increase its transcription. Manyenhancer sequences are now known from mammalian genes (globin,elastase, albumin, .alpha.-fetoprotein, and insulin). Typically,however, one will use an enhancer from a eukaryotic cell virus.Examples include the SV40 enhancer on the late side of thereplication origin (bp 100-270), the cytomegalovirus early promoterenhancer, the polyoma enhancer on the late side of the replicationorigin, and adenovirus enhancers. The enhancer may be spliced intothe vector at a position 5' or 3' to the PRO coding sequence, butis preferably located at a site 5' from the promoter.

Expression vectors used in eukaryotic host cells (yeast, fungi,insect, plant, animal, human, or nucleated cells from othermulticellular organisms) will also contain sequences necessary forthe termination of transcription and for stabilizing the mRNA. Suchsequences are commonly available from the 5' and, occasionally 3',untranslated regions of eukaryotic or viral DNAs or cDNAs. Theseregions contain nucleotide segments transcribed as polyadenylatedfragments in the untranslated portion of the mRNA encoding PRO.

Still other methods, vectors, and host cells suitable foradaptation to the synthesis of PRO in recombinant vertebrate cellculture are described in Gething et al., Nature, 293:620-625(1981); Mantei et al., Nature, 281:40-46 (1979); EP 117,060; and EP117,058.

4. Detecting Gene Amplification/Expression

Gene amplification and/or expression may be measured in a sampledirectly, for example, by conventional Southern blotting, Northernblotting to quantitate the transcription of mRNA [Thomas, Proc.Natl. Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNAanalysis), or in situ hybridization, using an appropriately labeledprobe, based on the sequences provided herein. Alternatively,antibodies may be employed that can recognize specific duplexes,including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexesor DNA-protein duplexes. The antibodies in turn may be labeled andthe assay may be carried out where the duplex is bound to asurface, so that upon the formation of duplex on the surface, thepresence of antibody bound to the duplex can be detected.

Gene expression, alternatively, may be measured by iununologicalmethods, such as immunohistochemical staining of cells or tissuesections and assay of cell culture or body fluids, to quantitatedirectly the expression of gene product. Antibodies useful forimmunohistochemical staining and/or assay of sample fluids may beeither monoclonal or polyclonal, and may be prepared in any mammal.Conveniently, the antibodies may be prepared against a nativesequence PRO polypeptide or against a synthetic peptide based onthe DNA sequences provided herein or against exogenous sequencefused to PRO DNA and encoding a specific antibody epitope.

5. Purification of Polypeptide

Forms of PRO may be recovered from culture medium or from host celllysates. If membrane-bound, it can be released from the membraneusing a suitable detergent solution (e.g. Triton-X 100) or byenzymatic cleavage. Cells employed in expression of PRO can bedisrupted by various physical or chemical means, such asfreeze-thaw cycling, sonication, mechanical disruption, or celllysing agents.

It may be desired to purify PRO from recombinant cell proteins orpolypeptides. The following procedures are exemplary of suitablepurification procedures: by fractionation on an ion-exchangecolumn; ethanol precipitation; reverse phase HPLC; chromatographyon silica or on a cation-exchange resin such as DEAE;chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gelfiltration using, for example, Sephadex G-75; protein A Sepharosecolumns to remove contaminants such as IgG; and metal chelatingcolumns to bind epitope-tagged forms of the PRO. Various methods ofprotein purification may be employed and such methods are known inthe art and described for example in Deutscher, Methods inEnzymology, 182 (1990); Scopes, Protein Purification: Principlesand Practice, Springer-Verlag, New York (1982). The purificationstep(s) selected will depend, for example, on the nature of theproduction process used and the particular PRO produced.

E. Uses for PRO

Nucleotide sequences (or their complement) encoding PRO havevarious applications in the art of molecular biology, includinguses as hybridization probes, in chromosome and gene mapping and inthe generation of anti-sense RNA and DNA. PRO nucleic acid willalso be useful for the preparation of PRO polypeptides by therecombinant techniques described herein.

The full-length native sequence PRO gene, or portions thereof, maybe used as hybridization probes for a cDNA library to isolate thefull-length PRO cDNA or to isolate still other cDNAs (for instance,those encoding naturally-occurring variants of PRO or PRO fromother species) which have a desired sequence identity to the nativePRO sequence disclosed herein. Optionally, the length of the probeswill be about 20 to about 50 bases. The hybridization probes may bederived from at least partially novel regions of the full lengthnative nucleotide sequence wherein those regions may be determinedwithout undue experimentation or from genomic sequences includingpromoters, enhancer elements and introns of native sequence PRO. Byway of example, a screening method will comprise isolating thecoding region of the PRO gene using the known DNA sequence tosynthesize a selected probe of about 40 bases. Hybridization probesmay be labeled by a variety of labels, including radionucleotidessuch as .sup.32P or .sup.35S, or enzymatic labels such as alkalinephosphatase coupled to the probe via avidin/biotin couplingsystems. Labeled probes having a sequence complementary to that ofthe PRO gene of the present invention can be used to screenlibraries of human cDNA, genomic DNA or mRNA to determine whichmembers of such libraries the probe hybridizes to. Hybridizationtechniques are described in further detail in the Examplesbelow.

Any EST sequences disclosed in the present application maysimilarly be employed as probes, using the methods disclosedherein.

Other useful fragments of the PRO nucleic acids include antisenseor sense oligonucleotides comprising a singe-stranded nucleic acidsequence (either RNA or DNA) capable of binding to target PRO mRNA(sense) or PRO DNA (antisense) sequences. Antisense or senseoligonucleotides, according to the present invention, comprise afragment of the coding region of PRO DNA. Such a fragment generallycomprises at least about 14 nucleotides, preferably from about 14to 30 nucleotides. The ability to derive an antisense or a senseoligonucleotide, based upon a cDNA sequence encoding a givenprotein is described in, for example, Stein and Cohen (Cancer Res.48:2659, 1988) and van der Krol et al. (BioTechniques 6:958,1988).

Binding of antisense or sense oligonucleotides to target nucleicacid sequences results in the formation of duplexes that blocktranscription or translation of the target sequence by one ofseveral means, including enhanced degradation of the duplexes,premature termination of transcription or translation, or by othermeans. The antisense oligonucleotides thus may be used to blockexpression of PRO proteins. Antisense or sense oligonucleotidesfurther comprise oligonucleotides having modifiedsugar-phosphodiester backbones (or other sugar linkages, such asthose described in WO 91/06629) and wherein such sugar linkages areresistant to endogenous nucleases. Such oligonucleotides withresistant sugar linkages are stable in vivo (i.e., capable ofresisting enzymatic degradation) but retain sequence specificity tobe able to bind to target nucleotide sequences.

Other examples of sense or antisense oligonucleotides include thoseoligonucleotides which are covalently linked to organic moieties,such as those described in WO 90/10048, and other moieties thatincreases affinity of the oligonucleotide for a target nucleic acidsequence, such as poly-(L-lysine). Further still, intercalatingagents, such as ellipticine, and alkylating agents or metalcomplexes may be attached to sense or antisense oligonucleotides tomodify binding specificities of the antisense or senseoligonucleotide for the target nucleotide sequence.

Antisense or sense oligonucleotides may be introduced into a cellcontaining the target nucleic acid sequence by any gene transfermethod, including, for example, CaPO.sub.4-mediated DNAtransfection, electroporation, or by using gene transfer vectorssuch as Epstein-Barr virus. In a preferred procedure, an antisenseor sense oligonucleotide is inserted into a suitable retroviralvector. A cell containing the target nucleic acid sequence iscontacted with the recombinant retroviral vector, either in vivo orex vivo. Suitable retroviral vectors include, but are not limitedto, those derived from the murine retrovirus M-MuLV, N2 (aretrovirus derived from M-MuLV), or the double copy vectorsdesignated DCT5A, DCT5B and DCT5C (see WO 90/13641).

Sense or antisense oligonucleotides also may be introduced into acell containing the target nucleotide sequence by formation of aconjugate with a ligand binding molecule, as described in WO91/04753. Suitable ligand binding molecules include, but are notlimited to, cell surface receptors, growth factors, othercytokines, or other ligands that bind to cell surface receptors.Preferably, conjugation of the ligand binding molecule does notsubstantially interfere with the ability of the ligand bindingmolecule to bind to its corresponding molecule or receptor, orblock entry of the sense or antisense oligonucleotide or itsconjugated version into the cell.

Alternatively, a sense or an antisense oligonucleotide may beintroduced into a cell containing the target nucleic acid sequenceby formation of an oligonucleotide-lipid complex, as described inWO 90/10448. The sense or antisense oligonucleotide-lipid complexis preferably dissociated within the cell by an endogenouslipase.

Antisense RNA or DNA molecules are generally at least about 5 basesin length, about 10 bases in length, about 15 bases in length,about 20 bases in length, about 25 bases in length, about 30 basesin length, about 35 bases in length, about 40 bases in length,about 45 bases in length, about 50 bases in length, about 55 basesin length, about 60 bases in length, about 65 bases in length,about 70 bases in length, about 75 bases in length, about 80 basesin length, about 85 bases in length, about 90 bases in length,about 95 bases in length, about 100 bases in length, or more.

The probes may also be employed in PCR techniques to generate apool of sequences for identification of closely related PRO codingsequences.

Nucleotide sequences encoding a PRO can also be used to constructhybridization probes for mapping the gene which encodes that PROand for the genetic analysis of individuals with genetic disorders.The nucleotide sequences provided herein may be mapped to achromosome and specific regions of a chromosome using knowntechniques, such as in situ hybridization, linkage analysis againstknown chromosomal markers, and hybridization screening withlibraries.

When the coding sequences for PRO encode a protein which binds toanother protein (example, where the PRO is a receptor), the PRO canbe used in assays to identify the other proteins or moleculesinvolved in the binding interaction. By such methods, inhibitors ofthe receptor/ligand binding interaction can be identified. Proteinsinvolved in such binding interactions can also be used to screenfor peptide or small molecule inhibitors or agonists of the bindinginteraction. Also, the receptor PRO can be used to isolatecorrelative ligand(s). Screening assays can be designed to findlead compounds that mimic the biological activity of a native PROor a receptor for PRO. Such screening assays will include assaysamenable to high-throughput screening of chemical libraries, makingthem particularly suitable for identifying small molecule drugcandidates. Small molecules contemplated include synthetic organicor inorganic compounds. The assays can be performed in a variety offormats, including protein-protein binding assays, biochemicalscreening assays, immunoassays and cell based assays, which arewell characterized in the art.

Nucleic acids which encode PRO or its modified forms can also beused to generate either transgenic animals or "knock out" animalswhich, in turn, are useful in the development and screening oftherapeutically useful reagents. A transgenic animal (e.g., a mouseor rat) is an animal having cells that contain a transgene, whichtransgene was introduced into the animal or an ancestor of theanimal at a prenatal, e.g., an embryonic stage. A transgene is aDNA which is integrated into the genome of a cell from which atransgenic animal develops. In one embodiment, cDNA encoding PROcan be used to clone genomic DNA encoding PRO in accordance withestablished techniques and the genomic sequences used to generatetransgenic animals that contain cells which express DNA encodingPRO. Methods for generating transgenic animals, particularlyanimals such as mice or rats, have become conventional in the artand are described, for example, in U.S. Pat. Nos. 4,736,866 and4,870,009. Typically, particular cells would be targeted for PROtransgene incorporation with tissue-specific enhancers. Transgenicanimals that include a copy of a transgene encoding PRO introducedinto the germ line of the animal at an embryonic stage can be usedto examine the effect of increased expression of DNA encoding PRO.Such animals can be used as tester animals for reagents thought toconfer protection from, for example, pathological conditionsassociated with its overexpression. In accordance with this facetof the invention, an animal is treated with the reagent and areduced incidence of the pathological condition, compared tountreated animals bearing the transgene, would indicate a potentialtherapeutic intervention for the pathological condition.

Alternatively, non-human homologues of PRO can be used to constructa PRO "knock out" animal which has a defective or altered geneencoding PRO as a result of homologous recombination between theendogenous gene encoding PRO and altered genomic DNA encoding PROintroduced into an embryonic stem cell of the animal. For example,cDNA encoding PRO can be used to clone genomic DNA encoding PRO inaccordance with established techniques. A portion of the genomicDNA encoding PRO can be deleted or replaced with another gene, suchas a gene encoding a selectable marker which can be used to monitorintegration. Typically, several kilobases of unaltered flanking DNA(both at the 5' and 3' ends) are included in the vector [see e.g.,Thomas and Capecchi, Cell, 51:503 (1987) for a description ofhomologous recombination vectors]. The vector is introduced into anembryonic stem cell line (e.g., by electroporation) and cells inwhich the introduced DNA has homologously recombined with theendogenous DNA are selected [see e.g., Li et al., Cell, 69:915(1992)]. The selected cells are then injected into a blastocyst ofan animal (e.g., a mouse or rat) to form aggregation chimeras [seee.g., Bradley, in Teratocarcinomas and Embryonic Stem Cells: APractical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp.113-152]. A chimeric embryo can then be implanted into a suitablepseudopregnant female foster animal and the embryo brought to termto create a "knock out" animal. Progeny harboring the homologouslyrecombined DNA in their germ cells can be identified by standardtechniques and used to breed animals in which all cells of theanimal contain the homologously recombined DNA. Knockout animalscan be characterized for instance, for their ability to defendagainst certain pathological conditions and for their developmentof pathological conditions due to absence of the PROpolypeptide.

Nucleic acid encoding the PRO polypeptides may also be used in genetherapy. In gene therapy applications, genes are introduced intocells in order to achieve in vivo synthesis of a therapeuticallyeffective genetic product, for example for replacement of adefective gene. "Gene therapy" includes both conventional genetherapy where a lasting effect is achieved by a single treatment,and the administration of gene therapeutic agents, which involvesthe one time or repeated administration of a therapeuticallyeffective DNA or mRNA. Antisense RNAs and DNAs can be used astherapeutic agents for blocking the expression of certain genes invivo. It has already been shown that short antisenseoligonucleotides can be imported into cells where they act asinhibitors, despite their low intracellular concentrations causedby their restricted uptake by the cell membrane. (Zamecnik et al.,Proc. Natl. Acad. Sci. USA 83:4143-4146 [1986]). Theoligonucleotides can be modified to enhance their uptake, e.g. bysubstituting their negatively charged phosphodiester groups byuncharged groups.

There are a variety of techniques available for introducing nucleicacids into viable cells. The techniques vary depending upon whetherthe nucleic acid is transferred into cultured cells in vitro, or invivo in the cells of the intended host. Techniques suitable for thetransfer of nucleic acid into mammalian cells in vitro include theuse of liposomes, electroporation, microinjection, cell fusion,DEAE-dextran, the calcium phosphate precipitation method, etc. Thecurrently preferred in vivo gene transfer techniques includetransfection with viral (typically retroviral) vectors and viralcoat protein-liposome mediated transfection (Dzau et al., Trends inBiotechnology 11, 205-210 [1993]). In some situations it isdesirable to provide the nucleic acid source with an agent thattargets the target cells, such as an antibody specific for a cellsurface membrane protein or the target cell, a ligand for areceptor on the target cell, etc. Where liposomes are employed,proteins which bind to a cell surface membrane protein associatedwith endocytosis may be used for targeting and/or to facilitateuptake, e.g. capsid proteins or fragments thereof tropic for aparticular cell type, antibodies for proteins which undergointernalization in cycling, proteins that target intracellularlocalization and enhance intracellular half-life. The technique ofreceptor-mediated endocytosis is described, for example, by Wu etal., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc.Natl. Acad. Sci. USA 87, 3410-3414 (1990). For review of genemarking and gene therapy protocols see Anderson et al., Science256, 808-813 (1992).

The PRO polypeptides described herein may also be employed asmolecular weight markers for protein electrophoresis purposes andthe isolated nucleic acid sequences may be used for recombinantlyexpressing those markers.

The nucleic acid molecules encoding the PRO polypeptides orfragments thereof described herein are useful for chromosomeidentification. In this regard, there exists an ongoing need toidentify new chromosome markers, since relatively few chromosomemarking reagents, based upon actual sequence data are presentlyavailable. Each PRO nucleic acid molecule of the present inventioncan be used as a chromosome marker.

The PRO polypeptides and nucleic acid molecules of the presentinvention may also be used for tissue typing, wherein the PROpolypeptides of the present invention may be differentiallyexpressed in one tissue as compared to another. PRO nucleic acidmolecules will find use for generating probes for PCR, Northernanalysis, Southern analysis and Western analysis.

The PRO polypeptides described herein may also be employed astherapeutic agents. The PRO polypeptides of the present inventioncan be formulated according to known methods to preparepharmaceutically useful compositions, whereby the PRO producthereof is combined in admixture with a pharmaceutically acceptablecarrier vehicle. Therapeutic formulations are prepared for storageby mixing the active ingredient having the desired degree of puritywith optional physiologically acceptable carriers, excipients orstabilizers (Remington's Pharmaceutical Sciences 16th edition,Osol, A. Ed. (1980)), in the form of lyophilized formulations oraqueous solutions. Acceptable carriers, excipients or stabilizersare nontoxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, citrate and otherorganic acids; antioxidants including ascorbic acid; low molecularweight (less than about 10 residues) polypeptides; proteins, suchas serum albumin, gelatin or immunoglobulins; hydrophilic polymerssuch as polyvinylpyrrolidone, amino acids such as glycine,glutamine, asparagine, arginine or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose,or dextrins; chelating agents such as EDTA; sugar alcohols such asmannitol or sorbitol; salt-forming counterions such as sodium;and/or nonionic surfactants such as TWEEN.TM., PLURONICS.TM. orPEG.

The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes, prior to or following lyophilization andreconstitution.

Therapeutic compositions herein generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by a hypodermicinjection needle.

The route of administration is in accord with known methods, e.g.injection or infusion by intravenous, intraperitoneal,intracerebral, intramuscular, intraocular, intraarterial orintralesional routes, topical administration, or by sustainedrelease systems.

Dosages and desired drug concentrations of pharmaceuticalcompositions of the present invention may vary depending on theparticular use envisioned. The determination of the appropriatedosage or route of administration is well within the skill of anordinary physician. Animal experiments provide reliable guidancefor the determination of effective doses for human therapy.Interspecies scaling of effective doses can be performed followingthe principles laid down by Mordenti, J. and Chappell, W. "The useof interspecies scaling in toxicokinetics" In Toxicokinetics andNew Drug Development, Yacobi et al., Eds., Pergamon Press, New York1989, pp. 42-96.

When in vivo administration of a PRO polypeptide or agonist orantagonist thereof is employed, normal dosage amounts may vary fromabout 10 ng/kg to up to 100 mg/kg of mammal body weight or more perday, preferably about 1 .mu.g/kg/day to 10 mg/kg/day, dependingupon the route of administration. Guidance as to particular dosagesand methods of delivery is provided in the literature; see, forexample, U.S. Pat. Nos. 4,657,760; 5,206,344; or 5,225,212. It isanticipated that different formulations will be effective fordifferent treatment compounds and different disorders, thatadministration targeting one organ or tissue, for example, maynecessitate delivery in a manner different from that to anotherorgan or tissue.

Where sustained-release administration of a PRO polypeptide isdesired in a formulation with release characteristics suitable forthe treatment of any disease or disorder requiring administrationof the PRO polypeptide, microencapsulation of the PRO polypeptideis contemplated. Microencapsulation of recombinant proteins forsustained release has been successfully performed with human growthhormone (rhGH), interferon-(rhIFN-), interleukin-2, and MN rgp120.Johnson et al., Nat. Med., 2:795-799 (1996); Yasuda, Biomed. Ther.,27:1221-1223 (1993); Hora et al., Bio/Technology, 8:755-758 (1990);Cleland, "Design and Production of Single Immunization VaccinesUsing Polylactide Polyglycolide Microsphere Systems," in VaccineDesign: The Subunit and Adjuvant Approach, Powell and Newman, eds,(Plenum Press: New York, 1995), pp. 439-462; WO 97/03692, WO96/40072, WO 96/07399; and U.S. Pat. No. 5,654,010.

The sustained-release formulations of these proteins were developedusing poly-lactic-coglycolic acid (PLGA) polymer due to itsbiocompatibility and wide range of biodegradable properties. Thedegradation products of PLGA, lactic and glycolic acids, can becleared quickly within the human body. Moreover, the degradabilityof this polymer can be adjusted from months to years depending onits molecular weight and composition. Lewis, "Controlled release ofbioactive agents from lactide/glycolide polymer," in: M. Chasin andR. Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems(Marcel Dekker: New York, 1990), pp. 1-41.

This invention encompasses methods of screening compounds toidentify those that mimic the PRO polypeptide (agonists) or preventthe effect of the PRO polypeptide (antagonists). Screening assaysfor antagonist drug candidates are designed to identify compoundsthat bind or complex with the PRO polypeptides encoded by the genesidentified herein, or otherwise interfere with the interaction ofthe encoded polypeptides with other cellular proteins. Suchscreening assays will include assays amenable to high-throughputscreening of chemical libraries, making them particularly suitablefor identifying small molecule drug candidates.

The assays can be performed in a variety of formats, includingprotein-protein binding assays, biochemical screening assays,immunoassays, and cell-based assays, which are well characterizedin the art.

All assays for antagonists are common in that they call forcontacting the drug candidate with a PRO polypeptide encoded by anucleic acid identified herein under conditions and for a timesufficient to allow these two components to interact.

In binding assays, the interaction is binding and the complexformed can be isolated or detected in the reaction mixture. In aparticular embodiment, the PRO polypeptide encoded by the geneidentified herein or the drug candidate is immobilized on a solidphase, e.g., on a microtiter plate, by covalent or non-covalentattachments. Non-covalent attachment generally is accomplished bycoating the solid surface with a solution of the PRO polypeptideand drying. Alternatively, an immobilized antibody, e.g., amonoclonal antibody, specific for the PRO polypeptide to beimmobilized can be used to anchor it to a solid surface. The assayis performed by adding the non-immobilized component, which may belabeled by a detectable label, to the immobilized component, e.g.,the coated surface containing the anchored component. When thereaction is complete, the non-reacted components are removed, e.g.,by washing, and complexes anchored on the solid surface aredetected. When the originally non-immobilized component carries adetectable label, the detection of label immobilized on the surfaceindicates that complexing occurred. Where the originallynon-immobilized component does not carry a label, complexing can bedetected, for example, by using a labeled antibody specificallybinding the immobilized complex.

If the candidate compound interacts with but does not bind to aparticular PRO polypeptide encoded by a gene identified herein, itsinteraction with that polypeptide can be assayed by methods wellknown for detecting protein-protein interactions. Such assaysinclude traditional approaches, such as, e.g., cross-linking,co-immunoprecipitation, and co-purification through gradients orchromatographic columns. In addition, protein-protein interactionscan be monitored by using a yeast-based genetic system described byFields and co-workers (Fields and Song, Nature (London),340:245-246 (1989); Chien et al., Proc. Natl. Acad. Sci. USA,88:9578-9582 (1991)) as disclosed by Chevray and Nathans, Proc.Natl. Acad. Sci. USA, 89: 5789-5793 (1991). Many transcriptionalactivators, such as yeast GAL4, consist of two physically discretemodular domains, one acting as the DNA-binding domain, the otherone functioning as the transcription-activation domain. The yeastexpression system described in the foregoing publications(generally referred to as the "two-hybrid system") takes advantageof this property, and employs two hybrid proteins, one in which thetarget protein is fused to the DNA-binding domain of GAL4, andanother, in which candidate activating proteins are fused to theactivation domain. The expression of a GAL1-lacZ reporter geneunder control of a GAL4-activated promoter depends onreconstitution of GAL4 activity via protein-protein interaction.Colonies containing interacting polypeptides are detected with achromogenic substrate for .beta.-galactosidase. A complete kit(MATCHMAKER.TM.) for identifying protein-protein interactionsbetween two specific proteins using the two-hybrid technique iscommercially available from Clontech. This system can also beextended to map protein domains involved in specific proteininteractions as well as to pinpoint amino acid residues that arecrucial for these interactions.

Compounds that interfere with the interaction of a gene encoding aPRO polypeptide identified herein and other intra- or extracellularcomponents can be tested as follows: usually a reaction mixture isprepared containing the product of the gene and the intra- orextracellular component under conditions and for a time allowingfor the interaction and binding of the two products. To test theability of a candidate compound to inhibit binding, the reaction isrun in the absence and in the presence of the test compound. Inaddition, a placebo may be added to a third reaction mixture, toserve as positive control. The binding (complex formation) betweenthe test compound and the intra- or extracellular component presentin the mixture is monitored as described hereinabove. The formationof a complex in the control reaction(s) but not in the reactionmixture containing the test compound indicates that the testcompound interferes with the interaction of the test compound andits reaction partner.

To assay for antagonists, the PRO polypeptide may be added to acell along with the compound to be screened for a particularactivity and the ability of the compound to inhibit the activity ofinterest in the presence of the PRO polypeptide indicates that thecompound is an antagonist to the PRO polypeptide. Alternatively,antagonists may be detected by combining the PRO polypeptide and apotential antagonist with membrane-bound PRO polypeptide receptorsor recombinant receptors under appropriate conditions for acompetitive inhibition assay. The PRO polypeptide can be labeled,such as by radioactivity, such that the number of PRO polypeptidemolecules bound to the receptor can be used to determine theeffectiveness of the potential antagonist. The gene encoding thereceptor can be identified by numerous methods known to those ofskill in the art, for example, ligand panning and FACS sorting.Coligan et al., Current Protocols in Immun., 1(2): Chapter 5(1991). Preferably, expression cloning is employed whereinpolyadenylated RNA is prepared from a cell responsive to the PROpolypeptide and a cDNA library created from this RNA is dividedinto pools and used to transfect COS cells or other cells that arenot responsive to the PRO polypeptide. Transfected cells that aregrown on glass slides are exposed to labeled PRO polypeptide. ThePRO polypeptide can be labeled by a variety of means includingiodination or inclusion of a recognition site for a site-specificprotein kinase. Following fixation and incubation, the slides aresubjected to autoradiographic analysis. Positive pools areidentified and sub-pools are prepared and re-transfected using aninteractive sub-pooling and re-screening process, eventuallyyielding a single clone that encodes the putative receptor.

As an alternative approach for receptor identification, labeled PROpolypeptide can be photoaffinity-linked with cell membrane orextract preparations that express the receptor molecule.Cross-linked material is resolved by PAGE and exposed to X-rayfilm. The labeled complex containing the receptor can be excised,resolved into peptide fragments, and subjected to proteinmicro-sequencing. The amino acid sequence obtained frommicro-sequencing would be used to design a set of degenerateoligonucleotide probes to screen a cDNA library to identify thegene encoding the putative receptor.

In another assay for antagonists, mammalian cells or a membranepreparation expressing the receptor would be incubated with labeledPRO polypeptide in the presence of the candidate compound. Theability of the compound to enhance or block this interaction couldthen be measured.

More specific examples of potential antagonists include anoligonucleotide that binds to the fusions of immunoglobulin withPRO polypeptide, and, in particular, antibodies including, withoutlimitation, poly- and monoclonal antibodies and antibody fragments,single-chain antibodies, anti-idiotypic antibodies, and chimeric orhumanized versions of such antibodies or fragments, as well ashuman antibodies and antibody fragments. Alternatively, a potentialantagonist may be a closely related protein, for example, a mutatedform of the PRO polypeptide that recognizes the receptor butimparts no effect, thereby competitively inhibiting the action ofthe PRO polypeptide.

Another potential PRO polypeptide antagonist is an antisense RNA orDNA construct prepared using antisense technology, where, e.g., anantisense RNA or DNA molecule acts to block directly thetranslation of mRNA by hybridizing to targeted mRNA and preventingprotein translation. Antisense technology can be used to controlgene expression through triple-helix formation or antisense DNA orRNA, both of which methods are based on binding of a polynucleotideto DNA or RNA. For example, the 5' coding portion of thepolynucleotide sequence, which encodes the mature PRO polypeptidesherein, is used to design an antisense RNA oligonucleotide of fromabout 10 to 40 base pairs in length. A DNA oligonucleotide isdesigned to be complementary to a region of the gene involved intranscription (triple helix--see Lee et al., Nucl. Acids Res.,6:3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan etal., Science, 251:1360 (1991)), thereby preventing transcriptionand the production of the PRO polypeptide. The antisense RNAoligonucleotide hybridizes to the mRNA in vivo and blockstranslation of the mRNA molecule into the PRO polypeptide(antisense--Okano, Neurochem., 56:560 (1991); Oligodeoxynucleotidesas Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton,Fla., 1988). The oligonucleotides described above can also bedelivered to cells such that the antisense RNA or DNA may beexpressed in vivo to inhibit production of the PRO polypeptide.When antisense DNA is used, oligodeoxyribonucleotides derived fromthe translation-initiation site, e.g., between about -10 and +10positions of the target gene nucleotide sequence, arepreferred.

Potential antagonists include small molecules that bind to theactive site, the receptor binding site, or growth factor or otherrelevant binding site of the PRO polypeptide, thereby blocking thenormal biological activity of the PRO polypeptide. Examples ofsmall molecules include, but are not limited to, small peptides orpeptide-like molecules, preferably soluble peptides, and syntheticnon-peptidyl organic or inorganic compounds.

Ribozymes are enzymatic RNA molecules capable of catalyzing thespecific cleavage of RNA. Ribozymes act by sequence-specifichybridization to the complementary target RNA, followed byendonucleolytic cleavage. Specific ribozyme cleavage sites within apotential RNA target can be identified by known techniques. Forfurther details see, e.g., Rossi, Current Biology, 4:469-471(1994), and PCT publication No. WO 97/33551 (published Sep. 18,1997).

Nucleic acid molecules in triple-helix formation used to inhibittranscription should be single-stranded and composed ofdeoxynucleotides. The base composition of these oligonucleotides isdesigned such that it promotes triple-helix formation via Hoogsteenbase-pairing rules, which generally require sizeable stretches ofpurines or pyrimidines on one strand of a duplex. For furtherdetails see, e.g., PCT publication No. WO 97/33551, supra.

These small molecules can be identified by any one or more of thescreening assays discussed hereinabove and/or by any otherscreening techniques well known for those skilled in the art.

With regard to the PRO211 and PRO217 polypeptide, therapeuticindications include disorders associated with the preservation andmaintenance of gastrointestinal mucosa and the repair of acute andchronic mucosal lesions (e.g., enterocolitis, Zollinger-Ellisonsyndrome, gastrointestinal ulceration and congenital microvillusatrophy), skin diseases associated with abnormal keratinocytedifferentiation (e.g., psoriasis, epithelial cancers such as lungsquamous cell carcinoma, epidermoid carcinoma of the vulva andgliomas.

Since the PRO232 polypeptide and nucleic acid encoding it possesssequence homology to a cell surface stem cell antigen and itsencoding nucleic acid, probes based upon the PRO232 nucleotidesequence may be employed to identify other novel stem cell surfaceantigen proteins. Soluble forms of the PRO232 polypeptide may beemployed as antagonists of membrane bound PRO232 activity both invitro and in vivo. PRO232 polypeptides may be employed in screeningassays designed to identify agonists or antagonists of the nativePRO232 polypeptide, wherein such assays may take the form of anyconventional cell-type or biochemical binding assay. Moreover, thePRO232 polypeptide may serve as a molecular marker for the tissuesin which the polypeptide is specifically expressed.

With regard to the PRO187 polypeptides disclosed herein, FGF-8 hasbeen implicated in cellular differentiation and embryogenesis,including the patterning which appears during limb formation. FGF-8and the PRO187 molecules of the invention therefore are likely tohave potent effects on cell growth and development. Diseases whichrelate to cellular growth and differentiation are thereforesuitable targets for therapeutics based on functionality similar toFGF-8. For example, diseases related to growth or survival of nervecells including Parkinson's disease, Alzheimer's disease, ALS,neuropathies. Additionally, disease related to uncontrolled cellgrowth, e.g., cancer, would also be expected therapeutictargets.

With regard to the PRO265 polypeptides disclosed herein, othermethods for use with PRO265 are described in U.S. Pat. No.5,654,270 to Ruoslahti et al. In particular, PRO265 can be used incomparison with the fibromodulin disclosed therein to compare itseffects on reducing dermal scarring and other properties of thefibromodulin described therein including where it is located andwith what it binds and does not.

The PRO219 polypeptides of the present invention which play aregulatory role in the blood coagulation cascade may be employed invivo for therapeutic purposes as well as for in vitro purposes.Those of ordinary skill in the art will well know how to employPRO219 polypeptides for such uses.

The PRO246 polypeptides of the present invention which serve ascell surface receptors for one or more viruses will find otheruses. For example, extracellular domains derived from these PRO246polypeptides may be employed therapeutically in vivo for lesseningthe effects of viral infection. Those PRO246 polypeptides whichserves as tumor specific antigens may be exploited as therapeutictargets for anti-tumor drugs, and the like. Those of ordinary skillin the art will well know how to employ PRO246 polypeptides forsuch uses.

Assays in which connective growth factor and other growth factorsare usually used should be performed with PRO261. An assay todetermine whether TGF beta induces PRO261, indicating a role incancer is performed as known in the art. Wound repair and tissuegrowth assays are also performed with PRO261. The results areapplied accordingly.

PRO228 polypeptides should be used in assays in which EMR1, CD97and latrophilin would be used in to determine their relativeactivities. The results can be applied accordingly. For example, acompetitive binding assay with PRO228 and CD97 can be performedwith the ligand for CD97, CD55.

Native PRO533 is a 216 amino acid polypeptide of which residues1-22 are the signal sequence. Residues 3 to 216 have a Blast scoreof 509, corresponding to 53% homology to fibroblast growth factor.At the nucleotide level, DNA47412, the EST from which PCR oligoswere generated to isolate the full length DNA49435-1219, has beenobserved to map to 11p15. Sequence homology to the 11p15 locuswould indicate that PRO533 may have utility in the treatment ofUsher Syndrome or Atrophia areata.

As mentioned previously, fibroblast growth factors can act uponcells in both a mitogenic and non-mitogenic manner. These factorsare mitogenic for a wide variety of normal diploid mesoderm-derivedand neural crest-derived cells, inducing granulosa cells, adrenalcortical cells, chrondrocytes, myoblasts, corneal and vascularendothelial cells (bovine or human), vascular smooth muscle cells,lens, retina and prostatic epithelial cells, oligodendrocytes,astrocytes, chrondocytes, myoblasts and osteoblasts.

Non-mitogenic actions of fibroblast growth factors includepromotion of cell migration into a wound area (chemotaxis),initiation of new blood vessel formulation (angiogenesis),modulation of nerve regeneration and survival (neurotrophism),modulation of endocrine functions, and stimulation or suppressionof specific cellular protein expression, extracellular matrixproduction and cell survival. Baird, A. & Bohlen, P., Handbookof Exp. Phrmacol. 95(1): 369-418 (1990). These properties provide abasis for using fibroblast growth factors in therapeutic approachesto accelerate wound healing, nerve repair, collateral blood vesselformation, and the like. For example, fibroblast growth factors,have been suggested to minimize myocardium damage in heart diseaseand surgery (U.S. Pat. No. 4,378,437).

Since the PRO245 polypeptide and nucleic acid encoding it possesssequence homology to a transmembrane protein tyrosine kinaseprotein and its encoding nucleic acid, probes based upon the PRO245nucleotide sequence may be employed to identify other noveltransmembrane tyrosine kinase proteins. Soluble forms of the PRO245polypeptide may be employed as antagonists of membrane bound PRO245activity both in vitro and in vivo. PRO245 polypeptides may beemployed in screening assays designed to identify agonists orantagonists of the native PRO245 polypeptide, wherein such assaysmay take the form of any conventional cell-type or biochemicalbinding assay. Moreover, the PRO245 polypeptide may serve as amolecular marker for the tissues in which the polypeptide isspecifically expressed.

PRO220, PRO221 and PRO227 all have leucine rich repeats.Additionally, PRO220 and PRO221 have homology to SLIT and leucinerich repeat protein. Therefore, these proteins are useful in assaysdescribed in the literature, supra, wherein the SLIT and leucinerich repeat protein are used. Regarding the SLIT protein, PRO227can be used in an assay to determine the affect of PRO227 onneurodegenerative disease. Additionally, PRO227 has homology tohuman glycoprotein V. In the case of PRO227, this polypeptide isused in an assay to determine its affect on bleeding, clotting,tissue repair and scarring.

The PRO266 polypeptide can be used in assays to determine if it hasa role in neurodegenerative diseases or their reversal.

PRO269 polypeptides and portions thereof which effect the activityof thrombin may also be useful for in vivo therapeutic purposes, aswell as for various in vitro applications. In addition, PRO269polypeptides and portions thereof may have therapeutic use as anantithrombotic agent with reduced risk for hemorrhage as comparedwith heparin. Peptides having homology to thrombomodulin areparticularly desirable.

PRO287 polypeptides and portions thereof which effect the activityof bone morphogenic protein "BMP1"/procollagen C-proteinase (PCP)may also be useful for in vivo therapeutic purposes, as well as forvarious in vitro applications. In addition, PRO287 polypeptides andportions thereof may have therapeutic applications in wound healingand tissue repair. Peptides having homology to procollagenC-proteinase enhancer protein and its precursor may also be used toinduce bone and/or cartilage formation and are therefore ofparticular interest to the scientific and medical communities.

Therapeutic indications for PRO214 polypeptides include disordersassociated with the preservation and maintenance ofgastrointestinal mucosa and the repair of acute and chronic mucosallesions (e.g., enterocolitis, Zollinger-Ellison syndrome,gastrointestinal ulceration and congenital microvillus atrophy),skin diseases associated with abnormal keratinocyte differentiation(e.g., psoriasis, epithelial cancers such as lung squamous cellcarcinoma, epidermoid carcinoma of the vulva and gliomas.

Studies on the generation and analysis of mice deficient in membersof the TGF-superfamily are reported in Matzuk, Trends inEndocrinol. and Metabol., 6: 120-127 (1995).

The PRO317 polypeptide, as well as PRO317-specific antibodies,inhibitors, agonists, receptors, or their analogs, herein areuseful in treating PRO317-associated disorders. Hence, for example,they may be employed in modulating endometrial bleedingangiogenesis, and may also have an effect on kidney tissue.Endometrial bleeding can occur in gynecological diseases such asendometrial cancer as abnormal bleeding. Thus, the compositionsherein may find use in diagnosing and treating abnormal bleedingconditions in the endometrium, as by reducing or eliminating theneed for a hysterectomy. The molecules herein may also find use inangiogenesis applications such as anti-tumor indications for whichthe antibody against vascular endothelial growth factor is used,or, conversely, ischemic indications for which vascular endothelialgrowth factor is employed.

Bioactive compositions comprising PRO317 or agonists or antagoniststhereof may be administered in a suitable therapeutic dosedetermined by any of several methodologies including clinicalstudies on mammalian species to determine maximal tolerable doseand on normal human subjects to determine safe dose. Additionally,the bioactive agent may be complexed with a variety of wellestablished compounds or compositions which enhance stability orpharmacological properties such as half-life. It is contemplatedthat the therapeutic, bioactive composition may be delivered byintravenous infusion into the bloodstream or any other effectivemeans which could be used for treating problems of the kidney,uterus, endometrium, blood vessels, or related tissue, e.g., in theheart or genital tract.

Dosages and administration of PRO317, PRO317 agonist, or PRO317antagonist in a pharmaceutical composition may be determined by oneof ordinary skill in the art of clinical pharmacology orpharmacokinetics. See, for example, Mordenti and Rescigno,Pharmaceutical Research, 9:17-25 (1992); Morenti et al.,Pharmaceutical Research, 8:1351-1359 (1991); and Mordenti andChappell, "The use of interspecies scaling in toxicokinetics" inToxicokinetics and New Drug Development, Yacobi et al. (eds)(Pergamon Press: NY, 1989), pp. 42-96. An effective amount ofPRO317, PRO317 agonist, or PRO317 antagonist to be employedtherapeutically will depend, for example, upon the therapeuticobjectives, the route of administration, and the condition of themammal. Accordingly, it will be necessary for the therapist totiter the dosage and modify the route of administration as requiredto obtain the optimal therapeutic effect. A typical daily dosagemight range from about 10 ng/kg to up to 100 mg/kg of the mammal'sbody weight or more per day, preferably about 1 .mu.g/kg/day to 10mg/kg/day. Typically, the clinician will administer PRO317, PRO317agonist, or PRO317 antagonist, until a dosage is reached thatachieves the desired effect for treatment of the above mentioneddisorders.

PRO317 or an PRO317 agonist or PRO317 antagonist may beadministered alone or in combination with another to achieve thedesired pharmacological effect. PRO317 itself, or agonists orantagonists of PRO317 can provide different effects whenadministered therapeutically. Such compounds for treatment will beformulated in a nontoxic, inert, pharmaceutically acceptableaqueous carrier medium preferably at a pH of about 5 to 8, morepreferably 6 to 8, although the pH may vary according to thecharacteristics of the PRO317, agonist, or antagonist beingformulated and the condition to be treated. Characteristics of thetreatment compounds include solubility of the molecule, half-life,and antigenicity/immunogenicity; these and other characteristicsmay aid in defining an effective carrier.

PRO317 or PRO317 agonists or PRO317 antagonists may be delivered byknown routes of administration including but not limited to topicalcreams and gels; transmucosal spray and aerosol, transdermal patchand bandage; injectable, intravenous, and lavage formulations; andorally administered liquids and pills, particularly formulated toresist stomach acid and enzymes. The particular formulation, exactdosage, and route of administration will be determined by theattending physician and will vary according to each specificsituation.

Such determinations of administration are made by consideringmultiple variables such as the condition to be treated, the type ofmammal to be treated, the compound to be administered, and thepharmacokinetic profile of the particular treatment compound.Additional factors which may be taken into account include diseasestate (e.g. severity) of the patient, age, weight, gender, diet,time of administration, drug combination, reaction sensitivities,and tolerance/response to therapy. Long-acting treatment compoundformulations (such as liposomally encapsulated PRO317 or PEGylatedPRO317 or PRO317 polymeric microspheres, such as polylacticacid-based microspheres) might be administered every 3 to 4 days,every week, or once every two weeks depending on half-life andclearance rate of the particular treatment compound.

Normal dosage amounts may vary from about 10 ng/kg to up to 100mg/kg of mammal body weight or more per day, preferably about 1.mu.g/kg/day to 10 mg/kg/day, depending upon the route ofadministration. Guidance as to particular dosages and methods ofdelivery is provided in the literature; see, for example, U.S. Pat.Nos. 4,657,760; 5,206,344; or 5,225,212. It is anticipated thatdifferent formulations will be effective for different treatmentcompounds and different disorders, that administration targetingthe uterus, for example, may necessitate delivery in a mannerdifferent from that to another organ or tissue, such as cardiactissue.

Where sustained-release administration of PRO317 is desired in aformulation with release characteristics suitable for the treatmentof any disease or disorder requiring administration of PRO317,microencapsulation of PRO317 is contemplated. Microencapsulation ofrecombinant proteins for sustained release has been successfullyperformed with human growth hormone (rhGH), interferon-(rhIFN-),interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2: 795-799(1996); Yasuda, Biomed. Ther., 27: 1221-1223 (1993); Hora et al.,Bio/Technology, 8: 755-758 (1990); Cleland, "Design and Productionof Single Immunization Vaccines Using Polylactide PolyglycolideMicrosphere Systems," in Vaccine Design: The Subunit and AdjuvantApproach, Powell and Newman, eds, (Plenum Press: New York, 1995),pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat.No. 5,654,010.

It is contemplated that conditions or diseases of the uterus,endometrial tissue, or other genital tissues or cardiac tissues mayprecipitate damage that is treatable with PRO317 or PRO317 agonistwhere PRO317 expression is reduced in the diseased state; or withantibodies to PRO317 or other PRO317 antagonists where theexpression of PRO317 is increased in the diseased state. Theseconditions or diseases may be specifically diagnosed by the probingtests discussed above for physiologic and pathologic problems whichaffect the function of the organ.

The PRO317, PRO317 agonist, or PRO317 antagonist may beadministered to a mammal with another biologically active agent,either separately or in the same formulation to treat a commonindication for which they are appropriate. For example, it iscontemplated that PRO317 can be administered together with EBAF-1for those indications on which they demonstrate the samequalitative biological effects. Alternatively, where they haveopposite effects, EBAF-1 may be administered together with anantagonist to PRO317, such as an anti-PRO317 antibody. Further,PRO317 may be administered together with VEGF for coronary ischemiawhere such indication is warranted, or with an anti-VEGF for canceras warranted, or, conversely, an antagonist to PRO317 may beadministered with VEGF for coronary ischemia or with anti-VEGF totreat cancer as warranted. These administrations would be ineffective amounts for treating such disorders.

Native PRO301 (SEQ ID NO:119) has a Blast score of 246 and 30%homology at residues 24 to 282 of FIG. 44 with A33_HUMAN, an A33antigen precursor. A33 antigen precursor, as explained in theBackground is a tumor-specific antigen, and as such, is arecognized marker and therapeutic target for the diagnosis andtreatment of colon cancer. The expression of tumor-specificantigens is often associated with the progression of neoplastictissue disorders. Native PRO301 (SEQ ID NO:119) and A33_HUMAN alsoshow a Blast score of 245 and 30% homology at residues 21 to 282 ofFIG. 44 with A33_HUMAN, the variation dependent upon how spaces areinserted into the compared sequences. Native PRO301 (SEQ ID NO:119)also has a Blast score of 165 and 29% homology at residues 60 to255 of FIG. 44 with HS46KDA.sub.--1, a human coxsackie andadenovirus receptor protein, also known as cell surface proteinHCAR. This region of PRO301 also shows a similar Blast score andhomology with HSU90716.sub.--1. Expression of such proteins isusually associated with viral infection and therapeutics for theprevention of such infection may be accordingly conceived. Asmentioned in the Background, the expression of viral receptors isoften associated with neoplastic tumors.

Therapeutic uses for the PRO234 polypeptides of the inventionincludes treatments associated with leukocyte homing or theinteraction between leukocytes and the endothelium during aninflammatory response. Examples include asthma, rheumatoidarthritis, psoriasis and multiple sclerosis.

Since the PRO231 polypeptide and nucleic acid encoding it possesssequence homology to a putative acid phosphatase and its encodingnucleic acid, probes based upon the PRO231 nucleotide sequence maybe employed to identify other novel phosphatase proteins. Solubleforms of the PRO231 polypeptide may be employed as antagonists ofmembrane bound PRO231 activity both in vitro and in vivo. PRO231polypeptides may be employed in screening assays designed toidentify agonists or antagonists of the native PRO231 polypeptide,wherein such assays may take the form of any conventional cell-typeor biochemical binding assay. Moreover, the PRO231 polypeptide mayserve as a molecular marker for the tissues in which thepolypeptide is specifically expressed.

PRO229 polypeptides can be fused with peptides of interest todetermine whether the fusion peptide has an increased half-lifeover the peptide of interest. The PRO229 polypeptides can be usedaccordingly to increase the half-life of polypeptides of interest.Portions of PRO229 which cause the increase in half-life are anembodiment of the invention herein.

PRO238 can be used in assays which measure its ability to reducesubstrates, including oxygen and Aceyl-CoA, and particularly,measure PRO238's ability to produce oxygen free radicals. This isdone by using assays which have been previously described. PRO238can further be used to assay for candidates which block, reduce orreverse its reducing abilities. This is done by performing side byside assays where candidates are added in one assay having PRO238and a substrate to reduce, and not added in another assay, beingthe same but for the lack of the presence of the candidate.

PRO233 polypeptides and portions thereof which have homology toreductase may also be useful for in vivo therapeutic purposes, aswell as for various other applications. The identification of novelreductase proteins and related molecules may be relevant to anumber of human disorders such as inflammatory disease, organfailure, atherosclerosis, cardiac injury, infertility, birthdefects, premature aging, AIDS, cancer, diabetic complications andmutations in general. Given that oxygen free radicals andantioxidants appear to play important roles in a number of diseaseprocesses, the identification of new reductase proteins andreductase-like molecules is of special importance in that suchproteins may serve as potential therapeutics for a variety ofdifferent human disorders. Such polypeptides may also playimportant roles in biotechnological and medical research, as wellas various industrial applications. As a result, there isparticular scientific and medical interest in new molecules, suchas PRO233.

The PRO223 polypeptides of the present invention which exhibitserine carboxypeptidease activity may be employed in vivo fortherapeutic purposes as well as for in vitro purposes. Those ofordinary skill in the art will well know how to employ PRO223polypeptides for such uses.

PRO235 polypeptides and portions thereof which may be involved incell adhesion are also useful for in vivo therapeutic purposes, aswell as for various in vitro applications. In addition, PRO235polypeptides and portions thereof may have therapeutic applicationsin disease states which involve cell adhesion. Given thephysiological importance of cell adhesion mechanisms in vivo,efforts are currently being under taken to identify new, nativeproteins which are involved in cell adhesion. Therefore, peptideshaving homology to plexin are of particular interest to thescientific and medical communities.

Because the PRO236 and PRO262 polypeptides disclosed herein arehomologous to various known .beta.-galactosidase proteins, thePRO236 and PRO262 polypeptides disclosed herein will find use inconjugates of monoclonal antibodies and the polypeptide forspecific killing of tumor cells by generation of active drug from agalactosylated prodrug (e.g., the generation of 5-fluorouridinefrom the prodrug .beta.-D-galactosyl-5-fluorouridine). The PRO236and PRO262 polypeptides disclosed herein may also find various usesboth in vivo and in vitro, wherein those uses will be similar oridentical to uses for which .beta.-galactosidase proteins are nowemployed. Those of ordinary skill in the art will well know how toemploy PRO236 and PRO262 polypeptides for such uses.

PRO239 polypeptides and portions thereof which have homology todensin may also be useful for in vivo therapeutic purposes, as wellas for various in vitro applications. In addition, PRO239polypeptides and portions thereof may have therapeutic applicationsin disease states which involve synaptic mechanisms, regenerationor cell adhesion. Given the physiological importance of synapticprocesses, regeneration and cell adhesion mechanisms in vivo,efforts are currently being under taken to identify new, nativeproteins which are involved in synaptic machinery and celladhesion. Therefore, peptides having homology to densin are ofparticular interest to the scientific and medical communities.

The PRO260 polypeptides described herein can be used in assays todetermine their relation to fucosidase. In particular, the PRO260polypeptides can be used in assays in determining their ability toremove fucose or other sugar residues from proteoglycans. ThePRO260 polypeptides can be assayed to determine if they have anyfunctional or locational similarities as fucosidase. The PRO260polypeptides can then be used to regulate the systems in which theyare integral.

PRO263 can be used in assays wherein CD44 antigen is generally usedto determine PRO263 activity relative to that of CD44. The resultscan be used accordingly.

PRO270 polypeptides and portions thereof which effectreduction-oxidation (redox) state may also be useful for in vivotherapeutic purposes, as well as for various in vitro applications.More specifically, PRO270 polypeptides may affect the expression ofa large variety of genes thought to be involved in the pathogenesisof AIDS, cancer, atherosclerosis, diabetic complications and inpathological conditions involving oxidative stress such as strokeand inflammation. In addition, PRO270 polypeptides and portionsthereof may affect the expression of a genes which have a role inapoptosis. Therefore, peptides having homology to thioredoxin areparticularly desirable to the scientific and medicalcommunities.

PRO272 polypeptides and portions thereof which possess the abilityto bind calcium may also have numerous in vivo therapeutic uses, aswell as various in vitro applications. Therefore, peptides havinghomology to reticulocalbin are particularly desirable. Those withordinary skill in the art will know how to employ PRO272polypeptides and portions thereof for such purposes.

PRO294 polypeptides and portions thereof which have homology tocollagen may also be useful for in vivo therapeutic purposes, aswell as for various other applications. The identification of novelcollagens and collage-like molecules may have relevance to a numberof human disorders. Thus, the identification of new collagens andcollage-like molecules is of special importance in that suchproteins may serve as potential therapeutics for a variety ofdifferent human disorders. Such polypeptides may also playimportant roles in biotechnological and medical research as well asvarious industrial applications. Given the large number of uses forcollagen, there is substantial interest in polypeptides withhomology to the collagen molecule.

PRO295 polypeptides and portions thereof which have homology tointegrin may also be useful for in vivo therapeutic purposes, aswell as for various other applications. The identification of novelintegrins and integrin-like molecules may have relevance to anumber of human disorders such as modulating the binding oractivity of cells of the immune system. Thus, the identification ofnew integrins and integrin-like molecules is of special importancein that such proteins may serve as potential therapeutics for avariety of different human disorders. Such polypeptides may alsoplay important roles in biotechnological and medical research aswell as various industrial applications. As a result, there isparticular scientific and medical interest in new molecules, suchas PRO295.

As the PRO293 polypeptide is clearly a leucine rich repeatpolypeptide homologue, the peptide can be used in all applicationsthat the known NLRR-1 and NLRR-2 polypeptides are used. Theactivity can be compared between these peptides and thus appliedaccordingly.

The PRO247 polypeptides described herein can be used in assays inwhich densin is used to determine the activity of PRO247 relativeto densin or these other proteins. The results can be usedaccordingly in diagnostics and/or therapeutic applications withPRO247.

PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides of thepresent invention which possess protease activity may be employedboth in vivo for therapeutic purposes and in vitro. Those ofordinary skill in the art will well know how to employ the PRO302,PRO303, PRO304, PRO307 and PRO343 polypeptides of the presentinvention for such purposes.

PRO328 polypeptides and portions thereof which have homology toGLIP and CRISP may also be useful for in vivo therapeutic purposes,as well as for various other applications. The identification ofnovel GLIP and CRISP-like molecules may have relevance to a numberof human disorders which involve transcriptional regulation or areover expressed in human tumors. Thus, the identification of newGLIP and CRISP-like molecules is of special importance in that suchproteins may serve as potential therapeutics for a variety ofdifferent human disorders. Such polypeptides may also playimportant roles in biotechnological and medical research as well asin various industrial applications. As a result, there isparticular scientific and medical interest in new molecules, suchas PRO328.

Uses for PRO335, PRO331 or PRO326 including uses in competitiveassays with LIG-1, ALS and decorin to determine their relativeactivities. The results can be used accordingly. PRO335, PRO331 orPRO326 can also be used in assays where LIG-1 would be used todetermine if the same effects are incurred.

PRO332 contains GAG repeat (GKEK) at amino acidpositions 625-628 inFIG. 108 (SEQ ID NO:310). Slippage in such repeats can beassociated with human disease. Accordingly, PRO332 can use usefulfor the treatment of such disease conditions by gene therapy, i.e.by introduction of a gene containing the correct GKEK sequencemotif.

Other uses of PRO334 include use in assays in which fibrillin orfibulin would be used to determine the relative activity of PRO334to fibrillin or fibulin. In particular, PRO334 can be used inassays which require the mechanisms imparted by epidermal growthfactor repeats.

Native PRO346 (SEQ ID NO:320) has a Blast score of 230,corresponding to 27% homology between amino acid residues 21 to 343with residues 35 to 1040 CGM6_HUMAN, a carcinoembryonic antigencgm6 precursor. This homology region includes nearly all but 2N-terminal extracellular domain residues, including animmunoglobulin superfamily homology at residues 148 to 339 ofPRO346 in addition to several transmembrane residues (340-343).Carcinoembryonic antigen precursor, as explained in the Backgroundis a tumor-specific antigen, and as such, is a recognized markerand therapeutic target for the diagnosis and treatment of coloncancer. The expression of tumor-specific antigens is oftenassociated with the progression of neoplastic tissue disorders.Native PRO346 (SEQ ID NO:320) and P_W06874, a humancarcinoembryonic antigen CEA-d have a Blast score of 224 andhomology of 28% between residues 2 to 343 and 67 to 342,respectively. This homology includes the entire extracellulardomain residues of native PRO346, minus the initiator methionine(residues 2 to 18) as well as several transmembrane residues(340-343).

PRO268 polypeptides which have protein disulfide isomerase activitywill be useful for many applications where protein disulfideisomerase activity is desirable including, for example, for use inpromoting proper disulfide bond formation in recombinantly producedproteins so as to increase the yield of correctly folded protein.Those of ordinary skill in the art will readily know how to employsuch PRO268 polypeptides for such purposes.

PRO330 polypeptides of the present invention which possessbiological activity related to that of the prolyl 4-hydroxylasealpha subunit protein may be employed both in vivo for therapeuticpurposes and in vitro. Those of ordinary skill in the art will wellknow how to employ the PRO330 polypeptides of the present inventionfor such purposes.

Uses of the herein disclosed molecules may also be based upon thepositive functional assay hits disclosed and described below.

F. Anti-PRO Antibodies

The present invention further provides anti-PRO antibodies.Exemplary antibodies include polyclonal, monoclonal, humanized,bispecific, and heteroconjugate antibodies.

1. Polyclonal Antibodies

The anti-PRO antibodies may comprise polyclonal antibodies. Methodsof preparing polyclonal antibodies are known to the skilledartisan. Polyclonal antibodies can be raised in a mammal, forexample, by one or more injections of an immunizing agent and, ifdesired, an adjuvant. Typically, the immunizing agent and/oradjuvant will be injected in the mammal by multiple subcutaneous orintraperitoneal injections. The immunizing agent may include thePRO polypeptide or a fusion protein thereof. It may be useful toconjugate the immunizing agent to a protein known to be immunogenicin the mammal being immunized. Examples of such immunogenicproteins include but are not limited to keyhole limpet hemocyanin,serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor.Examples of adjuvants which may be employed include Freund'scomplete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A,synthetic trehalose dicorynomycolate). The immunization protocolmay be selected by one skilled in the art without undueexperimentation.

2. Monoclonal Antibodies

The anti-PRO antibodies may, alternatively, be monoclonalantibodies. Monoclonal antibodies may be prepared using hybridomamethods, such as those described by Kohler and Milstein, Nature256:495 (1975). In a hybridoma method, a mouse, hamster, or otherappropriate host animal, is typically immunized with an immunizingagent to elicit lymphocytes that produce or are capable ofproducing antibodies that will specifically bind to the immunizingagent. Alternatively, the lymphocytes may be immunized invitro.

The immunizing agent will typically include the PRO polypeptide ora fusion protein thereof. Generally, either peripheral bloodlymphocytes ("PBLs") are used if cells of human origin are desired,or spleen cells or lymph node cells are used if non-human mammaliansources are desired. The lymphocytes are then fused with animmortalized cell line using a suitable fusing agent, such aspolyethylene glycol, to form a hybridoma cell [Goding, MonoclonalAntibodies: Principles and Practice, Academic Press, (1986) pp.59-103]. Immortalized cell lines are usually transformed mammaliancells, particularly myeloma cells of rodent, bovine and humanorigin. Usually, rat or mouse myeloma cell lines are employed. Thehybridoma cells may be cultured in a suitable culture medium thatpreferably contains one or more substances that inhibit the growthor survival of the unfused, immortalized cells. For example, if theparental cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the culture medium for the hybridomastypically will include hypoxanthine, aminopterin, and thymidine("HAT medium"), which substances prevent the growth ofHGPRT-deficient cells.

Preferred immortalized cell lines are those that fuse efficiently,support stable high level expression of antibody by the selectedantibody-producing cells, and are sensitive to a medium such as HATmedium. More preferred immortalized cell lines are murine myelomalines, which can be obtained, for instance, from the Salk InstituteCell Distribution Center, San Diego, Calif. and the American TypeCulture Collection, Manassas, Va. Human myeloma and mouse-humanheteromyeloma cell lines also have been described for theproduction of human monoclonal antibodies [Kozbor, J. Immunol.,133:3001(1984); Brodeur et al., Monoclonal Antibody ProductionTechniques and Applications, Marcel Dekker, Inc., New York, (1987)pp. 51-63].

The culture medium in which the hybridoma cells are cultured canthen be assayed for the presence of monoclonal antibodies directedagainst PRO. Preferably, the binding specificity of monoclonalantibodies produced by the hybridoma cells is determined byimmunoprecipitation or by an in vitro binding assay, such asradioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay(ELISA). Such techniques and assays are known in the art. Thebinding affinity of the monoclonal antibody can, for example, bedetermined by the Scatchard analysis of Munson and Pollard, Anal.Biochem., 107:220 (1980).

After the desired hybridoma cells are identified, the clones may besubcloned by limiting dilution procedures and grown by standardmethods [Goding, supra]. Suitable culture media for this purposeinclude, for example, Dulbecco's Modified Eagle's Medium andRPMI-1640 medium. Alternatively, the hybridoma cells may be grownin vivo as ascites in a mammal.

The monoclonal antibodies secreted by the subclones may be isolatedor purified from the culture medium or ascites fluid byconventional immunoglobulin purification procedures such as, forexample, protein A-Sepharose, hydroxylapatite chromatography, gelelectrophoresis, dialysis, or affinity chromatography.

The monoclonal antibodies may also be made by recombinant DNAmethods, such as those described in U.S. Pat. No. 4,816,567. DNAencoding the monoclonal antibodies of the invention can be readilyisolated and sequenced using conventional procedures (e.g., byusing oligonucleotide probes that are capable of bindingspecifically to genes encoding the heavy and light chains of murineantibodies). The hybridoma cells of the invention serve as apreferred source of such DNA. Once isolated, the DNA may be placedinto expression vectors, which are then transfected into host cellssuch as simian COS cells, Chinese hamster ovary (CHO) cells, ormyeloma cells that do not otherwise produce immunoglobulin protein,to obtain the synthesis of monoclonal antibodies in the recombinanthost cells. The DNA also may be modified, for example, bysubstituting the coding sequence for human heavy and light chainconstant domains in place of the homologous murine sequences [U.S.Pat. No. 4,816,567; Morrison et al., supra] or by covalentlyjoining to the immunoglobulin coding sequence all or part of thecoding sequence for a non-immunoglobulin polypeptide. Such anon-immunoglobulin polypeptide can be substituted for the constantdomains of an antibody of the invention, or can be substituted forthe variable domains of one antigen-combining site of an antibodyof the invention to create a chimeric bivalent antibody.

The antibodies may be monovalent antibodies. Methods for preparingmonovalent antibodies are well known in the art. For example, onemethod involves recombinant expression of immunoglobulin lightchain and modified heavy chain. The heavy chain is truncatedgenerally at any point in the Fc region so as to prevent heavychain crosslinking. Alternatively, the relevant cysteine residuesare substituted with another amino acid residue or are deleted soas to prevent crosslinking.

In vitro methods are also suitable for preparing monovalentantibodies. Digestion of antibodies to produce fragments thereof,particularly, Fab fragments, can be accomplished using routinetechniques known in the art.

3. Human and Humanized Antibodies

The anti-PRO antibodies of the invention may further comprisehumanized antibodies or human antibodies. Humanized forms ofnon-human (e.g., murine) antibodies are chimeric immunoglobulins,immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab',F(ab').sub.2 or other antigen-binding subsequences of antibodies)which contain minimal sequence derived from non-humanimmunoglobulin. Humanized antibodies include human immunoglobulins(recipient antibody) in which residues from a complementarydetermining region (CDR) of the recipient are replaced by residuesfrom a CDR of a non-human species (donor antibody) such as mouse,rat or rabbit having the desired specificity, affinity andcapacity. In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are foundneither in the recipient antibody nor in the imported CDR orframework sequences. In general, the humanized antibody willcomprise substantially all of at least one, and typically two,variable domains, in which all or substantially all of the CDRregions correspond to those of a non-human immunoglobulin and allor substantially all of the FR regions are those of a humanimmunoglobulin consensus sequence. The humanized antibody optimallyalso will comprise at least a portion of an immunoglobulin constantregion (Fc), typically that of a human immunoglobulin [Jones etal., Nature, 321:522-525 (1986); Riechmann et al., Nature,332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596(1992)].

Methods for humanizing non-human antibodies are well known in theart. Generally, a humanized antibody has one or more amino acidresidues introduced into it from a source which is non-human. Thesenon-human amino acid residues are often referred to as "import"residues, which are typically taken from an "import" variabledomain. Humanization can be essentially performed following themethod of Winter and co-workers [Jones et al., Nature, 321:522-525(1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen etal., Science 239:1534-1536 (1988)], by substituting rodent CDRs orCDR sequences for the corresponding sequences of a human antibody.Accordingly, such "humanized" antibodies are chimeric antibodies(U.S. Pat. No. 4,816,567), wherein substantially less than anintact human variable domain has been substituted by thecorresponding sequence from a non-human species. In practice,humanized antibodies are typically human antibodies in which someCDR residues and possibly some FR residues are substituted byresidues from analogous sites in rodent antibodies.

Human antibodies can also be produced using various techniquesknown in the art, including phage display libraries [Hoogenboom andWinter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol.,222:581 (1991)]. The techniques of Cole et al. and Boerner et al.are also available for the preparation of human monoclonalantibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy,Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol.,147(1):86-95 (1991)]. Similarly, human antibodies can be made byintroducing of human immunoglobulin loci into transgenic animals,e.g., mice in which the endogenous immunoglobulin genes have beenpartially or completely inactivated. Upon challenge, human antibodyproduction is observed, which closely resembles that seen in humansin all respects, including gene rearrangement, assembly, andantibody repertoire. This approach is described, for example, inU.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126;5,633,425; 5,661,016, and in the following scientific publications:Marks et al., Bio/Technology 10, 779-783(1992); Lonberg et al.,Nature 368 856-859(1994); Morrison, Nature 368, 812-13 (1994);Fishwild et al., Nature Biotechnology 14, 845-51 (1996); Neuberger,Nature Biotechnology 14, 826 (1996); Lonberg and Huszar, Intern.Rev. Immunol. 13 65-93 (1995).

4. Bispecific Antibodies

Bispecific antibodies are monoclonal, preferably human orhumanized, antibodies that have binding specificities for at leasttwo different antigens. In the present case, one of the bindingspecificities is for the PRO, the other one is for any otherantigen, and preferably for a cell-surface protein or receptor orreceptor subunit.

Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodiesis based on the co-expression of two immunoglobulinheavy-chain/light-chain pairs, where the two heavy chains havedifferent specificities [Milstein and Cuello, Nature, 305:537-539(1983)]. Because of the random assortment of immunoglobulin heavyand light chains, these hybridomas (quadromas) produce a potentialmixture of ten different antibody molecules, of which only one hasthe correct bispecific structure. The purification of the correctmolecule is usually accomplished by affinity chromatography steps.Similar procedures are disclosed in WO 93/08829, published May 13,1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at leastpart of the hinge, CH2, and CH3 regions. It is preferred to havethe first heavy-chain constant region (CH1) containing the sitenecessary for light-chain binding present in at least one of thefusions. DNAs encoding the immunoglobulin heavy-chain fusions and,if desired, the immunoglobulin light chain, are inserted intoseparate expression vectors, and are co-transfected into a suitablehost organism. For further details of generating bispecificantibodies see, for example, Suresh et al., Methods in Enzymology,121:210 (1986).

According to another approach described in WO 96/27011, theinterface between a pair of antibody molecules can be engineered tomaximize the percentage of heterodimers which are recovered fromrecombinant cell culture. The preferred interface comprises atleast a part of the CH3 region of an antibody constant domain. Inthis method, one or more small amino acid side chains from theinterface of the first antibody molecule are replaced with largerside chains (e.g. tyrosine or tryptophan). Compensatory "cavities"of identical or similar size to the large side chain(s) are createdon the interface of the second antibody molecule by replacing largeamino acid side chains with smaller ones (e.g. alanine orthreonine). This provides a mechanism for increasing the yield ofthe heterodimer over other unwanted end-products such ashomodimers.

Bispecific antibodies can be prepared as full length antibodies orantibody fragments (e.g. F(ab').sub.2 bispecific antibodies).Techniques for generating bispecific antibodies from antibodyfragments have been described in the literature. For example,bispecific antibodies can be prepared can be prepared usingchemical linkage. Brennan et al., Science 229:81 (1985) describe aprocedure wherein intact antibodies are proteolytically cleaved togenerate F(ab').sub.2 fragments. These fragments are reduced in thepresence of the dithiol complexing agent sodium arsenite tostabilize vicinal dithiols and prevent intermolecular disulfideformation. The Fab' fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab'-TNBderivatives is then reconverted to the Fab'-thiol by reduction withmercaptoethylamine and is mixed with an equimolar amount of theother Fab'-TNB derivative to form the bispecific antibody. Thebispecific antibodies produced can be used as agents for theselective immobilization of enzymes.

Fab' fragments may be directly recovered from E. coli andchemically coupled to form bispecific antibodies. Shalaby et al.,J. Exp. Med. 175:217-225 (1992) describe the production of a fullyhumanized bispecific antibody F(ab').sub.2 molecule. Each Fab'fragment was separately secreted from E. coli and subjected todirected chemical coupling in vitro to form the bispecificantibody. The bispecific antibody thus formed was able to bind tocells overexpressing the ErbB2 receptor and normal human T cells,as well as trigger the lytic activity of human cytotoxiclymphocytes against human breast tumor targets.

Various technique for making and isolating bispecific antibodyfragments directly from recombinant cell culture have also beendescribed. For example, bispecific antibodies have been producedusing leucine zippers. Kostelny et al., J. Immunol.148(5):1547-1553 (1992). The leucine zipper peptides from the Fosand Jun proteins were linked to the Fab' portions of two differentantibodies by gene fusion. The antibody homodimers were reduced atthe hinge region to form monomers and then re-oxidized to form theantibody heterodimers. This method can also be utilized for theproduction of antibody homodimers. The "diabody" technologydescribed by Hollinger et al., Proc. Natl. Acad. Sci. USA90:6444-6448 (1993) has provided an alternative mechanism formaking bispecific antibody fragments. The fragments comprise aheavy-chain variable domain (V.sub.H) connected to a light-chainvariable domain (V.sub.L) by a linker which is too short to allowpairing between the two domains on the same chain. Accordingly, theV.sub.H and V.sub.L domains of one fragment are forced to pair withthe complementary V.sub.L and V.sub.H domains of another fragment,thereby forming two antigen-binding sites. Another strategy formaking bispecific antibody fragments by the use of single-chain Fv(sFv) dimers has also been reported. See, Gruber et al., J.Immunol. 152:5368 (1994).

Antibodies with more than two valencies are contemplated. Forexample, trispecific antibodies can be prepared. Tutt et al., J.Immunol. 147:60 (1991).

Exemplary bispecific antibodies may bind to two different epitopeson a given PRO polypeptide herein. Alternatively, an anti-PROpolypeptide arm may be combined with an arm which binds to atriggering molecule on a leukocyte such as a T-cell receptormolecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG(Fc.gamma.R), such as Fc.gamma.RI (CD64), Fc.gamma.RII (CD32) andFc.gamma.RIII (CD16) so as to focus cellular defense mechanisms tothe cell expressing the particular PRO polypeptide. Bispecificantibodies may also be used to localize cytotoxic agents to cellswhich express a particular PRO polypeptide. These antibodiespossess a PRO-binding arm and an arm which binds a cytotoxic agentor a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA.Another bispecific antibody of interest binds the PRO polypeptideand further binds tissue factor (TF).

5. Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the presentinvention. Heteroconjugate antibodies are composed of twocovalently joined antibodies. Such antibodies have, for example,been proposed to target immune system cells to unwanted cells [U.S.Pat. No. 4,676,980], and for treatment of HIV infection [WO91/00360; WO 92/200373; EP 03089]. It is contemplated that theantibodies may be prepared in vitro using known methods insynthetic protein chemistry, including those involving crosslinkingagents. For example, immunotoxins may be constructed using adisulfide exchange reaction or by forming a thioether bond.Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate and thosedisclosed, for example, in U.S. Pat. No. 4,676,980.

6. Effector Function Engineering

It may be desirable to modify the antibody of the invention withrespect to effector function, so as to enhance, e.g., theeffectiveness of the antibody in treating cancer. For example,cysteine residue(s) may be introduced into the Fc region, therebyallowing interchain disulfide bond formation in this region. Thehomodimeric antibody thus generated may have improvedinternalization capability and/or increased complement-mediatedcell killing and antibody-dependent cellular cytotoxicity (ADCC).See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J.Immunol., 148: 2918-2922 (1992). Homodimeric antibodies withenhanced anti-tumor activity may also be prepared usingheterobifunctional cross-linkers as described in Wolff et al.Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibodycan be engineered that has dual Fc regions and may thereby haveenhanced complement lysis and ADCC capabilities. See Stevenson etal., Anti-Cancer Drug Design, 3: 219-230 (1989).

7. Immunoconiugates

The invention also pertains to immunoconjugates comprising anantibody conjugated to a cytotoxic agent such as a chemotherapeuticagent, toxin (e.g., an enzymatically active toxin of bacterial,fungal, plant, or animal origin, or fragments thereof), or aradioactive isotope (i.e., a radioconjugate).

Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically activetoxins and fragments thereof that can be used include diphtheria Achain, nonbinding active fragments of diphtheria toxin, exotoxin Achain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain,modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthinproteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S),momordica charantia inhibitor, curcin, crotin, sapaonariaofficinalis inhibitor, gelonin, mitogellin, restrictocin,phenomycin, enomycin, and the tricothecenes. A variety ofradionuclides are available for the production of radioconjugatedantibodies. Examples include .sup.212Bi, .sup.131I, .sup.131In,.sup.90Y, and .sup.186Re.

Conjugates of the antibody and cytotoxic agent are made using avariety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP),iminothiolane (IT), bifunctional derivatives of imidoesters (suchas dimethyl adipimidate HCL), active esters (such as disuccinimidylsuberate), aldehydes (such as glutareldehyde), bis-azido compounds(such as bis (p-azidobenzoyl) hexanediamine), bis-diazoniumderivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine),diisocyanates (such as tolyene 2,6-diisocyanate), and bis-activefluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). Forexample, a ricin immunotoxin can be prepared as described inVitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid(MX-DTPA) is an exemplary chelating agent for conjugation ofradionucleotide to the antibody. See WO94/11026.

In another embodiment, the antibody may be conjugated to a"receptor" (such streptavidin) for utilization in tumorpretargeting wherein the antibody-receptor conjugate isadministered to the patient, followed by removal of unboundconjugate from the circulation using a clearing agent and thenadministration of a "ligand" (e.g., avidin) that is conjugated to acytotoxic agent (e.g., a radionucleotide).

8. Immunoliposomes

The antibodies disclosed herein may also be formulated asimmunoliposomes. Liposomes containing the antibody are prepared bymethods known in the art, such as described in Epstein et al.,Proc. Natl. Acad. Sci. USA 82: 3688 (1985); Hwang et al., Proc.Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045and 4,544,545. Liposomes with enhanced circulation time aredisclosed in U.S. Pat. No. 5,013,556.

Particularly useful liposomes can be generated by the reverse-phaseevaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab' fragments of the antibody of the present inventioncan be conjugated to the liposomes as described in Martin et al.,J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchangereaction. A chemotherapeutic agent (such as Doxorubicin) isoptionally contained within the liposome. See Gabizon et al., J.National Cancer Inst., 81(19): 1484 (1989).

9. Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a PRO polypeptide identifiedherein, as well as other molecules identified by the screeningassays disclosed hereinbefore, can be administered for thetreatment of various disorders in the form of pharmaceuticalcompositions.

If the PRO polypeptide is intracellular and whole antibodies areused as inhibitors, internalizing antibodies are preferred.However, lipofections or liposomes can also be used to deliver theantibody, or an antibody fragment, into cells. Where antibodyfragments are used, the smallest inhibitory fragment thatspecifically binds to the binding domain of the target protein ispreferred. For example, based upon the variable-region sequences ofan antibody, peptide molecules can be designed that retain theability to bind the target protein sequence. Such peptides can besynthesized chemically and/or produced by recombinant DNAtechnology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA,90: 7889-7893 (1993). The formulation herein may also contain morethan one active compound as necessary for the particular indicationbeing treated, preferably those with complementary activities thatdo not adversely affect each other. Alternatively, or in addition,the composition may comprise an agent that enhances its function,such as, for example, a cytotoxic agent, cytokine, chemotherapeuticagent, or growth-inhibitory agent. Such molecules are suitablypresent in combination in amounts that are effective for thepurpose intended.

The active ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles,and nanocapsules) or in macroemulsions. Such techniques aredisclosed in Remington's Pharmaceutical Sciences, supra.

The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes.

Sustained-release preparations may be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the antibody, which matricesare in the form of shaped articles, e.g., films, or microcapsules.Examples of sustained-release matrices include polyesters,hydrogels (for example, poly(2-hydroxyethyl-methacrylate), orpoly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and .gamma. ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lacticacid-glycolic acid copolymers such as the LUPRON DEPOT.TM.(injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyricacid. While polymers such as ethylene-vinyl acetate and lacticacid-glycolic acid enable release of molecules for over 100 days,certain hydrogels release proteins for shorter time periods. Whenencapsulated antibodies remain in the body for a long time, theymay denature or aggregate as a result of exposure to moisture at37.degree. C., resulting in a loss of biological activity andpossible changes in immunogenicity. Rational strategies can bedevised for stabilization depending on the mechanism involved. Forexample, if the aggregation mechanism is discovered to beintermolecular S--S bond formation through thio-disulfideinterchange, stabilization may be achieved by modifying sulfhydrylresidues, lyophilizing from acidic solutions, controlling moisturecontent, using appropriate additives, and developing specificpolymer matrix compositions.

G. Uses for anti-PRO Antibodies

The anti-PRO antibodies of the invention have various utilities.For example, anti-PRO antibodies may be used in diagnostic assaysfor PRO, e.g., detecting its expression in specific cells, tissues,or serum. Various diagnostic assay techniques known in the art maybe used, such as competitive binding assays, direct or indirectsandwich assays and immunoprecipitation assays conducted in eitherheterogeneous or homogeneous phases [Zola, Monoclonal Antibodies: AManual of Techniques, CRC Press, Inc. (1987) pp. 147-158]. Theantibodies used in the diagnostic assays can be labeled with adetectable moiety. The detectable moiety should be capable ofproducing, either directly or indirectly, a detectable signal. Forexample, the detectable moiety may be a radioisotope, such as.sup.3H, .sup.14C, .sup.32P, .sup.35S, or .sup.125I, a fluorescentor chemiluminescent compound, such as fluorescein isothiocyanate,rhodamine, or luciferin, or an enzyme, such as alkalinephosphatase, beta-galactosidase or horseradish peroxidase. Anymethod known in the art for conjugating the antibody to thedetectable moiety may be employed, including those methodsdescribed by Hunter et al., Nature, 144:945 (1962); David et al.,Biochemistry, 13:1014 (1974); Pain et al., J. Immunol. Meth.,40:219 (1981); and Nygren, J. Histochem. and Cytochem., 30:407(1982).

Anti-PRO antibodies also are useful for the affinity purificationof PRO from recombinant cell culture or natural sources. In thisprocess, the antibodies against PRO are immobilized on a suitablesupport, such a Sephadex resin or filter paper, using methods wellknown in the art. The immobilized antibody then is contacted with asample containing the PRO to be purified, and thereafter thesupport is washed with a suitable solvent that will removesubstantially all the material in the sample except the PRO, whichis bound to the immobilized antibody. Finally, the support iswashed with another suitable solvent that will release the PRO fromthe antibody.

The following examples are offered for illustrative purposes only,and are not intended to limit the scope of the present invention inany way.

All patent and literature references cited in the presentspecification are hereby incorporated by reference in theirentirety.

EXAMPLES

Commercially available reagents referred to in the examples wereused according to manufacturer's instructions unless otherwiseindicated. The source of those cells identified in the followingexamples, and throughout the specification, by ATCC accessionnumbers is the American Type Culture Collection, Rockville, Md.

Example 1

Extracellular Domain Homology Screening to Identify NovelPolypeptides and cDNA Encoding Therefor

The extracellular domain (ECD) sequences (including the secretionsignal sequence, if any) from about 950 known secreted proteinsfrom the Swiss-Prot public database were used to search ESTdatabases. The EST databases included public databases (e.g.,Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQ.TM.,Incyte Pharmaceuticals, Palo Alto, Calif.). The search wasperformed using the computer program BLAST or BLAST2 (Altschul, andGish, Methods in Enzymology 266: 460-80 (1996)) as a comparison ofthe ECD protein sequences to a 6 frame translation of the ESTsequences. Those comparisons with a Blast score of 70 (or in somecases 90) or greater that did not encode known proteins wereclustered and assembled into consensus DNA sequences with theprogram "phrap" (Phil Green, University of Washington, Seattle,Wash.).

Using this extracellular domain homology screen, consensus DNAsequences were assembled relative to the other identified ESTsequences. In addition, the consensus DNA sequences obtained wereoften (but not always) extended using repeated cycles of BLAST andphrap to extend the consensus sequence as far as possible using thesources of EST sequences discussed above.

Based upon the consensus sequences obtained as described above,oligonucleotides were then synthesized and used to identify by PCRa cDNA library that contained the sequence of interest and for useas probes to isolate a clone of the full-length coding sequence fora PRO polypeptide. Forward (.f) and reverse (.r) PCR primersgenerally range from 20 to 30 nucleotides and are often designed togive a PCR product of about 100-1000 bp in length. The probe (.p)sequences are typically 40-55 bp in length. In some cases,additional oligonucleotides are synthesized when the consensussequence is greater than about 1-1.5 kbp. In order to screenseveral libraries for a full-length clone, DNA from the librarieswas screened by PCR amplification, as per Ausubel et al., CurrentProtocols in Molecular Biology, with the PCR primer pair. Apositive library was then used to isolate clones encoding the geneof interest using the probe oligonucleotide and one of the primerpairs.

The cDNA libraries used to isolate the cDNA clones were constructedby standard methods using commercially available reagents such asthose from Invitrogen, San Diego, Calif. The cDNA was primed witholigo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into asuitable cloning vector (such as pRKB or pRKD; pRK5B is a precursorof pRK5D that does not contain the SfiI site; see, Holmes et al.,Science, 253:1278-1280 (1991)) in the unique XhoI and NotIsites.

Example 2

Isolation of cDNA Clones Encoding PRO211 and PRO217

Consensus DNA sequences were assembled as described in Example 1above and were designated as DNA28730 and DNA28760, respectively.Based on these consensus sequences, oligonucleotides weresynthesized and used to identify by PCR a cDNA library thatcontained the sequences of interest and for use as probes toisolate a clone of the full-length coding sequence for the PRO211and PRO217 polypeptides. The libraries used to isolateDNA32292-1131 and DNA33094-1131 were fetal lung libraries.

cDNA clones were sequenced in their entirety. The entire nucleotidesequences of PRO211 (DNA32292-1131) and PRO217 (UNQ191) are shownin FIG. 1 (SEQ ID NO:1) and FIG. 3 (SEQ ID NO:3), respectively. Thepredicted polypeptides are 353 and 379 amino acid in length,respectively, with respective molecular weights of approximately38,190 and 41,520 daltons.

The oligonucleotide sequences used in the above procedures were thefollowing:

TABLE-US-00006 28730.p (OLI 516) (SEQ ID NO:5)5'-AGGGAGCACGGACAGTGTGCAGATGTGGACGAG TGCTCACTAGCA-3' 28730.f (OLI517) (SEQ ID NO:6) 5'-AGAGTGTATCTCTGGCTACGC-3 28730.r (OLI 518)(SEQ ID NO:7) 5'-TAAGTCCGGCACATTACAGGTC-3' 28760.p (OLI 617) (SEQID NO:8) 5'-CCCACGATGTATGAATGGTGGACTTTGTGTGAC TCCTGGTTTCTGCATC-3'28760.f (OLI 618) (SEQ ID NO:9) 5'-AAAGACGCATCTGCGAGTGTCC-3'28760.r (OLI 619) (SEQ ID NO:10) 5'-TGCTGATTTCACACTGCTCTCCC-3'

Example 3

Isolation of cDNA Clones Encoding Human PRO230

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA30857. An ESTproprietary to Genentech was employed in the consensus assembly.The EST is designated as DNA20088 and has the nucleotide sequenceshown in FIG. 7 (SEQ ID NO:13).

Based on the DNA30857 consensus sequence, oligonucleotides weresynthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone ofthe full-length coding sequence for PRO230.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00007 forward PCR primer 5'-TTCGAGGCCTCTGAGAAGTGGCCC-3'(SEQ ID NO:14) reverse PCR primer 5'-GGCGGTATCTCTCTGGCCTCCC-3' (SEQID NO:15)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30857 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-TTCTCCACAGCAGCTGTGGCATCCGATCGTGTCTCAATCCATTCTCTGGG-3' (SEQ IDNO:16)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO230 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO230(herein designated as DNA33223-1136 and the derived proteinsequence for PRO230.

The entire nucleotide sequence of DNA33223-1136 is shown in FIG. 5(SEQ ID NO:11). Clone DNA33223-1136 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 100-103 and ending at the stop codon at nucleotidepositions 1501-1503 (FIG. 5; SEQ ID NO:11). The predictedpolypeptide precursor is 467 amino acids long FIG. 6).

Example 4

Isolation of cDNA Clones Encoding Human PRO232

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA30935. Based onthe DNA30935 consensus sequence, oligonucleotides were synthesizedto identify by PCR a cDNA library that contained the sequence ofinterest and for use as probes to isolate a clone of thefull-length coding sequence for PRO232.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00008 forward PCR primer 5'-TGCTGTGCTACTCCTGCAAAGCCC-3'(SEQ ID NO:19) reverse PCR primer 5'-TGCACAAGTCGGTGTCACAGCACG-3'(SEQ ID NO:20)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30935 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-AGCAACGAGGACTGCCTGCAGGTGGAGAACTGCACCCAGCTGGG-3' (SEQ IDNO:21)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO232 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO232 [herein designated asDNA34435-1140] and the derived protein sequence for PRO232.

The entire nucleotide sequence of DNA34435-1140 is shown in FIG. 8(SEQ ID NO:17). Clone DNA34435-1140 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 17-19 and ending at the stop codon at nucleotidepositions 359-361 (FIG. 8; SEQ ID NO:17). The predicted polypeptideprecursor is 114 amino acids long (FIG. 9). Clone DNA34435-1140 hasbeen deposited with ATCC on Sep. 16, 1997 and is assigned ATCCdeposit no. ATCC 209250.

Analysis of the amino acid sequence of the full-length PRO232suggests that it possesses 35% sequence identity with a stem cellsurface antigen from Gallus gallus.

Example 5

Isolation of cDNA Clones Encoding PRO187

A proprietary expressed sequence tag (EST) DNA database(LIFESEQ.TM., Incyte Pharmaceuticals, Palo Alto, Calif.) wassearched and an EST (#843193) was identified which showed homologyto fibroblast growth factor (FGF-8) also known as androgen-inducedgrowth factor. mRNA was isolated from human fetal lung tissue usingreagents and protocols from Invitrogen, San Diego, Calif. (FastTrack 2). The cDNA libraries used to isolate the cDNA clones wereconstructed by standard methods using commercially availablereagents (e.g., Invitrogen, San Diego, Calif., Life Technologies,Gaithersburg, Md.). The cDNA was primed with oligo dT containing aNotI site, linked with blunt to SalI hemikinased adaptors, cleavedwith NotI, sized appropriately by gel electrophoresis, and clonedin a defined orientation into the cloning vector pRK5D usingreagents and protocols from Life Technologies, Gaithersburg, Md.(Super Script Plasmid System). The double-stranded cDNA was sizedto greater than 1000 bp and the SalI/NotI linkered cDNA was clonedinto XhoI/NotI cleaved vector. pRK5D is a cloning vector that hasan sp6 transcription initiation site followed by an SfiIrestriction enzyme site preceding the XhoI/NotI cDNA cloningsites.

Several libraries from various tissue sources were screened by PCRamplification with the following oligonucleotide probes: IN843193.f (OLI 315) (SEQ ID NO:24) 5'-CAGTACGTGAGGGACCAGGGCGCCATGA-3'IN843193. r (OLI 317) (SEQ ID NO:25) 5'-CCGGTGACCTGCACGTGCTTGCCA-3'A positive library was then used to isolate clones encoding thePRO187 gene using one of the above oligonucleotides and thefollowing oligonucleotide probe: IN843193. p (OLI 316) (SEQ IDNO:26) 5'-GCGGATCTGCCGCCTGCTCANCTGGTCGGTCATGGCGCCCT-3'

A cDNA clone was sequenced in entirety. The entire nucleotidesequence of PRO187 (DNA27864-1155) is shown in FIG. 10 (SEQ IDNO:22). Clone DNA27864-1155 contains a single open reading framewith an apparent translational initiation site at nucleotideposition 1 (FIG. 10; SEQ ID NO:22). The predicted polypeptideprecursor is 205 amino acids long. Clone DNA27864-1155 has beendeposited with the ATCC (designation: DNA27864-1155) and isassigned ATCC deposit no. ATCC 209375.

Based on a BLAST and FastA sequence alignment analysis (using theALIGN computer program) of the full-length sequence, the PRO187polypeptide shows 74% amino acid sequence identity (Blast score310) to human fibroblast growth factor-8 (androgen-induced growthfactor).

Example 6

Isolation of cDNA Clones Encoding PRO265

A consensus DNA sequence was assembled relative to other ESTsequences as described in Example 1 above using phrap. Thisconsensus sequence is herein designated DNA33679. Based on theDNA33679 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO265.

PCR primers (two forward and one reverse) were synthesized:

TABLE-US-00009 forward PCR primer A: 5'-CGGTCTACCTGTATGGCAACC-3';(SEQ ID NO:29) forward PCR primer B: 5'-GCAGGACAACCAGATAAACCAC-3';(SEQ ID NO:30) reverse PCR primer 5'-ACGCAGATTTGAGAAGGCTGTC-3' (SEQID NO:31)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA33679 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-TTCACGGGCTGCTCTTGCCCAGCTCTTGAAGCTTGAAGAGCTGCAC-3' (SEQ IDNO:32)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith PCR primer pairs identified above. A positive library was thenused to isolate clones encoding the PRO265 gene using the probeoligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humana fetal brain library.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO265 [herein designated asDNA36350-1158] (SEQ ID NO:27) and the derived protein sequence forPRO265.

The entire nucleotide sequence of DNA36350-1158 is shown in FIG. 12(SEQ ID NO:27). Clone DNA36350-1158 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 352-354 and ending at the stop codon at positions2332-2334 (FIG. 12). The predicted polypeptide precursor is 660amino acids long (FIG. 13). Clone DNA36350-1158 has been depositedwith ATCC and is assigned ATCC deposit no. ATCC 209378.

Analysis of the amino acid sequence of the full-length PRO265polypeptide suggests that portions of it possess significanthomology to the fibromodulin and the fibromodulin precursor,thereby indicating that PRO265 may be a novel member of the leucinerich repeat family, particularly related to fibromodulin.

Example 7

Isolation of cDNA Clones Encoding Human PRO219

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA28729. Based on theDNA28729 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO219.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00010 forward PCR primer 5'-GTGACCCTGGTTGTGAATACTCC-3'(SEQ ID NO:35) reverse PCR primer 5'-ACAGCCATGGTCTATAGCTTGG-3' (SEQID NO:36)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28729 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GCCTGTCAGTGTCCTGAGGGACACGTGCTCCGCAGCGATGGGAAG-3' (SEQ IDNO:37)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO219 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO219 [herein designated asDNA32290-1164] (SEQ ID NO:33) and the derived protein sequence forPRO219.

The entire nucleotide sequence of DNA32290-1164 is shown in FIG. 14(SEQ ID NO:33). Clone DNA32290-1164 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 204-206 and ending at the stop codon at nucleotidepositions 2949-2951 (FIG. 14). The predicted polypeptide precursoris 915 amino acids long (FIG. 15). Clone DNA32290-1164 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209384.

Analysis of the amino acid sequence of the full-length PRO219polypeptide suggests that portions of it possess significanthomology to the mouse and human matrilin-2 precursorpolypeptides.

Example 8

Isolation of cDNA Clones Encoding Human PRO246

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA30955. Based on theDNA30955 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO246.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00011 forward PCR primer 5'-AGGGTCTCCAGGAGAAAGACTC-3' (SEQID NO:40) reverse PCR primer 5'-ATTGTGGGCCTTGCAGACATAGAC-3' (SEQ IDNO:41)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30955 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGCCACAGCATCAAAACCTTAGAACTCAATGTACTGGTTCCTCCAGCTCC-3' (SEQ IDNO:42)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO246 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO246[herein designated as DNA35639-1172] (SEQ ID NO:38) and the derivedprotein sequence for PRO246.

The entire nucleotide sequence of DNA35639-1172 is shown in FIG. 16(SEQ ID NO:38). Clone DNA35639-1172 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 126-128 and ending at the stop codon at nucleotidepositions 1296-1298 (FIG. 16). The predicted polypeptide precursoris 390 amino acids long (FIG. 17). Clone DNA35639-1172 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209396.

Analysis of the amino acid sequence of the full-length PRO246polypeptide suggests that it possess significant homology to thehuman cell surface protein HCAR, thereby indicating that PRO246 maybe a novel cell surface virus receptor.

Example 9

Isolation of cDNA Clones Encoding Human PRO228

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA28758. An ESTproprietary to Genentech was employed in the consensus assembly.This EST is shown in FIG. 20 (SEQ ID NO:50) and is hereindesignated as DNA21951.

Based on the DNA28758 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence for PRO228.

PCR primers (forward and reverse) were synthesized:

TABLE-US-00012 forward PCR primer 5'-GGTAATGAGCTCCATTACAG-3' (SEQID NO:51) forward PCR primer 5'-GGAGTAGAAAGCGCATGG-3' (SEQ IDNO:52) forward PCR primer 5'-CACCTGATACCATGAATGGCAG-3' (SEQ IDNO:53) reverse PCR primer 5'-CGAGCTCGAATTAATTCG-3' (SEQ ID NO:54)reverse PCR primer 5'-GGATCTCCTGAGCTCAGG-3' (SEQ ID NO:55) reversePCR primer 5'-CCTAGTTGAGTGATCCTTGTAAG-3' (SEQ ID NO:56)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28758 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-ATGAGACCCACACCTCATGCCGCTGTAATCACCTGACACATTTTGCAATT-3' (SEQ IDNO:57)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO228 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO228 [herein designated asDNA33092-1202] (SEQ ID NO:48) and the derived protein sequence forPRO228.

The entire nucleotide sequence of DNA33092-1202 is shown in FIG. 18(SEQ ID NO:48). Clone DNA33092-1202 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 24-26 of SEQ ID NO:48 and ending at the stop codon afternucleotide position 2093 of SEQ ID NO:48. The predicted polypeptideprecursor is 690 amino acids long (FIG. 19). Clone DNA33092-1202has been deposited with ATCC and is assigned ATCC deposit no. ATCC209420.

Analysis of the amino acid sequence of the full-length PRO228polypeptide suggests that portions of it possess significanthomology to the secretin-related proteins CD97 and EMR1 as well asthe secretin member, latrophilin, thereby indicating that PRO228may be a new member of the secretin related proteins.

Example 10

Isolation of cDNA Clones Encoding Human PRO533

The EST sequence accession number AF007268, a murine fibroblastgrowth factor (FGF-15) was used to search various public ESTdatabases (e.g., GenBank, Dayhoff, etc.) The search was performedusing the computer program BLAST or BLAST2 as a comparison of theECD protein sequences to a 6 frame translation of the ESTsequences. The search resulted in a hit with GenBank EST AA220994,which has been identified as stratagene NT2 neuronal precursor937230.

Based on the Genbank EST AA220994 sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence. Forward and reverse PCRprimers may range from 20 to 30 nucleotides (typically about 24),and are designed to give a PCR product of 100-1000 bp in length.The probe sequences are typically 40-55 bp (typically about 50) inlength. In order to screen several libraries for a source of afull-length clone, DNA from the libraries was screened by PCRamplification, as per Ausubel et al., Current Protocols inMolecular Biology, with the PCR primer pair. A positive library wasthen used to isolate clones encoding the gene of interest using theprobe oligonucleotide and one of the PCR primers.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified below. A positive library wasthen used to isolate clones encoding the PRO533 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal retina. The cDNA libraries used to isolated the cDNA cloneswere constructed by standard methods using commercially availablereagents (e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) ThecDNA was primed with oligo dT containing a NotI site, linked withblunt to SalI hemikinased adaptors, cleaved with NotI, sizedappropriately by gel electrophoresis, and cloned in a definedorientation into a suitable cloning vector (such as pRKB or pRKD;pRK5B is a precursor of pRK5D that does not contain the SfiI site;see, Holmes et al., Science, 253:1278-1280 (1991)) in the uniqueXhoI and NotI sites.

A cDNA clone was sequenced in its entirety. The full lengthnucleotide sequence of PRO533 is shown in FIG. 21 (SEQ ID NO:58).Clone DNA49435-1219 contains a single open reading frame with anapparent translational initiation site at nucleotide positions459-461 (FIG. 21; SEQ ID NO:58). The predicted polypeptideprecursor is 216 amino acids long. Clone DNA47412-1219 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209480.

Based on a BLAST-2 and FastA sequence alignment analysis of thefull-length sequence, PRO533 shows amino acid sequence identity tofibroblast growth factor (53%).

The oligonucleotide sequences used in the above procedure were thefollowing:

TABLE-US-00013 FGF15.forward: 5'-ATCCGCCCAGATGGCTACAATGTGTA-3';(SEQ ID NO:60) FGF15.probe: 5'-GCCTCCCGGTCTCCCTGAGCAGTGCCAAACAGC(SEQ ID NO:61) GGCAGTGTA-3'; FGF15.reverse:5'-CCAGTCCGGTGACAAGCCCAAA-3'. (SEQ ID NO:62)

Example 11

Isolation of cDNA Clones Encoding Human PRO245

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA30954.

Based on the DNA30954 consensus sequence, oligonucleotides weresynthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone ofthe full-length coding sequence for PRO245.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00014 forward PCR primer 5'-ATCGTTGTGAAGTTAGTGCCCC-3' (SEQID NO:65) reverse PCR primer 5'-ACCTGCGATATCCAACAGAATTG-3' (SEQ IDNO:66)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30954 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGAAGAGGATACAGTCACTCTGGAAGTATTAGTGGCTCCAGCAGTTCC-3' (SEQ IDNO:67)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO245 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO245[herein designated as DNA35638-1141] and the derived proteinsequence for PRO245.

The entire nucleotide sequence of DNA35638-1141 is shown in FIG. 23(SEQ ID NO:63). Clone DNA35638-1141 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 89-91 and ending at the stop codon at nucleotidepositions 1025-1027 (FIG. 23; SEQ ID NO:63). The predictedpolypeptide precursor is 312 amino acids long (FIG. 24). CloneDNA35638-1141 has been deposited with ATCC on Sep. 16, 1997 and isassigned ATCC deposit no. ATCC 209265.

Analysis of the amino acid sequence of the full-length PRO245suggests that a portion of it possesses 60% amino acid identitywith the human c-myb protein and, therefore, may be a new member ofthe transmembrane protein receptor tyrosine kinase family.

Example 12

Isolation of cDNA Clones Encoding Human PRO220, PRO221 andPRO227

(a) PRO220

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA28749. Based onthe DNA28749 consensus sequence, oligonucleotides were synthesizedto identify by PCR a cDNA library that contained the sequence ofinterest and for use as probes to isolate a clone of thefull-length coding sequence for PRO220.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00015 forward PCR primer 5'-TCACCTGGAGCCTTTATTGGCC-3' (SEQID NO:74) reverse PCR primer 5'-ATACCAGCTATAACCAGGCTGCG-3' (SEQ IDNO:75)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28749 sequence which had thefollowing nucleotide sequence: Hybridization Probe5'-CAACAGTAAGTGGTTTGATGCTCTTCCAAATCTAGAGATTCTGATGATTGGG-3' (SEQ IDNO:76).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO220 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO220[herein designated as DNA32298-1132 and the derived proteinsequence for PRO220.

The entire nucleotide sequence of DNA32298-1132 is shown in FIG. 25(SEQ ID NO:68). Clone DNA32298-1132 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 480-482 and ending at the stop codon at nucleotidepositions 2604-2606 (FIG. 25). The predicted polypeptide precursoris 708 amino acids long (FIG. 26). Clone DNA32298-1132 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209257.

Analysis of the amino acid sequence of the full-length PRO220 showsit has homology to member of the leucine rich repeat proteinsuperfamily, including the leucine rich repeat protein and theneuronal leucine-rich repeat protein 1.

(b) PRO221

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA28756. Based onthe DNA28756 consensus sequence, oligonucleotides were synthesizedto identify by PCR a cDNA library that contained the sequence ofinterest and for use as probes to isolate a clone of thefull-length coding sequence for PRO221.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00016 forward PCR primer 5'-CCATGTGTCTCCTCCTACAAAG-3' (SEQID NO:77) reverse PCR primer 5'-GGGAATAGATGTGATCTGATTGG-3' (SEQ IDNO:78)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28756 sequence which had thefollowing nucleotide sequence: Hybridization Probe5'-CACCTGTAGCAATGCAAATCTCAAGGAAATACCTAGAGATCTTCCTCCTG-3' (SEQ IDNO:79)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO221 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO221[herein designated as DNA33089-1132 and the derived proteinsequence for PRO221.

The entire nucleotide sequence of DNA33089-1132 is shown in FIG. 27(SEQ ID NO:70). Clone DNA33089-1132 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 179-181 and ending at the stop codon at nucleotidepositions 956-958 (FIG. 27). The predicted polypeptide precursor is259 amino acids long (FIG. 28). PRO221 is believed to have atransmembrane region at amino acids 206-225. Clone DNA33089-1132has been deposited with ATCC and is assigned ATCC deposit no. ATCC209262.

Analysis of the amino acid sequence of the full-length PRO221 showsit has homology to member of the leucine rich repeat proteinsuperfamily, including the SLIT protein.

(c) PRO227

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA28740. Based onthe DNA28740 consensus sequence, oligonucleotides were synthesizedto identify by PCR a cDNA library that contained the sequence ofinterest and for use as probes to isolate a clone of thefull-length coding sequence for PRO227.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00017 forward PCR primer 5'-AGCAACCGCCTGAAGCTCATCC-3' (SEQID NO:80) reverse PCR primer 5'-AAGGCGCGGTGAAAGATGTAGACG-3' (SEQ IDNO:81)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28740 sequence which had thefollowing nucleotide sequence: Hybridization Probe5'GACTACATGTTTCAGGACCTGTACAACCTCAAGTCACTGGAGGTTGGCGA-3' (SEQ IDNO:82).

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO227 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO227[herein designated as DNA33786-1132 and the derived proteinsequence for PRO227.

The entire nucleotide sequence of DNA33786-1132 is shown in FIG. 29(SEQ ID NO:72). Clone DNA33786-1132 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 33-35 and ending at the stop codon at nucleotidepositions 1893-1895 (FIG. 29). The predicted polypeptide precursoris 620 amino acids long (FIG. 30). PRO227 is believed to have atransmembrane region. Clone DNA33786-1132 has been deposited withATCC and is assigned ATCC deposit no. ATCC 209253.

Analysis of the amino acid sequence of the full-length PRO221 showsit has homology to member of the leucine rich repeat proteinsuperfamily, including the platelet glycoprotein V precursor andthe human glycoprotein V.

Example 13

Isolation of cDNA Clones Encoding Human PRO258

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA28746.

Based on the DNA28746 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence for PRO258.

PCR primers (forward and reverse) were synthesized:

TABLE-US-00018 forward PCR primer 5'-GCTAGGAATTCCACAGAAGCCC-3' (SEQID NO:85) reverse PCR primer 5'-AACCTGGAATGTCACCGAGCTG-3' (SEQ IDNO:86) reverse PCR primer 5'-CCTAGCACAGTGACGAGGGACTTGGC-3' (SEQ IDNO:87)

Additionally, synthetic oligonucleotide hybridization probes wereconstructed from the consensus DNA28740 sequence which had thefollowing nucleotide sequence: Hybridization Probe

TABLE-US-00019 5'-AAGACACAGCCACCCTAAACTGTCAGTCTTCTG (SEQ ID NO:88)GGAGCAAGCCTGCAGCC-3' 5'-GCCCTGGCAGACGAGGGCGAGTACACCTGCTCA (SEQ IDNO:89) ATCTTCACTATGCCTGT-3'

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO258 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO258[herein designated as DNA35918-1174] (SEQ ID NO:83) and the derivedprotein sequence for PRO258.

The entire nucleotide sequence of DNA35918-1174 is shown in FIG. 31(SEQ ID NO:83). Clone DNA35918-1174 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 147-149 of SEQ ID NO:83 and ending at the stop codonafter nucleotide position 1340 of SEQ ID NO:83 (FIG. 31). Thepredicted polypeptide precursor is 398 amino acids long (FIG. 32).Clone DNA35918-1174 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209402.

Analysis of the amino acid sequence of the full-length PRO258polypeptide suggests that portions of it possess significanthomology to the CRTAM and the poliovirus receptor and have an Igdomain, thereby indicating that PRO258 is a new member of the Igsuperfamily.

Example 14

Isolation of cDNA Clones Encoding Human PRO266

An expressed sequence tag database was searched for ESTs havinghomology to SLIT, resulting in the identification of a single ESTsequence designated herein as T73996. Based on the T73996 ESTsequence, oligonucleotides were synthesized: 1) to identify by PCRa cDNA library that contained the sequence of interest, and 2) foruse as probes to isolate a clone of the full-length coding sequencefor PRO266.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00020 forward PCR primer 5'-GTTGGATCTGGGCAACAATAAC-3' (SEQID NO:92) reverse PCR primer 5'-ATTGTTGTGCAGGCTGAGTTTAAG-3' (SEQ IDNO:93)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed which had the following nucleotide sequenceHybridization Probe5'-GGTGGCTATACATGGATAGCAATTACCTGGACACGCTGTCCCGGG-3' (SEQ IDNO:94)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO266 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal brain tissue. DNA sequencing of the clones isolated asdescribed above gave the full-length DNA sequence for PRO266[herein designated as DNA37150-1178] (SEQ ID NO:90) and the derivedprotein sequence for PRO266.

The entire nucleotide sequence of DNA37150-1178 is shown in FIG. 33(SEQ ID NO:90). Clone DNA37150-1178 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 167-169 and ending at the stop codon after nucleotideposition 2254 of SEQ ID NO:90. The predicted polypeptide precursoris 696 amino acids long (FIG. 34). Clone DNA37150-1178 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209401.

Analysis of the amino acid sequence of the full-length PRO266polypeptide suggests that portions of it possess significanthomology to the SLIT protein, thereby indicating that PRO266 may bea novel leucine rich repeat protein.

Example 15

Isolation of cDNA Clones Encoding Human PRO269

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA35705. Based on theDNA35705 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO269.

Forward and reverse PCR primers were synthesized:

TABLE-US-00021 forward PCR primer (.f1)5'-TGGAAGGAGATGCGATGCCACCTG-3' (SEQ ID NO:97) forward PCR primer(.f2) 5'-TGACCAGTGGGGAAGGACAG-3' (SEQ ID NO:98) forward PCR primer(.f3) 5'-ACAGAGCAGAGGGTGCCTTG-3' (SEQ ID NO:99) reverse PCR primer(.r1) 5'-TCAGGGACAAGTGGTGTCTCTCCC-3' (SEQ ID NO:100) reverse PCRprimer (.r2) 5'-TCAGGGAAGGAGTGTGCAGTTCTG-3' (SEQ ID NO:101)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35705 sequence which had thefollowing nucleotide sequence: Hybridization Probe5'-ACAGCTCCCGATCTCAGTTACTTGCATCGCGGACGAAATCGGCGCTCGCT-3' (SEQ IDNO:102)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO269 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO269 [herein designated asDNA38260-1180] (SEQ ID NO:95) and the derived protein sequence forPRO269.

The entire nucleotide sequence of DNA38260-1180 is shown in FIG. 35(SEQ ID NO:95). Clone DNA38260-1180 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 314-316 and ending at the stop codon at nucleotidepositions 1784-1786 (FIG. 35; SEQ ID NO:95). The predictedpolypeptide precursor is 490 amino acids long (FIG. 36). CloneDNA38260-1180 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209397.

Analysis of the amino acid sequence of the full-length PRO269suggests that portions of it possess significant homology to thehuman thrombomodulin proteins, thereby indicating that PRO269 maypossess one or more thrombomodulin-like domains.

Example 16

Isolation of cDNA Clones Encoding Human PRO287

A consensus DNA sequence encoding PRO287 was assembled relative tothe other identified EST sequences as described in Example 1 above,wherein the consensus sequence is designated herein as DNA28728.Based on the DNA28728 consensus sequence, oligonucleotides weresynthesized to identify by PCR a cDNA library that contained thesequence of interest and for use as probes to isolate a clone ofthe full-length coding sequence for PRO287.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00022 forward PCR primer 5'-CCGATTCATAGACCTCGAGAGT-3' (SEQID NO:105) reverse PCR primer 5'-GTCAAGGAGTCCTCCACAATAC-3' (SEQ IDNO:106)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28728 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GTGTACAATGGCCATGCCAATGGCCAGCGCATTGGCCGCTTCTGT-3' (SEQ IDNO:107)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO287 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO287 [herein designated asDNA39969-1185, SEQ ID NO:103] and the derived protein sequence forPRO287.

The entire nucleotide sequence of DNA39969-1185 is shown in FIG. 37(SEQ ID NO:103). Clone DNA39969-1185 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 307-309 and ending at the stop codon at nucleotidepositions 1552-1554 (FIG. 37; SEQ ID NO:103). The predictedpolypeptide precursor is 415 amino acids long (FIG. 38). CloneDNA39969-1185 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209400.

Analysis of the amino acid sequence of the full-length PRO287suggests that it may possess one or more procollagen C-proteinaseenhancer protein precursor or procollagen C-proteinase enhancerprotein-like domains. Based on a BLAST and FastA sequence alignmentanalysis of the full-length sequence, PRO287 shows nucleic acidsequence identity to procollagen C-proteinase enhancer proteinprecursor and procollagen C-proteinase enhancer protein (47 and54%, respectively).

Example 17

Isolation of cDNA Clones Encoding Human PRO214

A consensus DNA sequence was assembled using phrap as described inExample 1 above. This consensus DNA sequence is designated hereinas DNA28744. Based on this consensus sequence, oligonucleotideswere synthesized: 1) to identify by PCR a cDNA library thatcontained the sequence of interest, and 2) for use as probes toisolate a clone of the full-length coding sequence.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified below. A positive library wasthen used to isolate clones encoding the PRO214 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue.

A cDNA clone was sequenced in its entirety The full lengthnucleotide sequence of DNA32286-1191 is shown in FIG. 39 (SEQ IDNO:108). DNA32286-1191 contains a single open reading frame with anapparent translational initiation site at nucleotide position 103(FIG. 39; SEQ ID NO:108). The predicted polypeptide precursor is420 amino acids long (SEQ ID NO:109).

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO214 polypeptide shows amino acid sequenceidentity to HT protein and/or Fibulin (49% and 38%,respectively).

The oligonucleotide sequences used in the above procedure were thefollowing:

TABLE-US-00023 28744.P (OLI555) (SEQ ID NO:110)5'-CCTGGCTATCAGCAGGTGGGCTCCAAGTGTC TCGATGTGGATGAGTGTGA-3' 28744.f(OLI556) (SEQ ID NO:111) 5'-ATTCTGCGTGAACACTGAGGGC-3' 28744.r(OLI557) (SEQ ID NO:112) 5'-ATCTGCTTGTAGCCCTCGGCAC-3'

Example 18

Isolation of cDNA Clones Encoding Human PRO317

A consensus DNA sequence was assembled using phrap as described inExample 1 above, wherein the consensus sequence is hereindesignated as DNA28722. Based on this consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNAlibrary that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence. Theforward and reverse PCR primers, respectively, synthesized for thispurpose were:

TABLE-US-00024 (OLI489) (SEQ ID NO:115) 5'-AGGACTGCCATAACTTGCCTGand (OLI490) (SEQ ID NO:116) 5'-ATAGGAGTTGAAGCAGCGCTGC.

The probe synthesized for this purpose was:5'-TGTGTGGACATAGACGAGTGCCGCTACCGCTACTGCCAGCACCGC (OL1488) (SEQ IDNO:117)

mRNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplification, asper Ausubel et al., Current Protocols in Molecular Biology (1989),with the PCR primer pair identified above. A positive library wasthen used to isolate clones containing the PRO317 gene using theprobe oligonucleotide identified above and one of the PCRprimers.

A cDNA clone was sequenced in its entirety. The entire nucleotidesequence of DNA33461-1199 (encoding PRO317) is shown in FIG. 41(SEQ ID NO:113). Clone DNA33461-1199 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 68-70 (FIG. 41; SEQ ID NO:113). The predicted polypeptideprecursor is 366 amino acids long. The predicted signal sequence isamino acids 1-18 of FIG. 42 (SEQ ID NO:114). There is one predictedN-linked glycosylation site at amino acid residue 160. CloneDNA33461-1199 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209367.

Based on BLAST.TM. and FastA.TM. sequence alignment analysis (usingthe ALIGN.TM. computer program) of the full-length PRO317 sequence,PRO317 shows the most amino acid sequence identity to EBAF-1 (92%).The results also demonstrate a significant homology between humanPRO317 and mouse LEFTY protein. The C-terminal end of the PRO317protein contains many conserved sequences consistent with thepattern expected of a member of the TGF-superfamily.

In situ expression analysis in human tissues performed as describedbelow evidences that there is distinctly strong expression of thePRO317 polypeptide in pancreatic tissue.

Example 19

Isolation of cDNA Clones Encoding Human PRO301

A consensus DNA sequence designated herein as DNA35936 wasassembled using phrap as described in Example 1 above. Based onthis consensus sequence, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence.

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified below. A positive library wasthen used to isolate clones encoding the PRO301 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney.

A cDNA clone was sequenced in its entirety. The full lengthnucleotide sequence of native sequence PRO301 is shown in FIG. 43(SEQ ID NO:118). Clone DNA40628-1216 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 52-54 (FIG. 43; SEQ ID NO:118). The predicted polypeptideprecursor is 299 amino acids long with a predicted molecular weightof 32,583 daltons and pI of 8.29. Clone DNA40628-1216 has beendeposited with ATCC and is assigned ATCC deposit No. ATCC209432.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO301 shows amino acid sequence identity toA33 antigen precursor (30%) and coxsackie and adenovirus receptorprotein (29%).

The oligonucleotide sequences used in the above procedure were thefollowing:

TABLE-US-00025 OLI2162 (35936.f1) (SEQ ID NO:120)5'-TCGCGGAGCTGTGTTCTGTTTCCC-3' OLI2163 (35936.p1) (SEQ ID NO:121)5'-TGATCGCGATGGGGACAAAGGCGCAAGCTCG AGAGGAAACTGTTGTGCCT-3' OLI2164(35936.f2) (SEQ ID NO:122) 5'-ACACCTGGTTCAAAGATGGG-3' OLI2165(35936.r1) (SEQ ID NO:123) 5'-TAGGAAGAGTTGCTGAAGGCACGG-3' OLI2166(35936.f3) (SEQ ID NO:124) 5'-TTGCCTTACTCAGGTGCTAC-3' OLI2167(35936.r2) (SEQ ID NO:125) 5'-ACTCAGCAGTGGTAGGAAAG-3'

Example 20

Isolation of cDNA Clones Encoding Human PRO224

A consensus DNA sequence assembled relative to the other identifiedEST sequences as described in Example 1, wherein the consensussequence is designated herein as DNA30845. Based on the DNA30845consensus sequence, oligonucleotides were synthesized to identifyby PCR a cDNA library that contained the sequence of interest andfor use as probes to isolate a clone of the full-length codingsequence for PRO224.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00026 forward PCR primer 5'-AAGTTCCAGTGCCGCACCAGTGGC-3'(SEQ ID NO:128) reverse PCR primer 5'-TTGGTTCCACAGCCGAGCTCGTCG-3'(SEQ ID NO:129)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30845 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GAGGAGGAGTGCAGGATTGAGCCATGTACCCAGAAAGGGCAATGCCCACC-3' (SEQ IDNO:130)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO224 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO224 [herein designated asDNA33221-1133] and the derived protein sequence for PRO224.

The entire nucleotide sequence of DNA33221-1133 is shown in FIG. 45(SEQ ID NO:126). Clone DNA33221-1133 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 33-35 and ending at the stop codon at nucleotidepositions 879-899 (FIG. 45; SEQ ID NO:126). The start of atransmembrane region begins at nucleotide position 777. Thepredicted polypeptide precursor is 282 amino acids long (FIG. 46).Clone DNA33221-1133 has been deposited with ATCC and is assignedATCC deposit no. ATCC 209263.

Analysis of the amino acid sequence of the full-length PRO224suggests that it has homology to very low-density lipoproteinreceptors, apolipoprotein E receptor and chicken oocyte receptorsP95. Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO224 has amino acid identity to portions ofthese proteins in the range from 28% to 45%, and overall identitywith these proteins in the range from 33% to 39%.

Example 21

Isolation of cDNA Clones Encoding Human PRO222

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence is designated herein as DNA28771. Based onthe DNA28771 consensus sequence, oligonucleotides were synthesizedto identify by PCR a cDNA library that contained the sequence ofinterest and for use as probes to isolate a clone of thefull-length coding sequence for PRO222.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00027 forward PCR primer 5'-ATCTCCTATCGCTGCTTTCCCGG-3'(SEQ ID NO:133) reverse PCR primer 5'-AGCCAGGATCGCAGTAAAACTCC-3'(SEQ ID NO:134)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28771 sequence which had thefollowing nucleotide sequence: Hybridization Probe5'-ATTTAAACTTGATGGGTCTGCGTATCTTGAGTGCTTACAAAACCTTATCT-3' (SEQ IDNO:135)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO222 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO222 [herein designated asDNA33107-1135] and the derived protein sequence for PRO222.

The entire nucleotide sequence of DNA33107-1135 is shown in FIG. 47(SEQ ID NO:131). Clone DNA33107-1135 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 159-161 and ending at the stop codon at nucleotidepositions 1629-1631 (FIG. 47; SEQ ID NO:131). The predictedpolypeptide precursor is 490 amino acids long (FIG. 48). CloneDNA33107-1135 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209251.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO222 shows amino acid sequence identity tomouse complement factor h precursor (25-26%), complement receptor(27-29%), mouse complement C3b receptor type 2 long form precursor(25-47%) and human hypothetical protein kiaa0247 (40%).

Example 22

Isolation of cDNA clones Encoding PRO234

A consensus DNA sequence was assembled (DNA30926) using phrap asdescribed in Example 1 above. Based on this consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNAlibrary that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence.

RNA for the construction of the cDNA libraries was isolated usingstandard isolation protocols, e.g., Ausubel et al., CurrentProtocols in Molecular Biology, from tissue or cell line sources orit was purchased from commercial sources (e.g., Clontech). The cDNAlibraries used to isolate the cDNA clones were constructed bystandard methods (e.g., Ausubel et al.) using commerciallyavailable reagents (e.g., Invitrogen). This library was derivedfrom 22 week old fetal brain tissue.

A cDNA clone was sequenced in its entirety. The entire nucleotidesequence of PRO234 is shown in FIG. 49 (SEQ ID NO:136). Thepredicted polypeptide precursor is 382 amino acids long and has acalculated molecular weight of approximately 43.1 kDa.

The oligonucleotide sequences used in the above procedure were thefollowing:

TABLE-US-00028 30926.p (OLI826): (SEQ ID NO:138)5'-GTTCATTGAAAACCTCTTGCCATCTGATGGT GACTTCTGGATTGGGCTCA-3' 30926.f(OLI827): (SEQ ID NO:139) 5'-AAGCCAAAGAAGCCTGCAGGAGGG-3' 30926.r(OLI828): (SEQ ID NO:140) 5'-CAGTCCAAGCATAAAGGTCCTGGC-3'

Example 23

Isolation of cDNA Clones Encoding Human PRO231

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence was designated herein as DNA30933. Based onthe DNA30933 consensus sequence, oligonucleotides were synthesizedto identify by PCR a cDNA library that contained the sequence ofinterest and for use as probes to isolate a clone of thefull-length coding sequence for PRO231.

Three PCR primers (two forward and one reverse) weresynthesized:

TABLE-US-00029 forward PCR primer 1 5'-CCAACTACCAAAGCTGCTGGAGCC-3'(SEQ ID NO:143) forward PCR primer 2 5'-GCAGCTCTATTACCACGGGAAGGA-3'(SEQ ID NO:144) reverse PCR primer 5'-TCCTTCCCGTGGTAATAGAGCTGC-3'(SEQ ID NO:145)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30933 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGCAGAGAACCAGAGGCCGGAGGAGACTGCCTCTTTACAGCCAGG-3' (SEQ IDNO:146)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO231 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO231 [herein designated asDNA34434-1139] and the derived protein sequence for PRO231.

The entire nucleotide sequence of DNA34434-1139 is shown in FIG. 51(SEQ ID NO:141). Clone DNA34434-1139 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 173-175 and ending at the stop codon at nucleotidepositions 1457-1459 (FIG. 51; SEQ ID NO:141). The predictedpolypeptide precursor is 428 amino acids long (FIG. 52). CloneDNA34434-1139 has been deposited with ATCC on Sep. 16, 1997 and isassigned ATCC deposit no. ATCC 209252.

Analysis of the amino acid sequence of the full-length PRO231suggests that it possesses 30% and 31% amino acid identity with thehuman and rat prostatic acid phosphatase precursor proteins,respectively.

Example 24

Isolation of cDNA Clones Encoding Human PRO229

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA28762. Based on theDNA28762 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO229.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00030 forward PCR primer 5'-TTCAGCTCATCACCTTCACCTGCC-3'(SEQ ID NO:149) reverse PCR primer 5'-GGCTCATACAAAATACCACTAGGG-3'(SEQ ID NO:150)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28762 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGGCCTCCACCGCTGTGAAGGGCGGGTGGAGGTGGAACAGAAAGGCCAGT-3' (SEQ IDNO:151)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO229 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO229 [herein designated asDNA33100-1159] (SEQ ID NO:147) and the derived protein sequence forPRO229.

The entire nucleotide sequence of DNA33100-1159 is shown in FIG. 53(SEQ ID NO:147). Clone DNA33100-1159 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 98-100 and ending at the stop codon at nucleotidepositions 1139-1141 (FIG. 53). The predicted polypeptide precursoris 347 amino acids long (FIG. 54). Clone DNA33100-1159 has beendeposited with ATCC and is assigned ATCC deposit no.ATCC209377.

Analysis of the amino acid sequence of the full-length PRO229polypeptide suggests that portions of it possess significanthomology to antigen wc1.1, M130 antigen and CD6.

Example 25

Isolation of cDNA Clones Encoding Human PRO238

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described above in Example 1. Thisconsensus sequence is herein designated DNA30908. Based on theDNA30908 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO238.

PCR primers (forward and reverse) were synthesized:

TABLE-US-00031 forward PCR primer 1 5'-GGTGCTAAACTGGTGCTCTGTGGC-3'(SEQ ID NO:154) forward PCR primer 2 5'-CAGGGCAAGATGAGCATTCC-3'(SEQ ID NO:155) reverse PCR primer 5'-TCATACTGTTCCATCTCGGCACGC-3'(SEQ ID NO:156)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30908 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-AATGGTGGGGCCCTAGAAGAGCTCATCAGAGAACTCACCGCTTCTCATGC-3' (SEQ IDNO:157)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO238 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO238 and the derived proteinsequence for PRO238.

The entire nucleotide sequence of DNA35600-1162 is shown in FIG. 55(SEQ ID NO:152). Clone DNA35600-1162 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 134-136 and ending prior to the stop codon at nucleotidepositions 1064-1066 (FIG. 55). The predicted polypeptide precursoris 310 amino acids long (FIG. 56). Clone DNA35600-1162 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209370.

Analysis of the amino acid sequence of the full-length PRO238polypeptide suggests that portions of it possess significanthomology to reductase, particularly oxidoreductase, therebyindicating that PRO238 may be a novel reductase.

Example 26

Isolation of cDNA Clones Encoding Human PRO233

The extracellular domain (ECD) sequences (including the secretionsignal, if any) of from about 950 known secreted proteins from theSwiss-Prot public protein database were used to search expressedsequence tag (EST) databases. The EST databases included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database(LIFESEQ.TM., Incyte Pharmaceuticals, Palo Alto, Calif.). Thesearch was performed using the computer program BLAST or BLAST2(Altshul et al., Methods in Enzymology 266:460-480 (1996)) as acomparison of the ECD protein sequences to a 6 frame translation ofthe EST sequence. Those comparisons resulting in a BLAST score of70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into consensus DNA sequenceswith the program "phrap" (Phil Green, University of Washington,Seattle, Wash.).

An expressed sequence tag (EST) was identified by the EST databasesearch and a consensus DNA sequence was assembled relative to otherEST sequences using phrap. This consensus sequence is hereindesignated DNA30945. Based on the DNA30945 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNAlibrary that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO233.

Forward and reverse PCR primers were synthesized:

TABLE-US-00032 forward PCR primer 5'-GGTGAAGGCAGAAATTGGAGATG-3'(SEQ ID NO:160) reverse PCR primer 5'-ATCCCATGCATCAGCCTGTTTACC-3'(SEQ ID NO:161)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30945 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GCTGGTGTAGTCTATACATCAGATTTGTTTGCTACACAAGATCCTCAG-3' (SEQ IDNO:162)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO233 gene using theprobe oligonucleotide.

RNA for construction of the cDNA libraries was isolated from humanfetal brain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO233 [herein designated asDNA34436-1238] (SEQ ID NO:158) and the derived protein sequence forPRO233.

The entire nucleotide sequence of DNA34436-1238 is shown in FIG. 57(SEQ ID NO:158). Clone DNA34436-1238 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 101-103 and ending at the stop codon at nucleotidepositions 1001-1003 (FIG. 57). The predicted polypeptide precursoris 300 amino acids long (FIG. 58). The full-length PRO233 proteinshown in FIG. 58 has an estimated molecular weight of about 32,964daltons and a pI of about 9.52. Clone DNA34436-1238 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209523.

Analysis of the amino acid sequence of the full-length PRO233polypeptide suggests that portions of it possess significanthomology to reductase proteins, thereby indicating that PRO233 maybe a novel reductase.

Example 27

Isolation of cDNA Clones Encoding Human PRO223

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA30836. Based on theDNA30836 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO223.

PCR primer pairs (one forward and two reverse) weresynthesized:

TABLE-US-00033 forward PCR primer 5'-TTCCATGCCACCTAAGGGAGACTC-3'(SEQ ID NO:165) reverse PCR primer 1 5'-TGGATGAGGTGTGCAATGGCTGGC-3'(SEQ ID NO:166) reverse PCR primer 2 5'-AGCTCTCAGAGGCTGGTCATAGGG-3'(SEQ ID NO:167)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30836 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GTCGGCCCTTTCCCAGGACTGAACATGAAGAGTTATGCCGGCTTCCTCAC-3 ' (SEQ IDNO:168)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO223 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO223 [herein designated asDNA33206-1165] (SEQ ID NO:163) and the derived protein sequence forPRO223.

The entire nucleotide sequence of DNA33206-1165 is shown in FIG. 59(SEQ ID NO:163). Clone DNA33206-1165 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 97-99 and ending at the stop codon at nucleotidepositions 1525-1527 (FIG. 59). The predicted polypeptide precursoris 476 amino acids long (FIG. 60). Clone DNA33206-1165 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209372.

Analysis of the amino acid sequence of the full-length PRO223polypeptide suggests that it possesses significant homology tovarious serine carboxypeptidase proteins, thereby indicating thatPRO223 may be a novel serine carboxypeptidase.

Example 28

Isolation of cDNA Clones Encoding Human PRO235

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated "DNA30927". Based on theDNA30927 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO235.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00034 forward PCR primer 5'-TGGAATACCGCCTCCTGCAG-3' (SEQID NO:171) reverse PCR primer 5'-CTTCTGCCCTTTGGAGAAGATGGC-3' (SEQID NO:172)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30927 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGACTCACTGGCCCAGGCCTTCAATATCACCAGCCAGGACGAT-3' (SEQ IDNO:173)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO235 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO235 [herein designated asDNA35558-1167] (SEQ ID NO:169) and the derived protein sequence forPRO235.

The entire nucleotide sequence of DNA35558-1167 is shown in FIG. 61(SEQ ID NO:169). Clone DNA35558-1167 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 667-669 and ending at the stop codon at nucleotidepositions 2323-2325 (FIG. 61). The predicted polypeptide precursoris 552 amino acids long (FIG. 62). Clone DNA35558-1167 has beendeposited with ATCC and is assigned ATCC deposit no. 209374.

Analysis of the amino acid sequence of the full-length PRO235polypeptide suggests that portions of it possess significanthomology to the human, mouse and Xenopus plexin protein, therebyindicating that PRO235 may be a novel plexin protein.

Example 29

Isolation of cDNA Clones Encoding Human PRO236 and Human PRO262

Consensus DNA sequences were assembled relative to other ESTsequences using phrap as described in Example 1 above. Theseconsensus sequences are herein designated DNA30901 and DNA30847.Based on the DNA30901 and DNA30847 consensus sequences,oligonucleotides were synthesized: 1) to identify by PCR a cDNAlibrary that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO236 and PRO262, respectively.

Based upon the DNA30901 consensus sequence, a pair of PCR primers(forward and reverse) were synthesized:

TABLE-US-00035 forward PCR primer 5'-TGGCTACTCCAAGACCCTGGCATG-3'(SEQ ID NO:178) reverse PCR primer 5'-TGGACAAATCCCCTTGCTCAGCCC-3'(SEQ ID NO:179)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30901 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGGCTTCACCGAAGCAGTGGACCTTTATTTTGACCACCTGATGTCCAGGG-3' (SEQ IDNO:180)

Based upon the DNA30847 consensus sequence, a pair of PCR primers(forward and reverse) were synthesized:

TABLE-US-00036 forward PCR primer 5'-CCAGCTATGACTATGATGCACC-3' (SEQID NO:181) reverse PCR primer 5'-TGGCACCCAGAATGGTGTTGGCTC-3' (SEQID NO:182)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30847 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-CGAGATGTCATCAGCAAGTTCCAGGAAGTTCCTTTGGGACCTTTACCTCC-3' (SEQ IDNO:183)

In order to screen several libraries for a source of full-lengthclones, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. Positive libraries werethen used to isolate clones encoding the PRO236 and PRO262 genesusing the probe oligonucleotides and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue for PRO236 and human fetal liver tissue forPRO262.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO236 [herein designated asDNA35599-1168] (SEQ ID NO:174), the derived protein sequence forPRO236, the full-length DNA sequence for PRO262 [herein designatedas DNA36992-1168] (SEQ ID NO:176) and the derived protein sequencefor PRO262.

The entire nucleotide sequence of DNA35599-1168 is shown in FIG. 63(SEQ ID NO:174). Clone DNA35599-1168 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 69-71 and ending at the stop codon at nucleotidepositions 1977-1979 (FIG. 63). The predicted polypeptide precursoris 636 amino acids long (FIG. 64). Clone DNA35599-1168 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209373.

The entire nucleotide sequence of DNA36992-1168 is shown in FIG. 65(SEQ ID NO:176). Clone DNA36992-1168 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 240-242 and ending at the stop codon at nucleotidepositions 2202-2204 (FIG. 65). The predicted polypeptide precursoris 654 amino acids long (FIG. 66). Clone DNA36992-1168 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209382.

Analysis of the amino acid sequence of the full-length PRO236 andPRO262 polypeptides suggests that portions of those polypeptidespossess significant homology to .beta.-galactosidase proteinsderived from various sources, thereby indicating that PRO236 andPRO262 may be novel .beta.-galactosidase homologs.

Example 30

Isolation of cDNA Clones Encoding Human PRO239

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA30909. Based on theDNA30909 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO239.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00037 forward PCR primer 5'-CCTCCCTCTATTACCCATGTC-3' (SEQID NO:186) reverse PCR primer 5'-GACCAACTTTCTCTGGGAGTGAGG-3' (SEQID NO:187)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30909 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GTCACACTTTATTTCTCTAACAACAAGCTCGAATCCTTACCAGTGGCAG-3' (SEQ ID NO:188)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO239 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO239 [herein designated asDNA34407-1169] (SEQ ID NO:184) and the derived protein sequence forPRO239.

The entire nucleotide sequence of DNA34407-1169 is shown in FIG. 67(SEQ ID NO:184). Clone DNA34407-1169 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 72-74 and ending at the stop codon at nucleotidepositions 1575-1577 (FIG. 67). The predicted polypeptide precursoris 501 amino acids long (FIG. 68). Clone DNA34407-1169 has beendeposited with ATCC and is assigned ATCC deposit no.ATCC209383.

Analysis of the amino acid sequence of the full-length PRO239polypeptide suggests that portions of it possess significanthomology to the densin protein, thereby indicating that PRO239 maybe a novel molecule in the densin family.

Example 31

Isolation of cDNA Clones Encoding Human PRO257

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA28731. Based on theDNA28731 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO257.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00038 forward PCR primer 5'-TCTCTATTCCAAACTGTGGCG-3' (SEQID NO:191) reverse PCR primer 5'-TTTGATGACGATTCGAAGGTGG-3' (SEQ IDNO:192)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA28731 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGAAGGATCCTTCACCAGCCCCAATTACCCAAAGCCGCATCCTGAGC-3' (SEQ IDNO:193)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO257 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO257 [herein designated asDNA35841-1173 (SEQ ID NO:189) and the derived protein sequence forPRO257.

The entire nucleotide sequence of DNA35841-1173 is shown in FIG. 69(SEQ ID NO:189). Clone DNA35841-1173 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 964-966 and ending at the stop codon at nucleotidepositions 2785-2787 (FIG. 69). The predicted polypeptide precursoris 607 amino acids long (FIG. 70). Clone DNA35841-1173 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209403.

Analysis of the amino acid sequence of the full-length PRO257polypeptide suggests that portions of it possess significanthomology to the ebnerin protein, thereby indicating that PRO257 maybe a novel protein member related to the ebnerin protein.

Example 32

Isolation of cDNA Clones Encoding Human PRO260

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA30834. Based on theDNA30834 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO260.

PCR primers (forward and two reverse) were synthesized:

TABLE-US-00039 forward PCR primer: 5'-TGGTTTGACCAGGCCAAGTTCGG-3';(SEQ ID NO:196) reverse PCR primer A:5'-GGATTCATCCTCAAGGAAGAGCGG-3'; (SEQ ID NO:197) and reverse PCRprimer B: 5'-AACTTGCAGCATCAGCCACTCTGC-3' (SEQ ID NO:198)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30834 sequence which had thefollowing nucleotide sequence: Hybridization Probe:5'-TTCCGTGCCCAGCTTCGGTAGCGAGTGGTTCTGGTGGTATTGGCA-3' (SEQ IDNO:199)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO260 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO260 [herein designated asDNA33470-1175] (SEQ ID NO:194) and the derived protein sequence forPRO260.

The entire nucleotide sequence of DNA33470-1175 is shown in FIG. 71(SEQ ID NO:194). Clone DNA33470-1175 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 67-69 and ending at the stop codon 1468-1470 (see FIG.71). The predicted polypeptide precursor is 467 amino acids long(FIG. 72). Clone DNA33470-1175 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209398.

Analysis of the amino acid sequence of the full-length PRO260polypeptide suggests that portions of it possess significanthomology to the alpha-1-fucosidase precursor, thereby indicatingthat PRO260 may be a novel fucosidase.

Example 33

Isolation of cDNA Clones Encoding Human PRO263

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA30914. Based on theDNA30914 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO263.

PCR primers (tow forward and one reverse) were synthesized:

TABLE-US-00040 forward PCR primer 1:5'-GAGCTTTCCATCCAGGTGTCATGC-3'; (SEQ ID NO:202) forward PCR primer2: 5'-GTCAGTGACAGTACCTACTCGG-3'; (SEQ ID NO:203) reverse PCRprimer: 5'-TGGAGCAGGAGGAGTAGTAGTAGG-3' (SEQ ID NO:204)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30914 sequence which had thefollowing nucleotide sequence: Hybridization Probe:5'-AGGAGGCCTGTAGGCTGCTGGGACTAAGTTTGGCCGGCAAGGACCAAGTT-3' (SEQ IDNO:205)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO263 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO263 [herein designated asDNA34431-1177] (SEQ ID NO:200) and the derived protein sequence forPRO263.

The entire nucleotide sequence of DNA34431-1177 is shown in FIG. 73(SEQ ID NO:200). Clone DNA34431-1177 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 160-162 of SEQ ID NO:200 and ending at the stop codonafter the nucleotide at position 1126-1128 of SEQ ID NO:200 (FIG.73). The predicted polypeptide precursor is 322 amino acids long(FIG. 74). Clone DNA34431-1177 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209399.

Analysis of the amino acid sequence of the full-length PRO263polypeptide suggests that portions of it possess significanthomology to CD44 antigen, thereby indicating that PRO263 may be anovel cell surface adhesion molecule.

Example 34

Isolation of cDNA Clones Encoding Human PRO270

A consensus DNA sequence was assembled relative to the otheridentified EST sequences as described in Example 1 above, whereinthe consensus sequence was designated herein as DNA35712. Based onthe DNA35712 consensus sequence, oligonucleotides were synthesized:1) to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO270. Forward and reverse PCRprimers were synthesized:

TABLE-US-00041 forward PCR primer (.f1)5'-GCTTGGATATTCGCATGGGCCTAC-3' (SEQ ID NO:208) forward PCR primer(.f2) 5'-TGGAGACAATATCCCTGAGG-3' (SEQ ID NO:209) reverse PCR primer(.r1) 5'-AACAGTTGGCCACAGCATGGCAGG-3' (SEQ ID NO:210)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35712 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-CCATTGATGAGGAACTAGAACGGGACAAGAGGGTCACTTGGATTGTGGAG-3' (SEQ IDNO:211)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO270 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO270 [herein designated asDNA39510-1181] (SEQ ID NO:206) and the derived protein sequence forPRO270.

The entire nucleotide sequence of DNA39510-1181 is shown in FIG. 75(SEQ ID NO:206). Clone DNA39510-1181 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 3-5 and ending at the stop codon at nucleotide positions891-893 (FIG. 75; SEQ ID NO:206). The predicted polypeptideprecursor is 296 amino acids long (FIG. 76). Clone DNA39510-1181has been deposited with ATCC and is assigned ATCC deposit no. ATCC209392.

Analysis of the amino acid sequence of the full-length PRO270suggests that portions of it possess significant homology to thethioredoxin-protein, thereby indicating that the PRO270 protein maybe a novel member of the thioredoxin family.

Example 35

Isolation of cDNA Clones Encoding Human PRO271

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA35737. Based on theDNA35737 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO271.

Forward and reverse PCR primers were synthesized:

TABLE-US-00042 forward PCR primer 1 5'-TGCTTCGCTACTGCCCTC-3' (SEQID NO:214) forward PCR primer 2 5'-TTCCCTTGTGGGTTGGAG-3' (SEQ IDNO:215) forward PCR primer 3 5'-AGGGCTGGAAGCCAGTTC-3' (SEQ IDNO:216) reverse PCR primer 1 5'-AGCCAGTGAGGAAATGCG-3' (SEQ IDNO:217) reverse PCR primer 2 5'-TGTCCAAAGTACACACACCTGAGG-3' (SEQ IDNO:218)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35737 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GATGCCACGATCGCCAAGGTGGGACAGCTCTTTGCCGCCTGGAAG-3' (SEQ IDNO:219)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO271 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal brain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO271 [herein designated asDNA39423-1182] (SEQ ID NO:212) and the derived protein sequence forPRO271.

The entire nucleotide sequence of DNA39423-1182 is shown in FIG. 77(SEQ ID NO:212). Clone DNA39423-1182 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 101-103 and ending at the stop codon at nucleotidepositions 1181-1183 (FIG. 77). The predicted polypeptide precursoris 360 amino acids long (FIG. 78). Clone DNA39423-1182 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209387.

Analysis of the amino acid sequence of the full-length PRO271polypeptide suggests that it possess significant homology to theproteoglycan link protein, thereby indicating that PRO271 may be alink protein homolog.

Example 36

Isolation of cDNA Clones Encoding Human PRO272

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA36460. Based on theDNA36460 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO272.

Forward and reverse PCR primers were synthesized:

TABLE-US-00043 forward PCR primer (.f1) 5'-CGCAGGCCCTCATGGCCAGG-3'(SEQ ID NO:222) forward PCR primer (.f2) 5'-GAAATCCTGGGTAATTGG-3'(SEQ ID NO:223) reverse PCR primer 5'-GTGCGCGGTGCTCACAGCTCATC-3'(SEQ ID NO:224)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA36460 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-CCCCCCTGAGCGACGCTCCCCCATGATGACGCCCACGGGAACTTC-3' (SEQ IDNO:225)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO272 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO272 [herein designated asDNA40620-1183] (SEQ ID NO:220) and the derived protein sequence forPRO272.

The entire nucleotide sequence of DNA40620-1183 is shown in FIG. 79(SEQ ID NO:220). Clone DNA40620-1183 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 35-37 and ending at the stop codon at nucleotidepositions 1019-1021 (FIG. 79). The predicted polypeptide precursoris 328 amino acids long (FIG. 80). Clone DNA40620-1183 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209388.

Analysis of the amino acid sequence of the full-length PRO272polypeptide suggests that portions of it possess significanthomology to the human and mouse reticulocalbin proteins,respectively, thereby indicating that PRO272 may be a novelreticulocalbin protein.

Example 37

Isolation of cDNA Clones Encoding Human PRO294

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA35731. Based on theDNA35731 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO294.

Forward and reverse PCR primers were synthesized:

TABLE-US-00044 forward PCR primer (.f1) 5'-TGGTCTCGCACACCGATC-3'(SEQ ID NO:228) forward PCR primer (.f2) 5'-CTGCTGTCCACAGGGGAG-3'(SEQ ID NO:229) forward PCR primer (.f3) 5'-CCTTGAAGCATACTGCTC-3'(SEQ ID NO:230) forward PCR primer (.f4) 5'-GAGATAGCAATTTCCGCC-3'(SEQ ID NO:231) reverse PCR primer (.r1) 5'-TTCCTCAAGAGGGCAGCC-3'(SEQ ID NO:232) reverse PCR primer (.r2)5'-CTTGGCACCAATGTCCGAGATTTC-3' (SEQ ID NO:233)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35731 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GCTCTGAGGAAGGTGACGCGCGGGGCCTCCGAACCCTTGGCCTTG-3' (SEQ IDNO:234)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO294 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal brain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO294 [herein designated asDNA40604-1187] (SEQ ID NO:226) and the derived protein sequence forPRO294.

The entire nucleotide sequence of DNA40604-1187 is shown in FIG. 81(SEQ ID NO:226). Clone DNA40604-1187 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 396-398 and ending at the stop codon at nucleotidepositions 2046-2048 (FIG. 81). The predicted polypeptide precursoris 550 amino acids long (FIG. 82). Clone DNA40604-1187 has beendeposited with ATCC and is assigned ATCC deposit no. 209394.

Analysis of the amino acid sequence of the full-length PRO294polypeptide suggests that portions of it possess significanthomology to portions of various collagen proteins, therebyindicating that PRO294 may be collagen-like molecule.

Example 38

Isolation of cDNA Clones Encoding Human PRO295

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA35814. Based on theDNA35814 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO295.

Forward and reverse PCR primers were synthesized:

TABLE-US-00045 forward PCR primer (.f1)5'-GCAGAGCGGAGATGCAGCGGCTTG-3' (SEQ ID NO:238) forward PCR primer(.f2) 5'-CCCAGCATGTACTGCCAG-3' (SEQ ID NO:239) forward PCR primer(.f3) 5'-TTGGCAGCTTCATGGAGG-3' (SEQ ID NO:240) forward PCR primer(.f4) 5'-CCTGGGCAAAAATGCAAC-3' (SEQ ID NO:241) reverse PCR primer(.r1) 5'-CTCCAGCTCCTGGCGCACCTCCTC-3' (SEQ ID NO:242)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35814 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGCTCTCAGCTACCGAGCAGGAGCGAGGCCACCCTCAATGAGATG-3' (SEQ IDNO:243)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO295 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO295 [herein designated asDNA38268-1188] (SEQ ID NO:235) and the derived protein sequence forPRO295.

The entire nucleotide sequence of DNA38268-1188 is shown in FIG. 83(SEQ ID NO:235). Clone DNA38268-1188 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 153-155 and ending at the stop codon at nucleotidepositions 1202-1204 (FIG. 83). The predicted polypeptide precursoris 350 amino acids long (FIG. 84). Clone DNA38268-1188 has beendeposited with ATCC and is assigned ATCC deposit no. 209421.

Analysis of the amino acid sequence of the full-length PRO295polypeptide suggests that portions of it possess significanthomology to the integrin proteins, thereby indicating that PRO295may be a novel integrin.

Example 39

Isolation of cDNA Clones Encoding Human PRO293

The extracellular domain (ECD) sequences (including the secretionsignal, if any) of from about 950 known secreted proteins from theSwiss-Prot public protein database were used to search expressedsequence tag (EST) databases. The EST databases included public ESTdatabases (e.g., GenBank) and a proprietary EST DNA database(LIFESEQ.TM., Incyte Pharmaceuticals, Palo Alto, Calif.). Thesearch was performed using the computer program BLAST or BLAST2(Altshul et al., Methods in Enzvmologv 266:460-480 (1996)) as acomparison of the ECD protein sequences to a 6 frame translation ofthe EST sequence. Those comparisons resulting in a BLAST score of70 (or in some cases 90) or greater that did not encode knownproteins were clustered and assembled into consensus DNA sequenceswith the program "phrap" (Phil Green, University of Washington,Seattle, Wash.).

Based on an expression tag sequence designated herein as T08294identified in the above analysis, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence for PRO293.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00046 forward PCR primer 5'-AACAAGGTAAGATGCCATCCTG-3' (SEQID NO:246) reverse PCR primer 5'-AAACTTGTCGATGGAGACCAGCTC-3' (SEQID NO:247)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the expression sequence tag which had thefollowing nucleotide sequence Hybridization Probe5'-AGGGGCTGCAAAGCCTGGAGAGCCTCTCCTTCTATGACAACCAGC-3' (SEQ IDNO:248)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO293 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal brain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO293 [herein designated asDNA37151-1193] (SEQ ID NO:244) and the derived protein sequence forPRO293.

The entire nucleotide sequence of DNA37151-1193 is shown in FIG. 85(SEQ ID NO:244). Clone DNA37151-1193 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 881-883 and ending at the stop codon after nucleotideposition 3019 of SEQ ID NO:244, FIG. 85). The predicted polypeptideprecursor is 713 amino acids long (FIG. 86). Clone DNA37151-1193has been deposited with ATCC and is assigned ATCC deposit no. ATCC209393.

Analysis of the amino acid sequence of the full-length PRO293polypeptide suggests that portions of it possess significanthomology to the NLRR proteins, thereby indicating that PRO293 maybe a novel NLRR protein.

Example 40

Isolation of cDNA Clones Encoding Human PRO247

TABLE-US-00047 forward PCR primer 5'-CAACAATGAGGGCACCAAGC-3' (SEQID NO:251) reverse PCR primer 5'-GATGGCTAGGTTCTGGAGGTTCTG-3' (SEQID NO:252)

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA33480. Based on theDNA33480 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO247.

A pair of PCR primers (forward and reverse) were synthesized:5'-CAACCTGCAGGAGATTGACCTCAAGGACAACAACCTCAAGACCATCG-3' (SEQ IDNO:253) Additionally, a synthetic oligonucleotide hybridizationprobe was constructed from the DNA33480 expression sequence tagwhich had the following nucleotide sequence Hybridization Probe5'-CAACCTGCAGGAGATTGACCTCAAGGACAACAACCTCAAGACCATCG-3' (SEQ IDNO:253)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO247 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal brain tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO247 [herein designated asDNA35673-1201] (SEQ ID NO:249) and the derived protein sequence forPRO247.

The entire nucleotide sequence of DNA35673-1201 is shown in FIG. 89(SEQ ID NO:249). Clone DNA35673-1201 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 80-82 of SEQ ID NO:249 and ending at the stop codon afternucleotide position 1717 of SEQ ID NO:249 (FIG. 89). The predictedpolypeptide precursor is 546 amino acids long (FIG. 88). CloneDNA35673-1201 has been deposited with ATCC and is assigned ATCCdeposit no. 209418.

Analysis of the amino acid sequence of the full-length PRO247polypeptide suggests that portions of it possess significanthomology to the densin molecule and KIAA0231, thereby indicatingthat PRO247 may be a novel leucine rich repeat protein.

Example 41

Isolation of cDNA Clones Encoding Human PRO302, PRO303, PRO304,PRO307 and PRO343

Consensus DNA sequences were assembled relative to other ESTsequences using phrap as described in Example 1 above. Theseconsensus sequences are herein designated DNA35953, DNA35955,DNA35958, DNA37160 and DNA30895. Based on the DNA35953 consensussequence, oligonucleotides were synthesized: 1) to identify by PCRa cDNA library that contained the sequence of interest, and 2) foruse as probes to isolate a clone of the full-length coding sequencefor PRO302.

PCR primers (forward and reverse) were synthesized:

TABLE-US-00048 forward PCR primer 1 5'-GTCCGCAAGGATGCCTACATGTTC-3'(SEQ ID NO:264) forward PCR primer 2 5'-GCAGAGGTGTCTAAGGTTG-3' (SEQID NO:265) reverse PCR primer 5'-AGCTCTAGACCAATGCCAGCTTCC-3' (SEQID NO:266)

Also, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35953 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GCCACCAACTCCTGCAAGAACTTCTCAGAACTGCCCCTGGTCATG-3' (SEQ IDNO:267)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO302 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue (LIB228).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO302 [herein designated asDNA40370-1217] (SEQ ID NO:254) and the derived protein sequence forPRO302.

The entire nucleotide sequence of DNA40370-1217 is shown in FIG. 89(SEQ ID NO:254). Clone DNA40370-1217 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 34-36 and ending at the stop codon at nucleotidepositions 1390-1392 (FIG. 89). The predicted polypeptide precursoris 452 amino acids long (FIG. 90). Various unique aspects of thePRO302 protein are shown in FIG. 90. Clone DNA40370-1217 has beendeposited with the ATCC on Nov. 21, 1997 and is assigned ATCCdeposit no. ATCC 209485.

Based on the DNA35955 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence for PRO303.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00049 forward PCR primer 5'-GGGGAATTCACCCTATGACATTGCC-3'(SEQ ID NO:268) reverse PCR primer 5'-GAATGCCCTGCAAGCATCAACTGG-3'(SEQ ID NO:269)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35955 sequence which had thefollowing nucleotide sequence: Hybridization Probe5'-GCACCTGTCACCTACACTAAACACATCCAGCCCATCTGTCTCCAGGCCTC-3' (SEQ IDNO:270)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO303 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue (LIB25).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO303 [herein designated asDNA42551-1217] (SEQ ID NO:256) and the derived protein sequence forPRO303.

The entire nucleotide sequence of DNA42551-1217 is shown in FIG. 91(SEQ ID NO:256). Clone DNA42551-1217 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 20-22 and ending at the stop codon at nucleotidepositions 962-964 (FIG. 91). The predicted polypeptide precursor is314 amino acids long (FIG. 92). Various unique aspects of thePRO303 protein are shown in FIG. 92. Clone DNA42551-1217 has beendeposited on Nov. 21, 1997 with the ATCC and is assigned ATCCdeposit no. ATCC 209483.

Based on the DNA35958 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence for PRO304.

Pairs of PCR primers (forward and reverse) were synthesized:

TABLE-US-00050 forward PCR primer 15'-GCGGAAGGGCAGAATGGGACTCCAAG-3' (SEQ ID NO:271) forward PCR primer2 5'-CAGCCCTGCCACATGTGC-3' (SEQ ID NO:272) forward PCR primer 35'-TACTGGGTGGTCAGCAAC-3' (SEQ ID NO:273) reverse PCR primer5'-GGCGAAGAGCAGGGTGAGACCCCG-3' (SEQ ID NO:274)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35958 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GCCCTCATCCTCTCTGGCAAATGCAGTTACAGCCCGGAGCCCGAC-3' (SEQ IDNO:275)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO304 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from 22week human fetal brain tissue (LIB153).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO304 [herein designated asDNA39520-1217] (SEQ ID NO:258) and the derived protein sequence forPRO304.

The entire nucleotide sequence of DNA39520-1217 is shown in FIG. 93(SEQ ID NO:258). Clone DNA39520-1217 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 34-36 and ending at the stop codon at nucleotidepositions 1702-1704 (FIG. 93). The predicted polypeptide precursoris 556 amino acids long (FIG. 94). Various unique aspects of thePRO304 protein are shown in FIG. 94. Clone DNA39520-1217 has beendeposited with ATCC on Nov. 21, 1997 and is assigned ATCC depositno. ATCC 209482.

Based on the DNA37160 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence for PRO307.

Pairs of PCR primers (forward and reverse) were synthesized:

TABLE-US-00051 forward PCR primer 1 5'-GGGCAGGGATTCCAGGGCTCC-3'(SEQ ID NO:276) forward PCR primer 2 5'-GGCTATGACAGCAGGTTC-3' (SEQID NO:277) forward PCR primer 3 5'-TGACAATGACCGACCAGG-3' (SEQ IDNO:278) reverse PCR primer 5'-GCATCGCATTGCTGGTAGAGCAAG-3' (SEQ IDNO:279)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA37160 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-TTACAGTGCCCCCTGGAAACCCACTTGGCCTGCATACCGCCTCCC-3' (SEQ IDNO:280)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO307 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue (LIB229).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO307 [herein designated asDNA41225-1217] (SEQ ID NO:260) and the derived protein sequence forPRO307.

The entire nucleotide sequence of DNA41225-1217 is shown in FIG. 95(SEQ ID NO:260). Clone DNA41225-1217 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 92-94 and ending at the stop codon at nucleotidepositions 1241-1243 (FIG. 95). The predicted polypeptide precursoris 383 amino acids long (FIG. 96). Various unique aspects of thePRO307 protein are shown in FIG. 96. Clone DNA41225-1217 has beendeposited with ATCC on Nov. 21, 1997 and is assigned ATCC depositno. ATCC 209491.

Based on the DNA30895 consensus sequence, oligonucleotides weresynthesized: 1) to identify by PCR a cDNA library that containedthe sequence of interest, and 2) for use as probes to isolate aclone of the full-length coding sequence for PRO343.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00052 forward PCR primer5'-CGTCTCGAGCGCTCCATACAGTTCCCTTGCCCCA-3' (SEQ ID NO:281) reversePCR primer5'-TGGAGGGGGAGCGGGATGCTTGTCTGGGCGACTCCGGGGGCCCCCTCATGTGCCAGGTGGA-3-' (SEQ ID NO:282)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA30895 sequence which had thefollowing nucleotide sequence Hybridization Probe

TABLE-US-000535'-CCCTCAGACCCTGCAGAAGCTGAAGGTTCCTATCATCGACTCGGAAGTCTGCAGCCATCTG(SEQ ID NO:283)TACTGGCGGGGAGCAGGACAGGGACCCATCACTGAGGACATGCTGTGTGCCGGCTACT-3'

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO343 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue (LIB26).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO343 [herein designated asDNA43318-1217] (SEQ ID NO:262) and the derived protein sequence forPRO343.

The entire nucleotide sequence of DNA43318-1217 is shown in FIG. 97(SEQ ID NO:262). Clone DNA43318-1217 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 53-55 and ending at the stop codon at nucleotidepositions 1004-1006 (FIG. 97). The predicted polypeptide precursoris 317 amino acids long (FIG. 98). Various unique aspects of thePRO343 protein are shown in FIG. 98. Clone DNA43318-1217 has beendeposited with ATCC on Nov. 21, 1997 and is assigned ATCC depositno. ATCC 209481.

Example 42

Isolation of cDNA Clones Encoding Human PRO328

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA35615. Based on theDNA35615 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO328.

Forward and reverse PCR primers were synthesized:

TABLE-US-00054 forward PCR primer 5'-TCCTGCAGTTTCCTGATGC-3' (SEQ IDNO:286) reverse PCR primer 5'-CTCATATTGCACACCAGTAATTCG-3' (SEQ IDNO:287)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35615 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-ATGAGGAGAAACGTTTGATGGTGGAGCTGCACAACCTCTACCGGG-3' (SEQ IDNO:288)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO328 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO328 [herein designated asDNA40587-1231] (SEQ ID NO:284) and the derived protein sequence forPRO328.

The entire nucleotide sequence of DNA40587-1231 is shown in FIG. 99(SEQ ID NO:284). Clone DNA40587-1231 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 15-17 and ending at the stop codon at nucleotidepositions 1404-1406 (FIG. 99). The predicted polypeptide precursoris 463 amino acids long (FIG. 100). Clone DNA40587-1231 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC209438.

Analysis of the amino acid sequence of the full-length PRO328polypeptide suggests that portions of it possess significanthomology to the human glioblastoma protein and to the cysteine richsecretory protein thereby indicating that PRO328 may be a novelglioblastoma protein or cysteine rich secretory protein.

Example 43

Isolation of cDNA Clones Encoding Human PRO335, PRO331 orPRO326

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA36685. Based on theDNA36685 consensus sequence, and Incyte EST sequence no. 2228990,oligonucleotides were synthesized: 1) to identify by PCR a cDNAlibrary that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length coding sequence forPRO335, PRO331 or PRO326.

Forward and reverse PCR primers were synthesized for thedetermination of PRO335:

TABLE-US-00055 forward PCR primer 5'-GGAACCGAATCTCAGCTA-3' (SEQ IDNO:295) forward PCR primer 5'-CCTAAACTGAACTGGACCA-3' (SEQ IDNO:296) forward PCR primer 5'-GGCTGGAGACACTGAACCT-3' (SEQ IDNO:297) forward PCR primer 5'-ACAGCTGCACAGCTCAGAACAGTG-3' (SEQ IDNO:298) reverse PCR primer 5'-CATTCCCAGTATAAAAATTTTC-3' (SEQ IDNO:299) reverse PCR primer 5'-GGGTCTTGGTGAATGAGG-3' (SEQ ID NO:300)reverse PCR primer 5'-GTGCCTCTCGGTTACCACCAATGG-3' (SEQ IDNO:301)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO335 which had the followingnucleotide sequence Hybridization Probe5'-GCGGCCACTGTTGGACCGAACTGTAACCAAGGGAGAAACAGCCGTCCTAC-3' (SEQ IDNO:302)

Forward and reverse PCR primers were synthesized for thedetermination of PRO331:

TABLE-US-00056 forward PCR primer5'-GCCTTTGACAACCTTCAGTCACTAGTGG-3' (SEQ ID NO:303) reverse PCRprimer 5'-CCCCATGTGTCCATGACTGTTCCC-3' (SEQ ID NO:304)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO331 which bad the followingnucleotide sequence Hybridization Probe5'-TACTGCCTCATGACCTCTTCACTCCCTTGCATCATCTTAGAGCGG-3' (SEQ IDNO:305)

Forward and reverse PCR primers were synthesized for thedetermination of PRO326:

TABLE-US-00057 forward PCR primer 5'-ACTCCAAGGAAATCGGATCCGTTC-3'(SEQ ID NO:306) reverse PCR primer 5'-TTAGCAGCTGAGGATGGGCACAAC-3'(SEQ ID NO:307)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO331 which had the followingnucleotide sequence Hybridization Probe5'-GCCTTCACTGGTTTGGATGCATTGGAGCATCTAGACCTGAGTGACAACGC-3' (SEQ IDNO:308)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO335, PRO331 or PRO326gene using the probe oligonucleotide and one of the PCRprimers.

RNA for construction of the cDNA libraries was isolated from humanfetal kidney tissue (PRO335 and PRO326) and human fetal brain(PRO331).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO335, PRO331 or PRO326 [hereindesignated as SEQ ID NOS:289, 291 and 293, respectively; see FIGS.101, 103 and 105, respectively], and the derived protein sequencefor PRO335, PRO331 or PRO326 (see FIGS. 102, 104 and 106,respectively; SEQ ID NOS:290, 292 and 294, respectively).

The entire nucleotide sequences are shown in FIGS. 101, 103 and105, deposited with the ATCC on Jun. 2, 1998, Nov. 7, 1997 and Nov.21, 1997, respectively.

Analysis of the amino acid sequence of the full-length PRO335,PRO331 or PRO326 polypeptide suggests that portions of it possesssignificant homology to the LIG-1 protein, thereby indicating thatPRO335, PRO331 and PRO326 may be a novel LIG-1-related protein.

Example 44

Isolation of cDNA Clones Encoding Human PRO332

Based upon an ECD homology search performed as described in Example1 above, a consensus DNA sequence designated herein as DNA36688 wasassembled. Based on the DNA36688 consensus sequence,oligonucleotides were synthesized to identify by PCR a cDNA librarythat contained the sequence of interest and for use as probes toisolate a clone of the full-length coding sequence for PRO332.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00058 5'-GCATTGGCCGCGAGACTTTGCC-3' (SEQ ID NO:311)5'-GCGGCCACGGTCCTTGGAAATG-3' (SEQ ID NO:312)

A probe was also synthesized:5'-TGGAGGAGCTCAACCTCAGCTACAACCGCATCACCAGCCCACAGG-3' (SEQ IDNO:313)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO332 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from ahuman fetal liver library (LIB229).

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for DNA40982-1235 and the derived proteinsequence for PRO332.

The entire nucleotide sequence of DNA40982-1235 is shown in FIG.107 (SEQ ID NO:309). Clone DNA40982-1235 contains a single openreading frame (with an apparent translational initiation site atnucleotide positions 342-344, as indicated in FIG. 107). Thepredicted polypeptide precursor is 642 amino acids long, and has acalculated molecular weight of 72,067 (pI: 6.60). CloneDNA40982-1235 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209433.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO332 shows about 30-40% amino acid sequenceidentity with a series of known proteoglycan sequences, including,for example, fibromodulin and fibromodulin precursor sequences ofvarious species (FMOD_BOVIN, FMOD CHICK, FMOD_RAT, FMOD_MOUSE,FMOD_HUMAN, P_R36773), osteomodulin sequences (AB0001141,AB007848.sub.--1), decorin sequences (CFU83141.sub.--1,OCU03394.sub.--1, P_R42266, P_R42267, P_R42260, P_R89439), keratansulfate proteoglycans (BTU48360.sub.--1, AF022890.sub.--1), cornealproteoglycan (AF022256.sub.--1), and bone/cartilage proteoglycansand proteoglycane precursors (PGS1_BOVIN, PGS2_MOUSE,PGS2_HUMAN).

Example 45

Isolation of cDNA clones Encoding Human PRO334

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Based on theconsensus sequence, oligonucleotides were synthesized: 1) toidentify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO334.

Forward and reverse PCR primers were synthesized for thedetermination of PRO334:

TABLE-US-00059 forward PCR primer 5'-GATGGTTCCTGCTCAAGTGCCCTG-3'(SEQ ID NO:316) reverse PCR primer 5'-TTGCACTTGTAGGACCCACGTACG-3'(SEQ ID NO:317)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed for the determination of PRO334 which had the followingnucleotide sequence Hybridization Probe5'CTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAGGAAGAGCC-3' (SEQ IDNO:318)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO334 gene using theprobe oligonucleotide and one of the PCR primers.

Human fetal kidney cDNA libraries used to isolate the cDNA cloneswere constructed by standard methods using commercially availablereagents such as those from Invitrogen, San Diego, Calif.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO334 [herein designated asDNA41379-1236] (SEQ ID NO:314) and the derived protein sequence forPRO334.

The entire nucleotide sequence of DNA41379-1236 (also referred toas UNQ295) is shown in FIG. 109 (SEQ ID NO:314). CloneDNA41379-1236 contains a single open reading frame with an apparenttranslational initiation site at nucleotide positions 203-205 andending at the stop codon at nucleotide positions 1730-1732 (FIG.109). The predicted polypeptide precursor is 509 amino acids long(FIG. 110). Clone DNA41379-1236 has been deposited with ATCC and isassigned ATCC deposit no. ATCC 209488.

Analysis of the amino acid sequence of the full-length PRO334polypeptide suggests that portions of it possess significanthomology to the fibulin and fibrillin proteins, thereby indicatingthat PRO334 may be a novel member of the EGF protein family.

Example 46

Isolation of cDNA Clones Encoding Human PRO346

A consensus DNA sequence was identified using phrap as described inExample 1 above. Specifically, this consensus sequence is hereindesignated DNA38240. Based on the DNA38240 consensus sequence,oligonucleotides were synthesized: 1) to identify by PCR a cDNAlibrary that contained the sequence of interest, and 2) for use asprobes to isolate a clone of the full-length PRO346 codingsequence.

RNA for construction of the cDNA libraries was isolated from humanfetal liver. The cDNA libraries used to isolated the cDNA cloneswere constructed by standard methods using commercially availablereagents (e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) ThecDNA was primed with oligo dT containing a NotI site, linked withblunt to SalI hemikinased adaptors, cleaved with NotI, sizedappropriately by gel electrophoresis, and cloned in a definedorientation into a suitable cloning vector (such as pRKB or pRKD;pRK5B is a precursor of pRK5D that does not contain the SfiI site;see, Holmes et al., Science, 253:1278-1280 (1991)) in the uniqueXhoI and NotI sites.

A cDNA clone was sequenced in entirety. The entire nucleotidesequence of DNA44167-1243 is shown in FIG. 111 (SEQ ID NO:319).Clone DNA44167-1243 contains a single open reading frame with anapparent translational initiation site at nucleotide positions64-66 (FIG. 111; SEQ ID NO:319). The predicted polypeptideprecursor is 450 amino acids long. Clone DNA44167-1243 has beendeposited with ATCC and is assigned ATCC deposit no. ATCC 209434(designation DNA44167-1243).

Based on a BLAST, BLAST-2 and FastA sequence alignment analysis(using the ALIGN computer program) of the full-length sequence,PRO346 shows amino acid sequence identity to carcinoembryonicantigen (28%).

The oligonucleotide sequences used in the above procedure were thefollowing:

TABLE-US-00060 OLI2691 (38240.f1) (SEQ ID NO: 321)5'-GATCCTGTCACAAAGCCAGTGGTGC-3' OLI2693 (38240.r1) (SEQ ID NO: 322)5'-CACTGACAGGGTTCCTCACCCAGG-3' OLI2692 (38240.p1) (SEQ ID NO: 323)5'-CTCCCTCTGGGCTGTGGAGTATGTGGGGAACATGACCCTGACATG-3'

Example 47

Isolation of cDNA Clones Encoding Human PRO268

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA35698. Based on theDNA35698 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO268.

Forward and reverse PCR primers were synthesized:

TABLE-US-00061 forward PCR primer 1 5'-TGAGGTGGGCAAGCGGCGAAATG-3'(SEQ ID NO:326) forward PCR primer 2 5'-TATGTGGATCAGGACGTGCC-3'(SEQ ID NO:327) forward PCR primer 3 5'-TGCAGGGTTCAGTCTAGATTG-3'(SEQ ID NO:328) reverse PCR primer 5'-TTGAAGGACAAAGGCAATCTGCCAC-3'(SEQ ID NO:329)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus DNA35698 sequence which had thefollowing nucleotide sequence Hybridization Probe5'-GGAGTCTTGCAGTTCCCCTGGCAGTCCTGGTGCTGTTGCTTTGGG-3' (SEQ IDNO:330)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO268 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal lung tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO268 [herein designated asDNA39427-1179] (SEQ ID NO:324) and the derived protein sequence forPRO268.

The entire nucleotide sequence of DNA39427-1179 is shown in FIG.113 (SEQ ID NO:324). Clone DNA39427-1179 contains a single openreading frame with an apparent translational initiation site atnucleotide positions 13-15 and ending at the stop codon atnucleotide positions 853-855 (FIG. 113). The predicted polypeptideprecursor is 280 amino acids long (FIG. 114). Clone DNA39427-1179has been deposited with ATCC and is assigned ATCC deposit no. ATCC209395.

Analysis of the amino acid sequence of the full-length PRO268polypeptide suggests that it possess significant homology toprotein disulfide isomerase, thereby indicating that PRO268 may bea novel protein disulfide isomerase.

Example 48

Isolation of cDNA Clones Encoding Human PRO330

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA35730. Based on theDNA35730 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO330.

Forward and reverse PCR primers were synthesized:

TABLE-US-00062 forward PCR primer 1 5'-CCAGGCACAATTTCCAGA-3' (SEQID NO:333) forward PCR primer 2 5'-GGACCCTTCTGTGTGCCAG-3' (SEQ IDNO:334) reverse PCR primer 1 5'-GGTCTCAAGAACTCCTGTC-3' (SEQ IDNO:335) reverse PCR primer 2 5'-ACACTCAGCATTGCCTGGTACTTG-3' (SEQ IDNO:336)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence Hybridization Probe5'-GGGCACATGACTGACCTGATTTATGCAGAGAAAGAGCTGGTGCAG-3' (SEQ IDNO:337)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO330 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO330 [herein designated asDNA40603-1232] (SEQ ID NO:331) and the derived protein sequence forPRO330.

The entire nucleotide sequence of DNA40603-1232 is shown in FIG.115 (SEQ ID NO:331). Clone DNA40603-1232 contains a single openreading frame with an apparent translational initiation site atnucleotide positions 167-169 and ending at the stop codon atnucleotide positions 1766-1768 (FIG. 115). The predictedpolypeptide precursor is 533 amino acids long (FIG. 116). CloneDNA40603-1232 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209486 on Nov. 21, 1997.

Analysis of the amino acid sequence of the full-length PRO330polypeptide suggests that portions of it possess significanthomology to the mouse prolyl 4-hydroxylase alpha subunit protein,thereby indicating that PRO330 may be a novel prolyl 4-hydroxylasealpha subunit polypeptide.

Example 49

Isolation of cDNA Clones Encoding Human PRO310

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA40553. Based on theDNA40553 consensus sequence, oligonucleotides were synthesized: 1)to identify by PCR a cDNA library that contained the sequence ofinterest, and 2) for use as probes to isolate a clone of thefull-length coding sequence for PRO310.

Forward and reverse PCR primers were synthesized:

TABLE-US-00063 forward PCR primer 1 5'-TCCCCAAGCCGTTCTAGACGCGG-3'(SEQ ID NO:342) forward PCR primer 2 5'-CTGGTTCTTCCTTGCACG-3' (SEQID NO:343) reverse PCR primer 5'-GCCCAAATGCCCTAAGGCGGTATACCCC-3'(SEQ ID NO:344)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence Hybridization Probe5'-GGGTGTGATGCTTGGAAGCATTTTCTGTGCTTTGATCACTATGCTAGGAC-3' (SEQ IDNO:345)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO310 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

DNA sequencing of the clones isolated as described above gave thefull-length DNA sequence for PRO310 [herein designated asDNA43046-1225 (SEQ ID NO:340) and the derived protein sequence forPRO310 (SEQ ID NO:341).

The entire nucleotide sequence of DNA43046-1225 is shown in FIG.119 (SEQ ID NO:340). Clone DNA43046-1225 contains a single openreading frame with an apparent translational initiation site atnucleotide positions 81-83 and ending at the stop codon atnucleotide positions 1035-1037 (FIG. 119). The predictedpolypeptide precursor is 318 amino acids long (FIG. 120) and has acalculated molecular weight of approximately 36,382 daltons. CloneDNA43046-1225 has been deposited with ATCC and is assigned ATCCdeposit no. ATCC 209484.

Analysis of the amino acid sequence of the full-length PRO310polypeptide suggests that portions of it possess homology to C.elegans proteins and to fringe, thereby indicating that PRO310 maybe involved in development.

Example 50

Isolation of cDNA clones Encoding Human PRO339

An expressed sequence tag (EST) DNA database (LIFESEQ.TM., IncytePharmaceuticals, Palo Alto, Calif.) was searched and ESTs wereidentified. An assembly of Incyte clones and a consensus sequencewas formed using phrap as described in Example 1 above.

Forward and reverse PCR primers were synthesized based upon theassembly-created consensus sequence:

TABLE-US-00064 forward PCR primer 1 5'-GGGATGCAGGTGGTGTCTCATGGGG-3'(SEQ ID NO:346) forward PCR primer 2 5'-CCCTCATGTACCGGCTCC-3' (SEQID NO:347) forward PCR primer 3 5'-GTGTGACACAGCGTGGGC-3' (SEQ IDNO:43) forward PCR primer 4 5'-GACCGGCAGGCTTCTGCG-3' (SEQ ID NO:44)reverse PCR primer 1 5'-CAGCAGCTTCAGCCACCAGGAGTGG-3' (SEQ ID NO:45)reverse PCR primer 2 5'-CTGAGCCGTGGGCTGCAGTCTCGC-3' (SEQ IDNO:46)

Additionally, a synthetic oligonucleotide hybridization probe wasconstructed from the consensus sequence which had the followingnucleotide sequence Hybridization Probe5'-CCGACTACGACTGGTTCTTCATCATGCAGGATGACACATATGTGC-3' (SEQ IDNO:47)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pairs identified above. A positive library wasthen used to isolate clones encoding the PRO339 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from humanfetal liver tissue.

A cDNA clone was sequenced in entirety. The entire nucleotidesequence of DNA43466-1225 is shown in FIG. 117 (SEQ ID NO:338).Clone DNA43466-1225 contains a single open reading frame with anapparent translational initiation site at nucleotide positions333-335 and ending at the stop codon found at nucleotide positions2649-2651 (FIG. 117; SEQ ID NO:338). The predicted polypeptideprecursor is 772 amino acids long and has a calculated molecularweight of approximately 86,226 daltons. Clone DNA43466-1225 hasbeen deposited with ATCC and is assigned ATCC deposit no. ATCC209490.

Based on a BLAST and FastA sequence alignment analysis (using theALIGN computer program) of the full-length sequence, PRO339 hashomology to C. elegans proteins and collagen-like polymer sequencesas well as to fringe, thereby indicating that PRO339 may beinvolved in development or tissue growth.

Example 51

Isolation of cDNA Clones Encoding Human PRO244

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Based onthis consensus sequence, oligonucleotides were synthesized toidentify by PCR a cDNA library that contained the sequence ofinterest and for use as probes to isolate a clone of thefull-length coding sequence for PRO244.

A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00065 5'-TTCAGCTTCTGGGATGTAGGG-3' (SEQ ID NO: 378)(30923.f1) 5'-TATTCCTACCATTTCACAAATCCG-3' (SEQ ID NO: 379)(30923.r1)

A probe was also synthesized:5'-GGAGGACTGTGCCACCATGAGAGACTCTTCAAACCCAAGGCAAAATTGG-3' (30923. p1)(SEQ ID NO:380)

In order to screen several libraries for a source of a full-lengthclone, DNA from the libraries was screened by PCR amplificationwith the PCR primer pair identified above. A positive library wasthen used to isolate clones encoding the PRO244 gene using theprobe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from ahuman fetal kidney library. DNA sequencing of the clones isolatedas described above gave the full-length DNA sequence and thederived protein sequence for PRO244.

The entire nucleotide sequence of PRO244 is shown in FIG. 121 (SEQID NO:376). Clone DNA35668-1171 contains a single open readingframe with an apparent translational initiation site at nucleotidepositions 106-108 (FIG. 121). The predicted polypeptide precursoris 219 amino acids long. Clone DNA35668-1171 has been depositedwith ATCC (designated as DNA35663-1171) and is assigned ATCCdeposit no. ATCC209371. The protein has a cytoplasmic domain (aa1-20), a transmembrane domain (aa 21-46), and an extracellulardomain (aa 47-219), with a C-lectin domain at aa 55-206.

Based on a BLAST and FastA sequence alignment analysis of thefull-length sequence, PRO244 shows notable amino acid sequenceidentity to hepatic lectin gallus gallus (43%), HIC hp120-bindingC-type lectin (42%), macrophage lectin 2 (HUMHML2-1, 41%), andsequence PR32188 (44%).

Example 52

Use of PRO Polypeptide-Encoding Nucleic Acid as HybridizationProbes

The following method describes use of a nucleotide sequenceencoding a PRO polypeptide as a hybridization probe.

DNA comprising the coding sequence of of a PRO polypeptide ofinterest as disclosed herein may be employed as a probe or used asa basis from which to prepare probes to screen for homologous DNAs(such as those encoding naturally-occurring variants of the PROpolypeptide) in human tissue cDNA libraries or human tissue genomiclibraries.

Hybridization and washing of filters containing either library DNAsis performed under the following high stringency conditions.Hybridization of radiolabeled PRO polypeptide-encoding nucleicacid-derived probe to the filters is performed in a solution of 50%formamide, 5.times. SSC, 0.1% SDS, 0.1% sodium pyrophosphate, 50 mMsodium phosphate, pH 6.8, 2.times. Denhardt's solution, and 10%dextran sulfate at 42.degree. C. for 20 hours. Washing of thefilters is performed in an aqueous solution of 0.1.times. SSC and0.1% SDS at 42.degree. C.

DNAs having a desired sequence identity with the DNA encodingfull-length native sequence PRO polypeptide can then be identifiedusing standard techniques known in the art.

Example 53

Expression of PRO Polypeptides in E. coli

This example illustrates preparation of an unglycosylated form of adesired PRO polypeptide by recombinant expression in E. coli.

The DNA sequence encoding the desired PRO polypeptide is initiallyamplified using selected PCR primers. The primers should containrestriction enzyme sites which correspond to the restriction enzymesites on the selected expression vector. A variety of expressionvectors may be employed. An example of a suitable vector is pBR322(derived from E. coli; see Bolivar et al., Gene, 2:95 (1977)) whichcontains genes for ampicillin and tetracycline resistance. Thevector is digested with restriction enzyme and dephosphorylated.The PCR amplified sequences are then ligated into the vector. Thevector will preferably include sequences which encode for anantibiotic resistance gene, a trp promoter, a polyhis leader(including the first six STII codons, polyhis sequence, andenterokinase cleavage site), the specific PRO polypeptide codingregion, lambda transcriptional terminator, and an argU gene.

The ligation mixture is then used to transform a selected E. colistrain using the methods described in Sambrook et al., supra.Transformants are identified by their ability to grow on LB platesand antibiotic resistant colonies are then selected. Plasmid DNAcan be isolated and confirmed by restriction analysis and DNAsequencing.

Selected clones can be grown overnight in liquid culture mediumsuch as LB broth supplemented with antibiotics. The overnightculture may subsequently be used to inoculate a larger scaleculture. The cells are then grown to a desired optical density,during which the expression promoter is turned on.

After culturing the cells for several more hours, the cells can beharvested by centrifugation. The cell pellet obtained by thecentrifugation can be solubilized using various agents known in theart, and the solubilized PRO polypeptide can then be purified usinga metal chelating column under conditions that allow tight bindingof the protein.

PRO187, PRO317, PRO301, PRO224 and PRO238 were successfullyexpressed in E. coli in a poly-His tagged form, using the followingprocedure. The DNA encoding PRO187, PRO317, PRO301, PRO224 orPRO238 was initially amplified using selected PCR primers. Theprimers contained restriction enzyme sites which correspond to therestriction enzyme sites on the selected expression vector, andother useful sequences providing for efficient and reliabletranslation initiation, rapid purification on a metal chelationcolumn, and proteolytic removal with enterokinase. ThePCR-amplified, poly-His tagged sequences were then ligated into anexpression vector, which was used to transform an E. coli hostbased on strain 52 (W3110 fuhA(tonA) Ion galE rpoHts(htpRts)clpP(lacIq). Transformants were first grown in LB containing 50mg/ml carbenicillin at 30.degree. C. with shaking until an O.D.600of 3-5 was reached. Cultures were then diluted 50-100 fold intoCRAP media (prepared by mixing 3.57 g (NH.sub.4).sub.2SO.sub.4,0.71 g sodium citrate2H.sub.2O, 1.07 g KCl, 5.36 g Difco yeastextract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110mM MPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO.sub.4) and grownfor approximately 20-30 hours at 30.degree. C. with shaking.Samples were removed to verify expression by SDS-PAGE analysis, andthe bulk culture is centrifuged to pellet the cells. Cell pelletswere frozen until purification and refolding.

E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) wasresuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8buffer. Solid sodium sulfite and sodium tetrathionate is added tomake final concentrations of 0.1M and 0.02 M, respectively, and thesolution was stirred overnight at 4.degree. C. This step results ina denatured protein with all cysteine residues blocked bysulfitolization. The solution was centrifuged at 40,000 rpm in aBeckman Ultracentifuge for 30 min. The supernatant was diluted with3-5 volumes of metal chelate column buffer (6 M guanidine, 20 mMTris, pH 7.4) and filtered through 0.22 micron filters to clarify.Depending the clarified extract was loaded onto a 5 ml QiagenNi-NTA metal chelate column equilibrated in the metal chelatecolumn buffer. The column was washed with additional buffercontaining 50 mM imidazole (Calbiochem, Utrol grade), pH 7.4. Theprotein was eluted with buffer containing 250 mM imidazole.Fractions containing the desired protein were pooled and stored at4.degree. C. Protein concentration was estimated by its absorbanceat 280 nm using the calculated extinction coefficient based on itsamino acid sequence.

The proteins were refolded by diluting sample slowly into freshlyprepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 MNaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA.Refolding volumes were chosen so that the final proteinconcentration was between 50 to 100 micrograms/ml. The refoldingsolution was stirred gently at 4.degree. C. for 12-36 hours. Therefolding reaction was quenched by the addition of TFA to a finalconcentration of 0.4% (pH of approximately 3). Before furtherpurification of the protein, the solution was filtered through a0.22 micron filter and acetonitrile was added to 2-10% finalconcentration. The refolded protein was chromatographed on a PorosR1/H reversed phase column using a mobile buffer of 0.1% TFA withelution with a gradient of acetonitrile from 10 to 80%. Aliquots offractions with A280 absorbance were analyzed on SDS polyacrylamidegels and fractions containing homogeneous refolded protein werepooled. Generally, the properly refolded species of most proteinsare eluted at the lowest concentrations of acetonitrile since thosespecies are the most compact with their hydrophobic interiorsshielded from interaction with the reversed phase resin. Aggregatedspecies are usually eluted at higher acetonitrile concentrations.In addition to resolving misfolded forms of proteins from thedesired form, the reversed phase step also removes endotoxin fromthe samples.

Fractions containing the desired folded PRO187, PRO317, PRO301,PRO224 and PRO238 proteins, respectively, were pooled and theacetonitrile removed using a gentle stream of nitrogen directed atthe solution. Proteins were formulated into 20 mM Hepes, pH 6.8with 0.14 M sodium chloride and 4% mannitol by dialysis or by gelfiltration using G25 Superfine (Pharmacia) resins equilibrated inthe formulation buffer and sterile filtered.

Example 54

Expression of PRO Polypeptides in Mammalian Cells

This example illustrates preparation of a glycosylated form of adesired PRO polypeptide by recombinant expression in mammaliancells.

The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), isemployed as the expression vector. Optionally, the PROpolypeptide-encoding DNA is ligated into pRK5 with selectedrestriction enzymes to allow insertion of the PRO polypeptide DNAusing ligation methods such as described in Sambrook et al., supra.The resulting vector is called pRK5-PRO polypeptide.

In one embodiment, the selected host cells may be 293 cells. Human293 cells (ATCC CCL 1573) are grown to confluence in tissue cultureplates in medium such as DMEM supplemented with fetal calf serumand optionally, nutrient components and/or antibiotics. About 10.mu.g pRK5-PRO polypeptide DNA is mixed with about 1 .mu.g DNAencoding the VA RNA gene [Thimmappaya et al., Cell, 31:543 (1982)]and dissolved in 500 .mu.l of 1 mM Tris-HCl, 0.1 mM EDTA, 0.227 MCaCl.sub.2. To this mixture is added, dropwise, 500 .mu.l of 50 mMHEPES (pH 7.35), 280 mM NaCl, 1.5 mM NAPO.sub.4, and a precipitateis allowed to form for 10 minutes at 25.degree. C. The precipitateis suspended and added to the 293 cells and allowed to settle forabout four hours at 37.degree. C. The culture medium is aspiratedoff and 2 ml of 20% glycerol in PBS is added for 30 seconds. The293 cells are then washed with serum free medium, fresh medium isadded and the cells are incubated for about 5 days.

Approximately 24 hours after the transfections, the culture mediumis removed and replaced with culture medium (alone) or culturemedium containing 200 .mu.Ci/ml .sup.35S-cysteine and 200 .mu.Ci/ml.sup.35S-methionine. After a 12 hour incubation, the conditionedmedium is collected, concentrated on a spin filter, and loaded ontoa 15% SDS gel. The processed gel may be dried and exposed to filmfor a selected period of time to reveal the presence of PROpolypeptide. The cultures containing transfected cells may undergofurther incubation (in serum free medium) and the medium is testedin selected bioassays.

In an alternative technique, PRO polypeptide may be introduced into293 cells transiently using the dextran sulfate method described bySomparyrac et al., Proc. Natl. Acad. Sci., 12:7575 (1981). 293cells are grown to maximal density in a spinner flask and 700 .mu.gpRK5-PRO polypeptide DNA is added. The cells are first concentratedfrom the spinner flask by centrifugation and washed with PBS. TheDNA-dextran precipitate is incubated on the cell pellet for fourhours. The cells are treated with 20% glycerol for 90 seconds,washed with tissue culture medium, and re-introduced into thespinner flask containing tissue culture medium, 5 .mu.g/ml bovineinsulin and 0.1 .mu.g/ml bovine transferrin. After about four days,the conditioned media is centrifuged and filtered to remove cellsand debris. The sample containing expressed PRO polypeptide canthen be concentrated and purified by any selected method, such asdialysis and/or column chromatography.

In another embodiment, PRO polypeptides can be expressed in CHOcells. The pRK5-PRO polypeptide can be transfected into CHO cellsusing known reagents such as CaPO.sub.4 or DEAE-dextran. Asdescribed above, the cell cultures can be incubated, and the mediumreplaced with culture medium (alone) or medium containing aradiolabel such as .sup.35S-methionine. After determining thepresence of PRO polypeptide, the culture medium may be replacedwith serum free medium. Preferably, the cultures are incubated forabout 6 days, and then the conditioned medium is harvested. Themedium containing the expressed PRO polypeptide can then beconcentrated and purified by any selected method.

Epitope-tagged PRO polypeptide may also be expressed in host CHOcells. The PRO polypeptide may be subcloned out of the pRK5 vector.The subclone insert can undergo PCR to fuse in frame with aselected epitope tag such as a poly-his tag into a Baculovirusexpression vector. The poly-his tagged PRO polypeptide insert canthen be subcloned into a SV40 driven vector containing a selectionmarker such as DHFR for selection of stable clones. Finally, theCHO cells can be transfected (as described above) with the SV40driven vector. Labeling may be performed, as described above, toverify expression. The culture medium containing the expressedpoly-His tagged PRO polypeptide can then be concentrated andpurified by any selected method, such as by Ni.sup.2+-chelateaffinity chromatography.

PRO211, PRO217, PRO230, PRO219, PRO245, PRO221, PRO258, PRO301,PRO224, PRO222, PRO234, PRO229, PRO223, PRO328 and PRO332 weresuccessfully expressed in CHO cells by both a transient and astable expression procedure. In addition, PRO232, PRO265, PRO246,PRO228, PRO227, PRO220, PRO266, PRO269, PRO287, PRO214, PRO231,PRO233, PRO238, PRO244, PRO235, PRO236, PRO262, PRO239, PRO257,PRO260, PRO263, PRO270, PRO271, PRO272, PRO294, PRO295, PRO293,PRO247, PRO303 and PRO268 were successfully transiently expressedin CHO cells.

Stable expression in CHO cells was performed using the followingprocedure. The proteins were expressed as an IgG construct(immunoadhesin), in which the coding sequences for the solubleforms (e.g. extracellular domains) of the respective proteins werefused to an IgG1 constant region sequence containing the hinge, CH2and CH2 domains and/or is a poly-His tagged form.

Following PCR amplification, the respective DNAs were subcloned ina CHO expression vector using standard techniques as described inAusubel et al., Current Protocols of Molecular Biology, Unit 3.16,John Wiley and Sons (1997). CHO expression vectors are constructedto have compatible restriction sites 5' and 3' of the DNA ofinterest to allow the convenient shuttling of cDNA's. The vectorused expression in CHO cells is as described in Lucas et al., Nucl.Acids Res. 24: 9 (1774-1779 (1996), and uses the SV40 earlypromoter/enhancer to drive expression of the cDNA of interest anddihydrofolate reductase (DHFR). DHFR expression permits selectionfor stable maintenance of the plasmid following transfection.

Twelve micrograms of the desired plasmid DNA were introduced intoapproximately 10 million CHO cells using commercially availabletransfection reagents SUPERFECT.RTM. (Quiagen), DOSPER.RTM. orFUGENE.RTM. (Boebringer Mannheim). The cells were grown anddescribed in Lucas et al., supra. Approximately 3.times.10.sup.-7cells are frozen in an ampule for further growth and production asdescribed below.

The ampules containing the plasmid DNA were thawed by placementinto water bath and mixed by vortexing. The contents were pipettedinto a centrifuge tube containing 10 mLs of media and centrifugedat 1000 rpm for 5 minutes. The supernatant was aspirated and thecells were resuspended in 10 mL of selective media (0.2 .mu.mfiltered PS20 with 5% 0.2 .mu.m diafiltered fetal bovine serum).The cells were then aliquoted into a 100 mL spinner containing 90mL of selective media. After 1-2 days, the cells were transferredinto a 250 mL spinner filled with 150 mL selective growth mediumand incubated at 37.degree. C. After another 2-3 days, a 250 mL,500 mL and 2000 mL spinners were seeded with 3.times.10.sup.5cells/mL. The cell media was exchanged with fresh media bycentrifugation and resuspension in production medium. Although anysuitable CHO media may be employed, a production medium describedin U.S. Pat. No. 5,122,469, issued Jun. 16, 1992 was actually used.3L production spinner is seeded at 1.2.times.10.sup.6 cells/mL. Onday 0, the cell number pH were determined. On day 1, the spinnerwas sampled and sparging with filtered air was commenced. On day 2,the spinner was sampled, the temperature shifted to 33.degree. C.,and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g., 35%polydimethylsiloxane emulsion, Dow Corning 365 Medical GradeEmulsion). Throughout the production, pH was adjusted as necessaryto keep at around 7.2. After 10 days, or until viability droppedbelow 70%, the cell culture was harvested by centrifugtion andfiltering through a 0.22 .mu.m filter. The filtrate was eitherstored at 4.degree. C. or immediately loaded onto columns forpurification.

For the poly-His tagged constructs, the proteins were purifiedusing a Ni-NTA column (Qiagen). Before purification, imidazole wasadded to the conditioned media to a concentration of 5 mM. Theconditioned media was pumped onto a 6 ml Ni-NTA column equilibratedin 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCl and 5 mMimidazole at a flow rate of 4-5 ml/min. at 4.degree. C. Afterloading, the column was washed with additional equilibration bufferand the protein eluted with equilibration buffer containing 0.25 Mimidazole. The highly purified protein was subsequently desaltedinto a storage buffer containing 10 mM Hepes, 0.14 M NaCl and 4%mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column andstored at -80.degree. C.

Immunoadhesin (Fc containing) constructs of were purified from theconditioned media as follows. The conditioned medium was pumpedonto a 5 ml Protein A column (Pharmacia) which had beenequilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading,the column was washed extensively with equilibration buffer beforeelution with 100 mM citric acid, pH 3.5. The eluted protein wasimmediately neutralized by collecting 1 ml fractions into tubescontaining 275 .mu.L of 1 M Tris buffer, pH 9. The highly purifiedprotein was subsequently desalted into storage buffer as describedabove for the poly-His tagged proteins. The homogeneity wasassessed by SDS polyacrylamide gels and by N-terminal amino acidsequencing by Edman degradation.

PRO211, PRO217, PRO230, PRO232, PRO187, PRO265, PRO219, PRO246,PRO228, PRO533, PRO245, PRO221, PRO227, PRO220, PRO258, PRO266,PRO269, PRO287, PRO214, PRO317, PRO301, PRO224, PRO222, PRO234,PRO231, PRO229, PRO233, PRO238, PRO223, PRO235, PRO236, PRO262,PRO239, PRO257, PRO260, PRO263, PRO270, PRO271, PRO272, PRO294,PRO295, PRO293, PRO247, PRO304, PRO302, PRO307, PRO303, PRO343,PRO328, PRO326, PRO331, PRO332, PRO334, PRO346, PRO268, PRO330,PRO310 and PRO339 were also successfully transiently expressed inCOS cells.

Example 55

Expression of PRO Polypeptides in Yeast

The following method describes recombinant expression of a desiredPRO polypeptide in yeast.

First, yeast expression vectors are constructed for intracellularproduction or secretion of PRO polypeptides from the ADH2/GAPDHpromoter. DNA encoding a desired PRO polypeptide, a selected signalpeptide and the promoter is inserted into suitable restrictionenzyme sites in the selected plasmid to direct intracellularexpression of the PRO polypeptide. For secretion, DNA encoding thePRO polypeptide can be cloned into the selected plasmid, togetherwith DNA encoding the ADH2/GAPDH promoter, the yeast alpha-factorsecretory signal/leader sequence, and linker sequences (if needed)for expression of the PRO polypeptide.

Yeast cells, such as yeast strain AB110, can then be transformedwith the expression plasmids described above and cultured inselected fermentation media. The transformed yeast supernatants canbe analyzed by precipitation with 10% trichloroacetic acid andseparation by SDS-PAGE, followed by staining of the gels withCoomassie Blue stain.

Recombinant PRO polypeptide can subsequently be isolated andpurified by removing the yeast cells from the fermentation mediumby centrifugation and then concentrating the medium using selectedcartridge filters. The concentrate containing the PRO polypeptidemay further be purified using selected column chromatographyresins.

Example 56

Expression of PRO Polypeptides in Baculovirus-Infected InsectCells

The following method describes recombinant expression of PROpolypeptides in Baculovirus-infected insect cells.

The desired PRO polypeptide is fused upstream of an epitope tagcontained with a baculovirus expression vector. Such epitope tagsinclude poly-his tags and immunoglobulin tags (like Fc regions ofIgG). A variety of plasmids may be employed, including plasmidsderived from commercially available plasmids such as pVL1393(Novagen). Briefly, the PRO polypeptide or the desired portion ofthe PRO polypeptide (such as the sequence encoding theextracellular domain of a transmembrane protein) is amplified byPCR with primers complementary to the 5' and 3' regions. The 5'primer may incorporate flanking (selected) restriction enzymesites. The product is then digested with those selected restrictionenzymes and subcloned into the expression vector.

Recombinant baculovirus is generated by co-transfecting the aboveplasmid and BACULOGOLD.RTM. virus DNA (Pharmingen) into Spodopterafrugiperda ("Sf9") cells (ATCC CRL 1711) using LIPOFECTIIN.RTM.(commercially available from GIBCO-BRL). After 4-5 days ofincubation at 28.degree. C., the released viruses are harvested andused for further amplifications. Viral infection and proteinexpression is perfonned as described by O'Reilley et al.,Baculovirus expression vectors: A laboratory Manual, Oxford: OxfordUniversity Press (1994).

Expressed poly-his tagged PRO polypeptide can then be purified, forexample, by Ni.sup.2+-chelate affinity chromatography as follows.Extracts are prepared from recombinant virus-infected Sf9 cells asdescribed by Rupert et al., Nature, 362:175-179 (1993). Briefly,Sf9 cells are washed, resuspended in sonication buffer (25 mLHepes, pH 7.9; 12.5 mM MgCl.sub.2; 0.1 mM EDTA; 10% Glycerol; 0.1%NP-40; 0.4 M KCl), and sonicated twice for 20 seconds on ice. Thesonicates are cleared by centrifugation, and the supernatant isdiluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCl,10% Glycerol, pH 7.8) and filtered through a 0.45 .mu.m filter. ANi.sup.2+-NTA agarose column (commercially available from Qiagen)is prepared with a bed volume of 5 mL, washed with 25 mL of waterand equilibrated with 25 mL of loading buffer. The filtered cellextract is loaded onto the column at 0.5 mL per minute. The columnis washed to baseline A.sub.280 with loading buffer, at which pointfraction collection is started. Next, the column is washed with asecondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% Glycerol,pH 6.0), which elutes nonspecifically bound protein. After reachingA.sub.280 baseline again, the column is developed with a 0 to 500mM Imidazole gradient in the secondary wash buffer. One mLfractions are collected and analyzed by SDS-PAGE and silverstaining or western blot with Ni.sup.2+-NTA-conjugated to alkalinephosphatase (Qiagen). Fractions containing the elutedHis.sub.10-tagged PRO polypeptide are pooled and dialyzed againstloading buffer.

Alternatively, purification of the IgG tagged (or Fc tagged) PROpolypeptide can be performed using known chromatography techniques,including for instance, Protein A or protein G columnchromatography.

PRO211, PRO217, PRO230, PRO187, PRO265, PRO246, PRO228, PRO533,PRO245, PRO221, PRO220, PRO258, PRO266, PRO269, PRO287, PRO214,PRO301, PRO224, PRO222, PRO234, PRO231, PRO229, PRO235, PRO239,PRO257, PRO272, PRO294, PRO295, PRO328, PRO326, PRO331, PRO334,PRO346 and PRO310 were successfully expressed in baculovirusinfected Sf9 or high5 insect cells. While the expression wasactually performed in a 0.5-2 L scale, it can be readily scaled upfor larger (e.g. 8 L) preparations. The proteins were expressed asan IgG construct (immunoadhesin), in which the proteinextracellular region was fused to an IgG1 constant region sequencecontaining the hinge, CH2 and CH3 domains and/or in poly-His taggedforms.

Following PCR amplification, the respective coding sequences weresubcloned into a baculovirus expression vector (pb.PH.IgG for IgGfusions and pb.PH.His.c for poly-His tagged proteins), and thevector and Baculogold.RTM. baculovirus DNA (Pharmingen) wereco-transfected into 105 Spodoptera frugiperda ("Sf9") cells (ATCCCRL 1711), using LIPOFECTIIN.RTM. (Gibco BRL). pb.PH.IgG andpb.PH.His are modifications of the commercially availablebaculovirus expression vector pVL1393 (Pharmingen), with modifiedpolylinker regions to include the His or Fc tag sequences. Thecells were grown in Hink's TNM-FH medium supplemented with 10% FBS(Hyclone). Cells were incubated for 5 days at 28.degree. C. Thesupernatant was harvested and subsequently used for the first viralamplification by infecting Sf9 cells in Hink's TNM-FH mediumsupplemented with 10% FBS at an approximate multiplicity ofinfection (MOI) of 10. Cells were incubated for 3 days at28.degree. C. The supernatant was harvested and the expression ofthe constructs in the baculovirus expression vector was determinedby batch binding of 1 ml of supernatant to 25 mL of Ni-NTA beads(QIAGEN) for histidine tagged proteins or Protein-A SEPHAROSE.TM.CL-4B beads (Pharmacia) for IgG tagged proteins followed bySDS-PAGE analysis comparing to a known concentration of proteinstandard by Coomassie blue staining.

The first viral amplification supernatant was used to infect aspinner culture (500 ml) of Sf9 cells grown in ESF-921 medium(Expression Systems LLC) at an approximate MOI of 0.1. Cells wereincubated for 3 days at 28.degree. C. The supernatant was harvestedand filtered. Batch binding and SDS-PAGE analysis was repeated, asnecessary, until expression of the spinner culture wasconfirmed.

The conditioned medium from the transfected cells (0.5 to 3 L) washarvested by centrifugation to remove the cells and filteredthrough 0.22 micron filters. For the poly-His tagged constructs,the protein construct were purified using a Ni-NTA column (Qiagen).Before purification, imidazole was added to the conditioned mediato a concentration of 5 mM. The conditioned media were pumped ontoa 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffercontaining 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5ml/min. at 4.degree. C. After loading, the column was washed withadditional equilibration buffer and the protein eluted withequilibration buffer containing 0.25 M imidazole. The highlypurified protein was subsequently desalted into a storage buffercontaining 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a25 ml G25 Superfine (Pharmacia) column and stored at -80.degree.C.

Immunoadhesin (Fc containing) constructs of proteins were purifiedfrom the conditioned media as follows. The conditioned media werepumped onto a 5 ml Protein A column (Pharmacia) which had beenequilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading,the column was washed extensively with equilibration buffer beforeelution with 100 mM citric acid, pH 3.5. The eluted protein wasimmediately neutralized by collecting 1 ml fractions into tubescontaining 275 mL of 1 M Tris buffer, pH 9. The highly purifiedprotein was subsequently desalted into storage buffer as describedabove for the poly-His tagged proteins. The homogeneity of theproteins was verified by SDS polyacrylamide gel (PEG)electrophoresis and N-terminal amino acid sequencing by Edmandegradation.

Example 57

Preparation of Antibodies that Bind to PRO Polypeptides

This example illustrates preparation of monoclonal antibodies whichcan specifically bind to a PRO polypeptide.

Techniques for producing the monoclonal antibodies are known in theart and are described, for instance, in Goding, supra. Immunogensthat may be employed include purified PRO polypeptide, fusionproteins containing the PRO polypeptide, and cells expressingrecombinant PRO polypeptide on the cell surface. Selection of theimmunogen can be made by the skilled artisan without undueexperimentation.

Mice, such as Balb/c, are immunized with the PRO polypeptideimmunogen emulsified in complete Freund's adjuvant and injectedsubcutaneously or intraperitoneally in an amount from 1-100micrograms. Alternatively, the immunogen is emulsified in MPL-TDMadjuvant (Ribi Immunochemical Research, Hamilton, Mont.) andinjected into the animal's hind foot pads. The immunized mice arethen boosted 10 to 12 days later with additional immunogenemulsified in the selected adjuvant. Thereafter, for several weeks,the mice may also be boosted with additional immunizationinjections. Serum samples may be periodically obtained from themice by retro-orbital bleeding for testing in ELISA assays todetect anti-PRO polypeptide antibodies.

After a suitable antibody titer has been detected, the animals"positive" for antibodies can be injected with a final intravenousinjection of PRO polypeptide. Three to four days later, the miceare sacrificed and the spleen cells are harvested. The spleen cellsare then fused (using 35% polyethylene glycol) to a selected murinemyeloma cell line such as P3.times.63AgU.1, available from ATCC,No. CRL 1597. The fusions generate hybridoma cells which can thenbe plated in 96 well tissue culture plates containing HAT(hypoxanthine, aminopterin, and thymidine) medium to inhibitproliferation of non-fused cells, myeloma hybrids, and spleen cellhybrids.

The hybridoma cells will be screened in an ELISA for reactivityagainst the PRO polypeptide. Determination of "positive" hybridomacells secreting the desired monoclonal antibodies against the PROpolypeptide is within the skill in the art.

The positive hybridoma cells can be injected intraperitoneally intosyngeneic Balb/c mice to produce ascites containing the anti-PROpolypeptide monoclonal antibodies. Alternatively, the hybridomacells can be grown in tissue culture flasks or roller bottles.Purification of the monoclonal antibodies produced in the ascitescan be accomplished using ammonium sulfate precipitation, followedby gel exclusion chromatography. Alternatively, affinitychromatography based upon binding of antibody to protein A orprotein G can be employed.

Example 58

Chimeric PRO Polypeptides

PRO polypeptides may be expressed as chimeric proteins with one ormore additional polypeptide domains added to facilitate proteinpurification. Such purification facilitating domains include, butare not limited to, metal chelating peptides such ashistidine-tryptophan modules that allow purification on immobilizedmetals, protein A domains that allow purification on immobilizedimmunoglobulin, and the domain utilized in the FLAGS.TM.extension/affinity purification system (Immunex Corp., Seattle,Wash.). The inclusion of a cleavable linker sequence such as FactorXA or enterokinase (Invitrogen, San Diego, Calif.) between thepurification domain and the PRO polypeptide sequence may be usefulto facilitate expression of DNA encoding the PRO polypeptide.

Example 59

Purification of PRO Polypeptides Using Specific Antibodies

Native or recombinant PRO polypeptides may be purified by a varietyof standard techniques in the art of protein purification. Forexample, pro-PRO polypeptide, mature PRO polypeptide, or pre-PROpolypeptide is purified by immunoaffinity chromatography usingantibodies specific for the PRO polypeptide of interest. Ingeneral, an immunoaffinity column is constructed by covalentlycoupling the anti-PRO polypeptide antibody to an activatedchromatographic resin.

Polyclonal immunoglobulins are prepared from immune sera either byprecipitation with ammonium sulfate or by purification onimmobilized Protein A (Pharmacia LKB Biotechnology, Piscataway,N.J.). Likewise, monoclonal antibodies are prepared from mouseascites fluid by ammonium sulfate precipitation or chromatographyon immobilized Protein A. Partially purified immunoglobulin iscovalently attached to a chromatographic resin such asCnBr-activated SEPHAROSE.TM. (Pharmacia LKB Biotechnology). Theantibody is coupled to the resin, the resin is blocked, and thederivative resin is washed according to the manufacturer'sinstructions.

Such an immunoaffinity column is utilized in the purification ofPRO polypeptide by preparing a fraction from cells containing PROpolypeptide in a soluble form. This preparation is derived bysolubilization of the whole cell or of a subcellular fractionobtained via differential centrifugation by the addition ofdetergent or by other methods well known in the art. Alternatively,soluble PRO polypeptide containing a signal sequence may besecreted in useful quantity into the medium in which the cells aregrown.

A soluble PRO polypeptide-containing preparation is passed over theimmunoaffinity column, and the column is washed under conditionsthat allow the preferential absorbance of PRO polypeptide (e.g.,high ionic strength buffers in the presence of detergent). Then,the column is eluted under conditions that disrupt antibody/PROpolypeptide binding (e.g., a low pH buffer such as approximately pH2-3, or a high concentration of a chaotrope such as urea orthiocyanate ion), and PRO polypeptide is collected.

Example 60

Drug Screening

This invention is particularly useful for screening compounds byusing PRO polypeptides or binding fragment thereof in any of avariety of drug screening techniques. The PRO polypeptide orfragment employed in such a test may either be free in solution,affixed to a solid support, borne on a cell surface, or locatedintracellularly. One method of drug screening utilizes eukaryoticor prokaryotic host cells which are stably transformed withrecombinant nucleic acids expressing the PRO polypeptide orfragment. Drugs are screened against such transformed cells incompetitive binding assays. Such cells, either in viable or fixedform, can be used for standard binding assays. One may measure, forexample, the formation of complexes between PRO polypeptide or afragment and the agent being tested. Alternatively, one can examinethe diminution in complex formation between the PRO polypeptide andits target cell or target receptors caused by the agent beingtested.

Thus, the present invention provides methods of screening for drugsor any other agents which can affect a PRO polypeptide-associateddisease or disorder. These methods comprise contacting such anagent with an PRO polypeptide or fragment thereof and assaying (I)for the presence of a complex between the agent and the PROpolypeptide or fragment, or (ii) for the presence of a complexbetween the PRO polypeptide or fragment and the cell, by methodswell known in the art. In such competitive binding assays, the PROpolypeptide or fragment is typically labeled. After suitableincubation, free PRO polypeptide or fragment is separated from thatpresent in bound form, and the amount of free or uncomplexed labelis a measure of the ability of the particular agent to bind to PROpolypeptide or to interfere with the PRO polypeptide/cellcomplex.

Another technique for drug screening provides high throughputscreening for compounds having suitable binding affinity to apolypeptide and is described in detail in WO 84/03564, published onSep. 13, 1984. Briefly stated, large numbers of different smallpeptide test compounds are synthesized on a solid substrate, suchas plastic pins or some other surface. As applied to a PROpolypeptide, the peptide test compounds are reacted with PROpolypeptide and washed. Bound PRO polypeptide is detected bymethods well known in the art. Purified PRO polypeptide can also becoated directly onto plates for use in the aforementioned drugscreening techniques. In addition, non-neutralizing antibodies canbe used to capture the peptide and immobilize it on the solidsupport.

This invention also contemplates the use of competitive drugscreening assays in which neutralizing antibodies capable ofbinding PRO polypeptide specifically compete with a test compoundfor binding to PRO polypeptide or fragments thereof. In thismanner, the antibodies can be used to detect the presence of anypeptide which shares one or more antigenic determinants with PROpolypeptide.

Example 61

Rational Drug Design

The goal of rational drug design is to produce structural analogsof biologically active polypeptide of interest (i.e., a PROpolypeptide) or of small molecules with which they interact, e.g.,agonists, antagonists, or inhibitors. Any of these examples can beused to fashion drugs which are more active or stable forms of thePRO polypeptide or which enhance or interfere with the function ofthe PRO polypeptide in vivo (cf., Hodgson, Bio/Technology, 9:19-21(1991)).

In one approach, the three-dimensional structure of the PROpolypeptide, or of an PRO polypeptide-inhibitor complex, isdetermined by x-ray crystallography, by computer modeling or, mosttypically, by a combination of the two approaches. Both the shapeand charges of the PRO polypeptide must be ascertained to elucidatethe structure and to determine active site(s) of the molecule. Lessoften, useful information regarding the structure of the PROpolypeptide may be gained by modeling based on the structure ofhomologous proteins. In both cases, relevant structural informationis used to design analogous PRO polypeptide-like molecules or toidentify efficient inhibitors. Useful examples of rational drugdesign may include molecules which have improved activity orstability as shown by Braxton and Wells, Biochemistry, 31:7796-7801(1992) or which act as inhibitors, agonists, or antagonists ofnative peptides as shown by Athauda et al., J. Biochem.,113:742-746 (1993).

It is also possible to isolate a target-specific antibody, selectedby functional assay, as described above, and then to solve itscrystal structure. This approach, in principle, yields a pharmacoreupon which subsequent drug design can be based. It is possible tobypass protein crystallography altogether by generatinganti-idiotypic antibodies (anti-ids) to a functional,pharmacologically active antibody. As a mirror image of a mirrorimage, the binding site of the anti-ids would be expected to be ananalog of the original receptor. The anti-id could then be used toidentify and isolate peptides from banks of chemically orbiologically produced peptides. The isolated peptides would thenact as the pharmacore.

By virtue of the present invention, sufficient amounts of the PROpolypeptide may be made available to perform such analyticalstudies as X-ray crystallography. In addition, knowledge of the PROpolypeptide amino acid sequence provided herein will provideguidance to those employing computer modeling techniques in placeof or in addition to x-ray crystallography.

Example 62

Diagnostic Test Using PRO317 Polypeptide-Specific Antibodies

Particular anti-PRO317 polypeptide antibodies are useful for thediagnosis of prepathologic conditions, and chronic or acutediseases such as gynecological diseases or ischemic diseases whichare characterized by differences in the amount or distribution ofPRO317. PRO317 has been found to be expressed in human kidney andis thus likely to be associated with abnormalities or pathologieswhich affect this organ. Further, since it is so closely related toEBAF-1, it is likely to affect the endometrium and other genitaltissues. Further, due to library sources of certain ESTs, itappears that PRO317 may be involved as well in forming bloodvessels and hence to be a modulator of angiogenesis.

Diagnostic tests for PRO317 include methods utilizing the antibodyand a label to detect PRO317 in human body fluids, tissues, orextracts of such tissues. The polypeptide and antibodies of thepresent invention may be used with or without modification.Frequently, the polypeptide and antibodies will be labeled byjoining them, either covalently or noncovalently, with a substancewhich provides for a detectable signal. A wide variety of labelsand conjugation techniques are known and have been reportedextensively in both the scientific and patent literature. Suitablelabels include radionuclides, enzymes, substrates, cofactors,inhibitors, fluorescent agents, chemiluminescent agents, magneticparticles, and the like. Patents teaching the use of such labelsinclude U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345;4,277,437; 4,275,149; and 4,366,241. Also, recombinantimmunoglobulins may be produced as shown in U.S. Pat. No.4,816,567.

A variety of protocols for measuring soluble or membrane-boundPRo317, using either polyclonal or monoclonal antibodies specificfor that PRO317, are known in the art. Examples includeenzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA),radioreceptor assay (RRA), and fluorescent activated cell sorting(FACS). A two-site monoclonal-based immunoassay utilizingmonoclonal antibodies reactive to two non-interfering epitopes onPRO317 is preferred, but a competitive binding assay may beemployed. These assays are described, among other places, in Maddoxet al. J. Exp. Med., 158:1211 (1983).

Example 63

Identification of PRO317 Receptors

Purified PRO317 is useful for characterization and purification ofspecific cell surface receptors and other binding molecules. Cellswhich respond to PRO317 by metabolic changes or other specificresponses are likely to express a receptor for PRO317. Suchreceptors include, but are not limited to, receptors associatedwith and activated by tyrosine and serine/threonine kinases. SeeKolodziejczyk and Hall, supra, for a review on known receptors forthe TGF-superfamily. Candidate receptors for this superfamily fallinto two primary groups, termed type I and type II receptors. Bothtypes are serine/threonine kinases. Upon activation by theappropriate ligand, type I and type II receptors physicallyinteract to form hetero-oligomers and subsequently activateintracellular signaling cascades, ultimately regulating genetranscription and expression. In addition, TGF-binds to a thirdreceptor class, type III, a membrane-anchored proteoglycan lackingthe kinase activity typical of signal transducing molecules.

PRO317 receptors or other PRO317-binding molecules may beidentified by interaction with radiolabeled PRO317. Radioactivelabels may be incorporated into PRO317 by various methods known inthe art. A preferred embodiment is the labeling of primary aminogroups in PRO317 with .sup.125I Bolton-Hunter reagent (Bolton andHunter, Biochem. J., 133:529 (1973)), which has been used to labelother polypeptides without concomitant loss of biological activity(Hebert et al., J. Biol. Chem., 266:18989 (1991); McColl et al., J.Immunol., 150:4550-4555 (1993)). Receptor-bearing cells areincubated with labeled PRO317. The cells are then washed to removedunbound PRO317, and receptor-bound PRO317 is quantified. The dataobtained using different concentrations of PRO317 are used tocalculate values for the number and affinity of receptors.

Labeled PRO317 is useful as a reagent for purification of itsspecific receptor. In one embodiment of affinity purification,PRO317 is covalently coupled to a chromatography column.Receptor-bearing cells are extracted, and the extract is passedover the column. The receptor binds to the column by virtue of itsbiological affinity for PRO317. The receptor is recovered from thecolumn and subjected to N-terminal protein sequencing. This aminoacid sequence is then used to design degenerate oligonucleotideprobes for cloning the receptor gene.

In an alternative method, mRNA is obtained from receptor-bearingcells and made into a cDNA library. The library is transfected intoa population of cells, and those cells expressing the receptor areselected using fluorescently labeled PRO317. The receptor isidentified by recovering and sequencing recombinant DNA from highlylabeled cells.

In another alternative method, antibodies are raised against thesurface of receptor bearing cells, specifically monoclonalantibodies. The monoclonal antibodies are screened to identifythose which inhibit the binding of labeled PRO317. These monoclonalantibodies are then used in affinity purification or expressioncloning of the receptor.

Soluble receptors or other soluble binding molecules are identifiedin a similar manner. Labeled PRO317 is incubated with extracts orother appropriate materials derived from the uterus. Afterincubation, PRO317 complexes larger than the size of purifiedPRO317 are identified by a sizing technique such as size-exclusionchromatography or density gradient centrifugation and are purifiedby methods known in the art. The soluble receptors or bindingprotein(s) are subjected to N-terminal sequencing to obtaininformation sufficient for database identification, if the solubleprotein is known, or for cloning, if the soluble protein isunknown.

Example 64

Determination of PRO317-Induced Cellular Response

The biological activity of PRO317 is measured, for example, bybinding of an PRO317 of the invention to an PRO317 receptor. A testcompound is screened as an antagonist for its ability to blockbinding of PRO317 to the receptor. A test compound is screened asan agonist of the PRO317 for its ability to bind an PRO317 receptorand influence the same physiological events as PRO317 using, forexample, the KIRA-ELISA assay described by Sadick et al.,Analytical Biochemistry, 235:207-214 (1996) in which activation ofa receptor tyrosine kinase is monitored by immuno-capture of theactivated receptor and quantitation of the level of ligand-inducedphosphorylation. The assay may be adapted to monitor PRO317-inducedreceptor activation through the use of an PRO317 receptor-specificantibody to capture the activated receptor. These techniques arealso applicable to other PRO polypeptides described herein.

Example 65

Use of PRO224 for Screening Compounds

PRO224 is expressed in a cell stripped of membrane proteins andcapable of expressing PRO224. Low density lipoproteins having adetectable label are added to the cells and incubated for asufficient time for endocytosis. The cells are washed. The cellsare then analysed for label bound to the membrane and within thecell after cell lysis. Detection of the low density lipoproteinswithin the cell determines that PRO224 is within the family of lowdensity lipoprotein receptor proteins. Members found within thisfamily are then used for screening compounds which affect thesereceptors, and particularly the uptake of cholesterol via thesereceptors.

Example 66

Ability of PRO Polypeptides to Inhibit Vascular Endothelial GrowthFactor (VEGF) Stimulated Proliferation of Endothelial Cell Growth(Assay 9)

The ability of various PRO polypeptides to inhibit VEGF stimulatedproliferation of endothelial cells was tested. Polypeptides testingpositive in this assay are useful for inhibiting endothelial cellgrowth in mammals where such an effect would be beneficial, e.g.,for inhibiting tumor growth.

Specifically, bovine adrenal cortical capillary endothelial cells(ACE) (from primary culture, maximum of 12-14 passages) were platedin 96-well plates at 500 cells/well per 100 microliter. Assay mediaincluded low glucose DMEM, 10% calf serum, 2 mM glutamine, and1.times. penicillin/streptomycin/fungizone. Control wells includedthe following: (1) no ACE cells added; (2) ACE cells alone; (3) ACEcells plus 5 ng/ml FGF; (4) ACE cells plus 3 ng/ml VEGF; (5) ACEcells plus 3 ng/ml VEGF plus 1 ng/ml TGF-beta; and (6) ACE cellsplus 3 ng/ml VEGF plus 5 ng/ml LIF. The test samples, poly-histagged PRO polypeptides (in 100 microliter volumes), were thenadded to the wells (at dilutions of 1%, 0.1% and 0.01%,respectively). The cell cultures were incubated for 6-7 days at37.degree. C./5% CO.sub.2. After the incubation, the media in thewells was aspirated, and the cells were washed 1.times. with PBS.An acid phosphatase reaction mixture (100 microliter; 0.1M sodiumacetate, pH 5.5, 0.1% Triton X-100, 10 mM p-nitrophenyl phosphate)was then added to each well. After a 2 hour incubation at37.degree. C., the reaction was stopped by addition of 10microliters 1N NaOH. Optical density (OD) was measured on amicroplate reader at 405 nm.

The activity of PRO polypeptides was calculated as the percentinhibition of VEGF (3 ng/ml) stimulated proliferation (asdetermined by measuring acid phosphatase activity at OD 405 nm)relative to the cells without stimulation. TGF-beta was employed asan activity reference at 1 ng/ml, since TGF-beta blocks 70-90% ofVEGF-stimulated ACE cell proliferation. The results are indicativeof the utility of the PRO polypeptides in cancer therapy andspecifically in inhibiting tumor angiogenesis. Numerical values(relative inhibition) are determined by calculating the percentinhibition of VEGF stimulated proliferation by the PRO polypeptidesrelative to cells without stimulation and then dividing thatpercentage into the percent inhibition obtained by TGF-.beta. at 1ng/ml which is known to block 70-90% of VEGF stimulated cellproliferation. The results are considered positive if the PROpolypeptide exhibits 30% or greater inhibition of VEGF stimulationof endothelial cell growth (relative inhibition 30% orgreater).

The following polypeptides tested positive in this assay: PRO211,PRO217, PRO187, PRO219, PRO246, PRO228, PRO245, PRO221, PRO258,PRO301, PRO224, PRO272, PRO328, PRO331, PRO224, PRO328, PRO272,PRO301, PRO331 and PRO214.

Example 67

Retinal Neuron Survival (Assay 52)

This example demonstrates that certain PRO polypeptides haveefficacy in enhancing the survival of retinal neuron cells and,therefore, are useful for the therapeutic treatment of retinaldisorders or injuries including, for example, treating sight lossin mammals due to retinitis pigmentosum, AMD, etc.

Sprague Dawley rat pups at postnatal day 7 (mixed population: gliaand retinal neuronal types) are killed by decapitation followingCO.sub.2 anesthesia and the eyes are removed under sterileconditions. The neural retina is dissected away from the pigmentepithelium and other ocular tissue and then dissociated into asingle cell suspension using 0.25% trypsin in Ca.sup.2+,Mg.sup.2+-free PBS. The retinas are incubated at 37.degree. C. for7-10 minutes after which the trypsin is inactivated by adding 1 mlsoybean trypsin inhibitor. The cells are plated at 100,000 cellsper well in 96 well plates in DMEM/F12 supplemented with N2 andwith or without the specific test PRO polypeptide. Cells for allexperiments are grown at 37.degree. C. in a water saturatedatmosphere of 5% CO.sub.2. After 2-3 days in culture, cells arestained with calcein AM then fixed using 4% paraformaldehyde andstained with DAPI for determination of total cell count. The totalcells (fluorescent) are quantified at 20.times. objectivemagnification using CCD camera and NIH image software forMacIntosh. Fields in the well are chosen at random.

The effect of various concentration of PRO polypeptides arereported herein where percent survival is calculated by dividingthe total number of calcein AM positive cells at 2-3 days inculture by the total number of DAPI-labeled cells at 2-3 days inculture. Anything above 30% survival is considered positive.

The following PRO polypeptides tested positive in this assay usingpolypeptide concentrations within the range of 0.01% to 1.0% in theassay: PRO220 and PRO346.

Example 68

Rod Photoreceptor Cell Survival (Assay 56)

This assay shows that certain polypeptides of the invention act toenhance the survival/proliferation of rod photoreceptor cells and,therefore, are useful for the therapeutic treatment of retinaldisorders or injuries including, for example, treating sight lossin mammals due to retinitis pigmentosum, AMD, etc. Sprague Dawleyrat pups at 7 day postnatal (mixed population: glia and retinalneuronal cell types) are killed by decapitation following CO.sub.2anesthesis and the eyes are removed under sterile conditions. Theneural retina is dissected away form the pigment epithelium andother ocular tissue and then dissociated into a single cellsuspension using 0.25% trypsin in Ca.sup.2+, Mg.sup.2+-free PBS.The retinas are incubated at 37.degree. C. for 7-10 minutes afterwhich the trypsin is inactivated by adding 1 ml soybean trypsininhibitor. The cells are plated at 100,000 cells per well in 96well plates in DMEM/F12 supplemented with N.sub.2. Cells for allexperiments are grown at 37.degree. C. in a water saturatedatmosphere of 5% CO.sub.2. After 2-3 days in culture, cells arefixed using 4% paraformaldehyde, and then stained using CellTrackerGreen CMFDA. Rho 4D2 (ascites or IgG 1:100), a monoclonal antibodydirected towards the visual pigment rhodopsin is used to detect rodphotoreceptor cells by indirect immunofluorescence. The results arecalculated as % survival: total number of calcein--rhodopsinpositive cells at 2-3 days in culture, divided by the total numberof rhodopsin positive cells at time 2-3 days in culture. The totalcells (fluorescent) are quantified at 20.times. objectivemagnification using a CCD camera and NIH image software forMacIntosh. Fields in the well are chosen at random.

The following polypeptides tested positive in this assay: PRO220and PRO346.

Example 69

Induction of Endothelial Cell Apoptosis (Assay 73)

The ability of PRO polypeptides to induce apoptosis in endothelialcells was tested in human venous umbilical vein endothelial cells(HUVEC, Cell Systems). A positive test in the assay is indicativeof the usefulness of the polypeptide in therapeutically treatingtumors as well as vascular disorders where inducing apoptosis ofendothelial cells would be beneficial.

The cells were plated on 96-well microtiter plates (Amersham LifeScience, cytostar-T scintillating microplate, RPNQ160, sterile,tissue-culture treated, individually wrapped), in 10% serum(CSG-medium, Cell Systems), at a density of 2.times.10.sup.4 cellsper well in a total volume of 100 .mu.l. On day 2, test samplescontaining the PRO polypeptide were added in triplicate atdilutions of 1%, 0.33% and 0.11%. Wells without cells were used asa blank and wells with cells only were used as a negative control.As a positive control 1:3 serial dilutions of 50 .mu.l of a3.times. stock of staurosporine were used. The ability of the PROpolypeptide to induce apoptosis was determined by processing of the96 well plates for detection of Annexin V, a member of the calciumand phospholipid binding proteins, to detect apoptosis.

0.2 ml Annexin V--Biotin stock solution (100 .mu.g/ml) was dilutedin 4.6 ml 2.times. Ca.sup.2+ binding buffer and 2.5% BSA (1:25dilution). 50 .mu.l of the diluted Annexin V--Biotin solution wasadded to each well (except controls) to a final concentration of1.0 .mu.g/ml. The samples were incubated for 10-15 minutes withAnnexin-Biotin prior to direct addition of .sup.35S-Streptavidin..sup.35S-Streptavidin was diluted in 2.times. Ca.sup.2+ Bindingbuffer, 2.5% BSA and was added to all wells at a finalconcentration of 3.times.10.sup.4 cpm/well. The plates were thensealed, centrifuged at 1000 rpm for 15 minutes and placed onorbital shaker for 2 hours. The analysis was performed on a 1450Microbeta Trilux (Wallac). Percent above background represents thepercentage amount of counts per minute above the negative controls.Percents greater than or equal to 30% above background areconsidered positive.

The following PRO polypeptides tested positive in this assay:PRO228, PRO217 and PRO301.

Example 70

PDB12 Cell Inhibition (Assay 40)

This example demonstrates that various PRO polypeptides haveefficacy in inhibiting protein production by PDB12 pancreaticductal cells and are, therefore, useful in the therapeutictreatment of disorders which involve protein secretion by thepancreas, including diabetes, and the like.

PDB 12 pancreatic ductal cells are plated on fibronectin coated 96well plates at 1.5.times.10.sup.3 cells per well in 100 .mu.L/180.mu.L of growth media. 100 .mu.L of growth media with the PROpolypeptide test sample or negative control lacking the PROpolypeptide is then added to well, for a final volume of 200 .mu.L.Controls contain growth medium containing a protein shown to beinactive in this assay. Cells are incubated for 4 days at37.degree. C. 20 .mu.L of ALAMAR BLUE.TM. dye (AB) is then added toeach well and the flourescent reading is measured at 4 hours postaddition of AB, on a microtiter plate reader at 530 nm excitationand 590 nm emission. The standard, employed is cells without BovinePituitary Extract (BPE) and with various concentrations of BPE.Buffer or CM controls from unknowns are run 2 times on each 96 wellplate.

These assays allow one to calculate a percent decrease in proteinproduction by comparing the ALAMAR BLUE.TM. Dye calculated proteinconcentration produced by the PRO polypeptide-treated cells withthe ALAMAR BLUE.TM. Dye calculated protein concentration producedby the negative control cells. A percent decrease in proteinproduction of greater than or equal to 25% as compared to thenegative control cells is considered positive.

The following polypeptides tested positive in this assay: PRO211,PRO287, PRO301 and PRO293.

Example 71

Stimulation of Adult Heart Hypertrophy (Assay 2)

This assay is designed to measure the ability of various PROpolypeptides to stimulate hypertrophy of adult heart. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of various cardiacinsufficiency disorders.

Ventricular myocytes freshly isolated from adult (250 g) SpragueDawley rats are plated at 2000 cell/well in 180 .mu.l volume. Cellsare isolated and plated on day 1, the PRO polypeptide-containingtest samples or growth medium only (negative control) (20 .mu.lvolume) is added on day 2 and the cells are then fixed and stainedon day 5. After staining, cell size is visualized wherein cellsshowing no growth enhancement as compared to control cells aregiven a value of 0.0, cells showing small to moderate growthenhancement as compared to control cells are given a value of 1.0and cells showing large growth enhancement as compared to controlcells are given a value of 2.0. Any degree of growth enhancement ascompared to the negative control cells is considered positive forthe assay.

The following PRO polypeptides tested positive in this assay:PRO287, PRO301, PRO293 and PRO303.

Example 72

PDB12 Cell Proliferation (Assay 29)

This example demonstrates that various PRO polypeptides haveefficacy in inducing proliferation of PDB12 pancreatic ductal cellsand are, therefore, useful in the therapeutic treatment ofdisorders which involve protein secretion by the pancreas,including diabetes, and the like.

PDB12 pancreatic ductal cells are plated on fibronectin coated 96well plates at 1.5.times.10.sup.3 cells per well in 100 .mu.L/180.mu.L of growth media. 100 .mu.L of growth media with the PROpolypeptide test sample or negative control lacking the PROpolypeptide is then added to well, for a final volume of 200 .mu.L.Controls contain growth medium containing a protein shown to beinactive in this assay. Cells are incubated for 4 days at37.degree. C. 20 .mu.L of Alamar Blue Dye (AB) is then added toeach well and the flourescent reading is measured at 4 hours postaddition of AB, on a microtiter plate reader at 530 nm excitationand 590 nm emission. The standard employed is cells without BovinePituitary Extract (BPE) and with various concentrations of BPE.Buffer or growth medium only controls from unknowns are run 2 timeson each 96 well plate.

Percent increase in protein production is calculated by comparingthe Alamar Blue Dye calculated protein concentration produced bythe PRO polypeptide-treated cells with the Alamar Blue Dyecalculated protein concentration produced by the negative controlcells. A percent increase in protein production of greater than orequal to 25% as compared to the negative control cells isconsidered positive.

The following PRO polypeptides tested positive in this assay:PRO301 and PRO303.

Example 73

Enhancement of Heart Neonatal Hypertrophy (Assay 1)

This assay is designed to measure the ability of PRO polypeptidesto stimulate hypertrophy of neonatal heart. PRO polypeptidestesting positive in this assay are expected to be useful for thetherapeutic treatment of various cardiac insufficiencydisorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats wereobtained. Cells (180 .mu.l at 7.5.times.10.sup.4/ml, serum<0.1%, freshly isolated) are added on day 1 to 96-well platespreviously coated with DMEM/F12+4% FCS. Test samples containing thetest PRO polypeptide or growth medium only (hegative control) (20.mu.l/well) are added directly to the wells on day 1. PGF (20.mu.l/well) is then added on day 2 at final concentration of10.sup.-6 M. The cells are then stained on day 4 and visuallyscored on day 5, wherein cells showing no increase in size ascompared to negative controls are scored 0.0, cells showing a smallto moderate increase in size as compared to negative controls arescored 1.0 and cells showing a large increase in size as comparedto negative controls are scored 2.0. A positive result in the assayis a score of 1.0 or greater.

The following polypeptides tested positive in this assay: PRO224and PRO231.

Example 74

Stimulatory Activity in Mixed Lymphotyte Reaction (MLR) Assay(Assay 24)

This example shows that certain polypeptides of the invention areactive as a stimulator of the proliferation of stimulatedT-lymphocytes. Compounds which stimulate proliferation oflymphocytes are useful therapeutically where enhancement of animmune response is beneficial. A therapeutic agent may take theform of antagonists of the polypeptide of the invention, forexample, murine-human chimeric, humanized or human antibodiesagainst the polypeptide.

The basic protocol for this assay is described in Current Protocolsin Immunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral bloodmononuclear cells (PBMC) are isolated from mammalian individuals,for example a human volunteer, by leukopheresis (one donor willsupply stimulator PBMCs, the other donor will supply responderPBMCs). If desired, the cells are frozen in fetal bovine serum andDMSO after isolation. Frozen cells may be thawed overnight in assaymedia (37.degree. C., 5% CO.sub.2) and then washed and resuspendedto 3.times.10.sup.6 cells/ml of assay media (RPMI; 10% fetal bovineserum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixtureof:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells.

100 microliters of cell culture media or 100 microliter of CD4-IgGis used as the control. The wells are then incubated at 37.degree.C., 5% CO.sub.2 for 4 days. On day 5, each well is pulsed withtritiated thymidine (1.0 mC/well; Amersham). After 6 hours thecells are washed 3 times and then the uptake of the label isevaluated.

In another variant of this assay, PBMCs are isolated from thespleens of Balb/c mice and C57B6 mice. The cells are teased fromfreshly harvested spleens in assay media (RPMI; 10% fetal bovineserum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate) and the PBMCs are isolatedby overlaying these cells over Lympholyte M (Organon Teknika),centrifuging at 2000 rpm for 20 minutes, collecting and washing themononuclear cell layer in assay media and resuspending the cells to1.times.10.sup.7 cells/ml of assay media. The assay is thenconducted as described above.

Positive increases over control are considered positive withincreases of greater than or equal to 180% being preferred.However, any value greater than control indicates a stimulatoryeffect for the test protein.

The following PRO polypeptides tested positive in this assay:PRO245, PRO269, PRO217, PRO301, PRO266, PRO335, PRO331, PRO533 andPRO326.

Example 75

Pericyte c-Fos Induction (Assay 93)

This assay shows that certain polypeptides of the invention act toinduce the expression of c-fos in pericyte cells and, therefore,are useful not only as diagnostic markers for particular types ofpericyte-associated tumors but also for giving rise to antagonistswhich would be expected to be useful for the therapeutic treatmentof pericyte-associated tumors. Specifically, on day 1, pericytesare received from VEC Technologies and all but 5 ml of media isremoved from flask. On day 2, the pericytes are trypsinized,washed, spun and then plated onto 96 well plates. On day 7, themedia is removed and the pericytes are treated with 100 .mu.l ofPRO polypeptide test samples and controls (positive control=DME+5%serum+-PDGF at 500 ng/ml; negative control=protein 32). Replicatesare averaged and SD/CV are determined. Fold increase over Protein32 (buffer control) value indicated by chemiluminescence units(RLU) luminometer reading verses frequency is plotted on ahistogram. Two-fold above Protein 32 value is considered positivefor the assay. ASY Matrix: Growth media=low glucose DMEM=20%FBS+1.times. pen strep+1.times. fungizone. Assay Media=low glucoseDMEM+5% FBS.

The following polypeptides tested positive in this assay: PRO214,PRO219, PRO221 and PRO224.

Example 76

Ability of PRO Polypeptides to Stimulate the Release ofProteoglycans from Cartilage (Assay 97)

The ability of various PRO polypeptides to stimulate the release ofproteoglycans from cartilage tissue was tested as follows.

The metacarphophalangeal joint of 4-6 month old pigs wasaseptically dissected, and articular cartilage was removed by freehand slicing being careful to avoid the underlying bone. Thecartilage was minced and cultured in bulk for 24 hours in ahumidified atmosphere of 95% air, 5% CO.sub.2 in serum free (SF)media (DME/F12 1:1) woth 0.1% BSA and 100 U/ml penicillin and 100.mu.g/ml streptomycin. After washing three times, approximately 100mg of articular cartilage was aliquoted into micronics tubes andincubated for an additional 24 hours in the above SF media. PROpolypeptides were then added at 1% either alone or in combinationwith 18 ng/ml interleukin-1.alpha., a known stimulator ofproteoglycan release from cartilage tissue. The supernatant wasthen harvested and assayed for the amount of proteoglycans usingthe 1,9-dimethyl-methylene blue (DMB) colorimetric assay (Farndaleand Buttle, Biochem. Biophys. Acta 883:173-177 (1985)). A positiveresult in this assay indicates that the test polypeptide will finduse, for example, in the treatment of sports-related jointproblems, articular cartilage defects, osteoarthritis or rheumatoidarthritis.

When various PRO polypeptides were tested in the above assay, thepolypeptides demonstrated a marked ability to stimulate release ofproteoglycans from cartilage tissue both basally and afterstimulation with interleukin-1.alpha. and at 24 and 72 hours aftertreatment, thereby indicating that these PRO polypeptides areuseful for stimulating proteoglycan release from cartilage tissue.As such, these PRO polypeptides are useful for the treatment ofsports-related joint problems, articular cartilage defects,osteoarthritis or rheumatoid arthritis. The polypeptides testingpositive in this assay are: PRO211.

Example 77

Skin Vascular Permeability Assay (Assay 64)

This assay shows that certain polypeptides of the inventionstimulate an immune response and induce inflammation by inducingmononuclear cell, eosinophil and PMN infiltration at the site ofinjection of the animal. Compounds which stimulate an immuneresponse are useful therapeutically where stimulation of an immuneresponse is beneficial. This skin vascular permeability assay isconducted as follows. Hairless guinea pigs weighing 350 grams ormore are anesthetized with ketamine (75-80 mg/Kg) and 5 mg/Kgxylazine intramuscularly (IM). A sample of purified polypeptide ofthe invention or a conditioned media test sample is injectedintradermally onto the backs of the test animals with 100 .mu.l perinjection site. It is possible to have about 10-30, preferablyabout 16-24, injection sites per animal. One .mu.l of Evans bluedye (1% in physiologic buffered saline) is injected intracardially.Blemishes at the injection sites are then measured (mm diameter) at1 hr and 6 hr post injection. Animals were sacrificed at 6 hrsafter injection. Each skin injection site is biopsied and fixed informalin. The skins are then prepared for histopathologicevaluation. Each site is evaluated for inflammatory cellinfiltration into the skin. Sites with visible inflammatory cellinflammation are scored as positive. Inflammatory cells may beneutrophilic, eosinophilic, monocytic or lymphocytic. At least aminimal perivascular infiltrate at the injection site is scored aspositive, no infiltrate at the site of injection is scored asnegative.

The following polypeptides tested positive in this assay: PRO245,PRO217, PRO326, PRO266, PRO272, PRO301, PRO331 and PRO335.

Example 78

Enhancement of Heart Neonatal Hypertrophy Induced by F2a (Assay37)

This assay is designed to measure the ability of PRO polypeptidesto stimulate hypertrophy of neonatal heart. PRO polypeptidestesting positive in this assay are expected to be useful for thetherapeutic treatment of various cardiac insufficiencydisorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats wereobtained. Cells (180 .mu.l at 7.5.times.10.sup.4/ml, serum<0.1%, freshly isolated) are added on day 1 to 96-well platespreviously coated with DMEM/F12+4% FCS. Test samples containing thetest PRO polypeptide (20 .mu.l/well) are added directly to thewells on day 1. PGF (20 .mu.l/well) is then added on day 2 at afinal concentration of 10.sup.-6 M. The cells are then stained onday 4 and visually scored on day 5. Visual scores are based on cellsize, wherein cells showing no increase in size as compared tonegative controls are scored 0.0, cells showing a small to moderateincrease in size as compared to negative controls are scored 1.0and cells showing a large increase in size as compared to negativecontrols are scored 2.0. A score of 1.0 or greater is consideredpositive.

No PBS is included, since calcium concentration is critical forassay response. Plates are coated with DMEM/F12 plus 4% FCS (200.mu.l/well). Assay media included: DMEM/F12 (with 2.44 gmbicarbonate), 10 .mu.g/ml transferrin, 1 .mu.g/ml insulin, 1.mu.g/ml aprotinin, 2 mmol/L glutamine, 100 U/ml penicillin G, 100.mu.g/ml streptomycin. Protein buffer containing mannitol (4%) gavea positive signal (score 3.5) at 1/10 (0.4%) and 1/100 (0.04%), butnot at 1/1000 (0.004%). Therefore the test sample buffer containingmannitol is not run.

The following PRO polypeptides tested positive in this assay:PRO224.

Example 79

Inhibitory Activity in Mixed Lymphocyte Reaction (MLR) Assay (Assay67)

This example shows that one or more of the polypeptides of theinvention are active as inhibitors of the proliferation ofstimulated T-lymphocytes. Compounds which inhibit proliferation oflymphocytes are useful therapeutically where suppression of animmune response is beneficial.

The basic protocol for this assay is described in Current Protocolsin Immunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D HMarglies, E M Shevach, W Strober, National Insitutes of Health,Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral bloodmononuclear cells (PBMC) are isolated from mammalian individuals,for example a human volunteer, by leukopheresis (one donor willsupply stimulator PBMCs, the other donor will supply responderPBMCs). If desired, the cells are frozen in fetal bovine serum andDMSO after isolation. Frozen cells may be thawed overnight in assaymedia (37.degree. C., 5% CO.sub.2) and then washed and resuspendedto 3.times.10.sup.6 cells/ml of assay media (RPMI; 10% fetal bovineserum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate). The stimulator PBMCs areprepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixtureof:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells.

100 microliters of cell culture media or 100 microliter of CD4-IgGis used as the control. The wells are then incubated at 37.degree.C., 5% CO.sub.2 for 4 days. On day 5, each well is pulsed withtritiated thymidine (1.0 mC/well; Amersham). After 6 hours thecells are washed 3 times and then the uptake of the label isevaluated.

In another variant of this assay, PBMCs are isolated from thespleens of Balb/c mice and C57B6 mice. The cells are teased fromfreshly harvested spleens in assay media (RPMI; 10% fetal bovineserum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1%non-essential amino acids, 1% pyruvate) and the PBMCs are isolatedby overlaying these cells over Lympholyte M (Organon Teknika),centrifuging at 2000 rpm for 20 minutes, collecting and washing themononuclear cell layer in assay media and resuspending the cells to1.times.10.sup.7 cells/ml of assay media. The assay is thenconducted as described above.

Any decreases below control is considered to be a positive resultfor an inhibitory compound, with decreases of less than or equal to80% being preferred. However, any value less than control indicatesan inhibitory effect for the test protein.

The following polypeptide tested positive in this assay: PRO235,PRO245 and PRO332.

Example 80

Induction of Endothelial Cell Apoptosis (ELISA) (Assay 109)

The ability of PRO polypeptides to induce apoptosis in endothelialcells was tested in human venous umbilical vein endothelial cells(HUVEC, Cell Systems) using a 96-well format, in 0% serum mediasupplemented with 100 ng/ml VEGF, 0.1% BSA, 1.times. penn/strep. Apositive result in this assay indicates the usefulness of thepolypeptide for therapeutically treating any of a variety ofconditions associated with undesired endothelial cell growthincluding, for example, the inhibition of tumor growth. The 96-wellplates used were manufactured by Falcon (No. 3072). Coating of 96well plates were prepared by allowing gelatinization to occur for>30 minutes with 100 .mu.l of 0.2% gelatin in PBS solution. Thegelatin mix was aspirated thoroughly before plating HUVEC cells ata final concentration of 2.times.10.sup.4 cells/ml in 10% serumcontaining medium -100 .mu.l volume per well. The cells were grownfor 24 hours before adding test samples containing the PROpolypeptide of interest.

To all wells, 100 .mu.l of 0% serum media (Cell Systems)complemented with 100 ng/ml VEGF, 0.1% BSA, 1.times. penn/strep wasadded. Test samples containing PRO polypeptides were added intriplicate at dilutions of 1%, 0.33% and 0.11%. Wells without cellswere used as a blank and wells with cells only were used as anegative control. As a positive control, 1:3 serial dilutions of 50of a 3.times. stock of staurosporine were used. The cells wereincubated for 24 to 35 hours prior to ELISA.

ELISA was used to determine levels of apoptosis preparing solutionsaccording to the Boehringer Manual [Boehringer, Cell DeathDetection ELISA plus, Cat No. 1 920 685]. Sample preparations: 96well plates were spun down at 1 krpm for 10 minutes (200 g); thesupernatant was removed by fast inversion, placing the plate upsidedown on a paper towel to remove residual liquid. To each well, 200.mu.l of 1.times. Lysis buffer was added and incubation allowed atroom temperature for 30 minutes without shaking. The plates werespun down for 10 minutes at 1 krpm, and 20 .mu.l of the lysate(cytoplasmic fraction) was transferred into streptavidin coatedMTP. 80 .mu.l of immunoreagent mix was added to the 20 .mu.llystate in each well. The MTP was covered with adhesive foil andincubated at room tempearature for 2 hours by placing it on anorbital shaker (200 rpm). After two hours, the supernatant wasremoved by suction and the wells rinsed three times with 250 .mu.lof 1.times. incubation buffer per well (removed by suction).Substrate solution was added (100 .mu.l) into each well andincubated on an orbital shaker at room temperature at 250 rpm untilcolor development was sufficient for a photometric analysis(approx. after 10-20 minutes). A 96 well reader was used to readthe plates at 405 nm, reference wavelength, 492 nm. The levelsobtained for PIN 32 (control buffer) was set to 100%. Samples withlevels >130% were considered positive for induction ofapoptosis.

The following PRO polypeptides tested positive in this assay:PRO235.

Example 81

Human Venous Endothelial Cell Calcium Flux Assay (Assay 68)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to stimulate calcium flux inhuman umbilical vein endothelial cells (HUVEC, Cell Systems).Calcium influx is a well documented response upon binding ofcertain ligands to their receptors. A test compound that results ina positive response in the present calcium influx assay can be saidto bind to a specific receptor and activate a biological signalingpathway in human endothelial cells. This could ultimately lead, forexample, to endothelial cell division, inhibition of endothelialcell proliferation, endothelial tube formation, cell migration,apoptosis, etc.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems)in growth media (50:50 without glycine, 1% glutamine, 10 mM Hepes,10% FBS, 10 ng/ml bFGF), were plated on 96-well microtiterViewPlates-96 (Packard Instrument Company Part #6005182) microtiterplates at a cell density of 2.times.10.sup.4 cells/well. The dayafter plating, the cells were washed three times with buffer (HBSSplus 10 MM Hepes), leaving 100 .mu.l/well. Then 100 .mu.l/well of 8.mu.M Fluo-3 (2.times.) was added. The cells were incubated for 1.5hours at 37.degree. C./5% CO.sub.2. After incubation, the cellswere then washed 3.times. with buffer (described above) leaving 100.mu.l/well. Test samples of the PRO polypeptides were prepared ondifferent 96-well plates at 5.times. concentration in buffer. Thepositive control corresponded to 50 .mu.M ionomycin (5.times.); thenegative control corresponded to Protein 32. Cell plate and sampleplates were run on a FLIPR (Molecular Devices) machine. The FLIPRmachine added 25 .mu.l of test sample to the cells, and readingswere taken every second for one minute, then every 3 seconds forthe next three minutes.

The fluorescence change from baseline to the maximum rise of thecurve (.DELTA. change) was calculated, and replicates averaged. Therate of fluorescence increase was monitored, and only those sampleswhich had a .DELTA. change greater than 1000 and a rise within 60seconds, were considered positive.

The following PRO polypeptides tested positive in the presentassay: PRO245.

Example 82

Fibroblast (BHK-21) Proliferation (Assay 98)

This assay shows that certain PRO polypeptides of the invention actto induce proliferation of mammalian fibroblast cells in cultureand, therefore, function as useful growth factors in mammaliansystems. The assay is performed as follows. BHK-21 fibroblast cellsplated in standard growth medium at 2500 cells/well in a totalvolume of 100 .mu.l. The PRO polypeptide, .beta.-FGF (positivecontrol) or nothing (negative control) are then added to the wellsin the presence of 1 .mu.g/ml of heparin for a total final volumeof 200 .mu.l. The cells are then incubated at 37.degree. C. for 6to 7 days. After incubation, the media is removed, the cells arewashed with PBS and then an acid phosphatase substrate reactionmixture (100 .mu.l/well) is added. The cells are then incubated at37.degree. C. for 2 hours. 10 .mu.l per well of 1N NaOH is thenadded to stop the acid phosphatase reaction. The plates are thenread at OD 405 nm. A positive in the assay is acid phosphataseactivity which is at least 50% above the negative control.

The following PRO polypeptide tested positive in this assay:PRO258.

Example 83

Inhibition of Heart Adult Hypertrophy (Assay 42)

This assay is designed to measure the inhibition of heart adulthypertrophy. PRO polypeptides testing positive in this assay mayfind use in the therapeutic treatment of cardiac disordersassociated with cardiac hypertrophy.

Ventricular myocytes are freshly isolated from adult (250 g) HarlanSprague Dawley rats and the cells are plated at 2000/well in 180.mu.l volume. On day two, test samples (20 .mu.l) containing thetest PRO polypeptide are added. On day five, the cells are fixedand then stained. An increase in ANP message can also be measuredby PCR from cells after a few hours. Results are based on a visualscore of cell size: 0=no inhibition, -1=small inhibition, -2=largeinhibition. A score of less than 0 is considered positive. Activityreference corresponds to phenylephrin (PE) at 0.1 mM, as a positivecontrol. Assay media included: M199 (modified)-glutamine free,NaHCO.sub.3, phenol red, supplemented with 100 nM insulin, 0.2%BSA, 5 mM cretine, 2 mM L-carnitine, 5 mM taurine, 100 U/mlpenicillin G, 100 .mu.g/ml streptomycin (CCT medium). Only inner 60wells are used in 96 well plates. Of these, 6 wells are reservedfor negative and positive (PE) controls.

The following PRO polypeptides provided a score of less than 0 inthe above assay: PRO269.

Example 84

Induction of c-fos in Endothelial Cells (Assay 34)

This assay is designed to determine whether PRO polypeptides showthe ability to induce c-fos in endothelial cells. PRO polypeptidestesting positive in this assay would be expected to be useful forthe therapeutic treatment of conditions or disorders whereangiogenesis would be beneficial including, for example, woundhealing, and the like (as would agonists of these PROpolypeptides). Antagonists of the PRO polypeptides testing positivein this assay would be expected to be useful for the therapeutictreatment of cancerous tumors.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems)in growth media (50% Ham's F12 w/o GHT: low glucose, and 50% DMEMwithout glycine: with NaHCO3, 1% glutamine, 10 mM HEPES, 10% FBS,10 ng/ml bFGF) were plated on 96-well microtiter plates at a celldensity of 1.times.10.sup.4 cells/well. The day after plating, thecells were starved by removing the growth media and treating thecells with 100 .mu.l/well test samples and controls (positivecontrol=growth media; negative control=Protein 32 buffer=10 mMHEPES, 140 mM NaCl, 4% (w/v) mannitol, pH 6.8). The cells wereincubated for 30 minutes at 37.degree. C., in 5% CO.sub.2. Thesamples were removed, and the first part of the bDNA kit protocol(Chiron Diagnostics, cat. #6005-037) was followed, where eachcapitalized reagent/buffer listed below was available from thekit.

Briefly, the amounts of the TM Lysis Buffer and Probes needed forthe tests were calculated based on information provided by themanufacturer. The appropriate amounts of thawed Probes were addedto the TM Lysis Buffer. The Capture Hybridization Buffer was warmedto room temperature. The bDNA strips were set up in the metal stripholders, and 100 .mu.l of Capture Hybridization Buffer was added toeach b-DNA well needed, followed by incubation for at least 30minutes. The test plates with the cells were removed from theincubator, and the media was gently removed using the vacuummanifold. 100 .mu.l of Lysis Hybridization Buffer with Probes werequickly pipetted into each well of the microtiter plates. Theplates were then incubated at 55.degree. C. for 15 minutes. Uponremoval from the incubator, the plates were placed on the vortexmixer with the microtiter adapter head and vortexed on the #2setting for one minute. 80 .mu.l of the lysate was removed andadded to the bDNA wells containing the Capture HybridizationBuffer, and pipetted up and down to mix. The plates were incubatedat 53.degree. C. for at least 16 hours.

On the next day, the second part of the bDNA kit protocol wasfollowed. Specifically, the plates were removed from the incubatorand placed on the bench to cool for 10 minutes. The volumes ofadditions needed were calculated based upon information provided bythe manufacturer. An Amplifier Working Solution was prepared bymaking a 1:100 dilution of the Amplifier Concentrate (20 fm/.mu.l)in AL Hybridization Buffer. The hybridization mixture was removedfrom the plates and washed twice with Wash A. 50 .mu.l of AmplifierWorking Solution was added to each well and the wells wereincubated at 53.degree. C. for 30 minutes. The plates were thenremoved from the incubator and allowed to cool for 10 minutes. TheLabel Probe Working Solution was prepared by making a 1:100dilution of Label Concentrate (40 pmoles/.mu.l) in AL HybridizationBuffer. After the 10-minute cool-down period, the amplifierhybridization mixture was removed and the plates were washed twicewith Wash A. 50 .mu.l of Label Probe Working Solution was added toeach well and the wells were incubated at 53.degree. C. for 15minutes. After cooling for 10 minutes, the Substrate was warmed toroom temperature. Upon addition of 3 .mu.l of Substrate Enhancer toeach ml of Substrate needed for the assay, the plates were allowedto cool for 10 minutes, the label hybridization mixture wasremoved, and the plates were washed twice with Wash A and threetimes with Wash D. 50 .mu.l of the Substrate Solution with Enhancerwas added to each well. The plates were incubated for 30 minutes at37.degree. C. and RLU was read in an appropriate luminometer.

The replicates were averaged and the coefficient of variation wasdetermined. The measure of activity of the fold increase over thenegative control (Protein 32/HEPES buffer described above) valuewas indicated by chemiluminescence units (RLU). The results areconsidered positive if the PRO polypeptide exhibits at least atwo-fold value over the negative buffer control. Negativecontrol=1.00 RLU at 1.00% dilution. Positive control=8.39 RLU at1.00% dilution.

The following PRO polypeptides tested positive in this assay:PRO287.

Example 85

Guinea Pig Vascular Leak (Assays 32 and 51)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to induce vascular permeability.Polypeptides testing positive in this assay are expected to beuseful for the therapeutic treatment of conditions which wouldbenefit from enhanced vascular permeability including, for example,conditions which may benefit from enhanced local immune system cellinfiltration.

Hairless guinea pigs weighing 350 grams or more were anesthetizedwith Ketamine (75-80 mg/kg) and 5 mg/kg Xylazine intramuscularly.Test samples containing the PRO polypeptide or a physiologicalbuffer without the test polypeptide are injected into skin on theback of the test animals with 100 .mu.l per injection siteintradermally. There were approximately 16-24 injection sites peranimal. One ml of Evans blue dye (1% in PBS) is then injectedintracardially. Skin vascular permeability responses to thecompounds (i.e., blemishes at the injection sites of injection) arevisually scored by measuring the diameter (in mm) of blue-coloredleaks from the site of injection at 1 and 6 hours postadministration of the test materials. The mm diameter of bluenessat the site of injection is observed and recorded as well as theseverity of the vascular leakage. Blemishes of at least 5 mm indiameter are considered positive for the assay when testingpurified proteins, being indicative of the ability to inducevascular leakage or permeability. A response greater than 7 mmdiameter is considered positive for conditioned media samples.Human VEGF at 0.1 .mu.g/100 .mu.l is used as a positive control,inducing a response of 15-23 mm diameter.

The following PRO polypeptides tested positive in this assay:PRO302 and PRO533.

Example 86

Detection of Endothelial Cell Apoptosis (FACS) (Assay 96)

The ability of PRO polypeptides of the present invention to induceapoptosis in endothelial cells was tested in human venous umbilicalvein endothelial cells (HUVEC, Cell Systems) in gelatinized T175flasks using HUVEC cells below passage 10. PRO polypeptides testingpositive in this assay are expected to be useful fortherapeutically treating conditions where apoptosis of endothelialcells would be beneficial including, for example, the therapeutictreatment of tumors.

On day one, the cells were split [420,000 cells per gelatinized 6cm dishes-(11.times.10.sup.3 cells/cm.sup.2 Falcon, Primaria)] andgrown in media containing serum (CS-C, Cell System) overnight orfor 16 hours to 24 hours.

On day 2, the cells were washed 1.times. with 5 ml PBS; 3 ml of 0%serum medium was added with VEGF (100 ng/ml); and 30 .mu.l of thePRO test compound (final dilution 1%) or 0% serum medium (negativecontrol) was added. The mixtures were incubated for 48 hours beforeharvesting.

The cells were then harvested for FACS analysis. The medium wasaspirated and the cells washed once with PBS. 5 ml of 1.times.trypsin was added to the cells in a T-175 flask, and the cells wereallowed to stand until they were released from the plate (about5-10 minutes). Trypsinization was stopped by adding 5 ml of growthmedia. The cells were spun at 1000 rpm for 5 minutes at 4.degree.C. The media was aspirated and the cells were resuspended in 10 mlof 10% serum complemented medium (Cell Systems), 5 .mu.l ofAnnexin-FITC (BioVison) added and chilled tubes were submitted forFACS. A positive result was determined to be enhanced apoptosis inthe PRO polypeptide treated samples as compared to the negativecontrol.

The following PRO polypeptides tested positive in this assay:PRO331.

Example 87

Induction of c-fos in Cortical Neurons (Assay 83)

This assay is designed to determine whether PRO polypeptides showthe ability to induce c-fos in cortical neurons. PRO polypeptidestesting positive in this assay would be expected to be useful forthe therapeutic treatment of nervous system disorders and injurieswhere neuronal proliferation would be beneficial.

Cortical neurons are dissociated and plated in growth medium at10,000 cells per well in 96 well plates. After aproximately 2cellular divisions, the cells are treated for 30 minutes with thePRO polypeptide or nothing (negative control). The cells are thenfixed for 5 minutes with cold methanol and stained with an antibodydirected against phosphorylated CREB. mRNA levels are thencalculated using chemiluminescence. A positive in the assay is anyfactor that results in at least a 2-fold increase in c-fos messageas compared to the negative controls.

The following PRO polypeptides tested positive in this assay:PRO229 and PRO269.

Example 88

Stimulation of Endothelial Tube Formation (Assay 85)

This assay is designed to determine whether PRO polypeptides showthe ability to promote endothelial vacuole and lumen formation inthe absence of exogenous growth factors. PRO polypeptides testingpositive in this assay would be expected to be useful for thetherapeutic treatment of disorders where endothelial vacuole and/orlumen formation would be beneficial including, for example, wherethe stimulation of pinocytosis, ion pumping, vascular permeabilityand/or junctional formation would be beneficial.

HUVEC cells (passage <8 from primary) are mixed with type I rattail collagen (final concentration 2.6 mg/ml) at a density of6.times.10.sup.5 cells per ml and plated at 50 .mu.l per well ofM199 culture media supplemented with 1% FBS and 1 .mu.M 6-FAM-FITCdye to stain the vacuoles while they are forming and in thepresence of the PRO polypeptide. The cells are then incubated at37.degree. C./5% CO.sub.2 for 48 hours, fixed with 3.7% formalin atroom temperature for 10 minutes, washed 5 times with M199 mediumand then stained with Rh-Phalloidin at 4.degree. C. overnightfollowed by nuclear staining with 4 .mu.M DAPI. A positive resultin the assay is when vacuoles are present in greater than 50% ofthe cells.

The following PRO polypeptides tested positive in this assay:PRO230.

Example 89

Detection of Polypeptides That Affect Glucose and/or FFA Uptake inSkeletal Muscle (Assay 106)

This assay is designed to determine whether PRO polypeptides showthe ability to affect glucose or FFA uptake by skeletal musclecells. PRO polypeptides testing positive in this assay would beexpected to be useful for the therapeutic treatment of disorderswhere either the stimulation or inhibition of glucose uptake byskeletal muscle would be beneficial including, for example,diabetes or hyper- or hypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added toprimary rat differentiated skeletal muscle, and allowed to incubateovernight. Then fresh media with the PRO polypeptide and +/-insulinare added to the wells. The sample media is then monitored todetermine glucose and FFA uptake by the skeletal muscle cells. Theinsulin will stimulate glucose and FFA uptake by the skeletalmuscle, and insulin in media without the PRO polypeptide is used asa positive control, and a limit for scoring. As the PRO polypeptidebeing tested may either stimulate or inhibit glucose and FFAuptake, results are scored as positive in the assay if greater than1.5 times or less than 0.5 times the insulin control.

The following PRO polypeptides tested positive as eitherstimulators or inhibitors of glucose and/or FFA uptake in thisassay: PRO187, PRO211, PRO221, PRO222, PRO224, PRO230, PRO239,PRO231, PRO245, PRO247, PRO258, PRO269, PRO328 and PRO533.

Example 90

Rod Photoreceptor Cell Survival Assay (Assay 46)

This assay shows that certain polypeptides of the invention act toenhance the survival/proliferation of rod photoreceptor cells and,therefore, are useful for the therapeutic treatment of retinaldisorders or injuries including, for example, treating sight lossin mammals due to retinitis pigmentosum, AMD, etc.

Sprague Dawley rat pups (postnatal day 7, mixed population: gliaand netinal neural cell types) are killed by decapitation followingCO.sub.2 anesthesia and the eyes removed under sterile conditions.The neural retina is dissected away from the pigment epithelium andother ocular tissue and then dissociated into a single cellsuspension using 0.25% trypsin in Ca.sup.2+, Mg.sup.2+-free PBS.The retinas are incubated at 37.degree. C. in this solution for7-10 minutes after which the trypsin is inactivated by adding 1 mlsoybean trypsin inhibitor. The cells are plated at a density ofapproximately 10, 000 cells/ml into 96 well plates in DMEM/F12supplemented with N.sub.2. Cells for all experiments are grown at37.degree. C. in a water saturated atmosphere of 5% CO.sub.2. After7-10 days in culture, the cells are stained using calcein AM orCellTracker Green CMFDA and then fixed using 4% paraformaldehyde.Rho 4D2 (ascities or IgG 1:100) monoclonal antibody directedtowards the visual pigment rhodopsin is used to detect rodphotoreceptor cells by indirect immunofluorescence. The results arecalculated as % survival: total number of calcein--rhodopsinpositive cells at 7-10 days in culture, divided by the total numberof rhodopsin positive cells at time 7-10 days in culture. The totalcells (fluorescent) are quantified at 20.times. objectivemagnification using a CCD camera and NIH image software forMacIntosh. Fields in the well are chosen at random.

The following polypeptides tested positive in this assay:PRO245.

Example 91

In Vitro Antitumor Assay (Assay 161)

The antiproliferative activity of various PRO polypeptides wasdetermined in the investigational, disease-oriented in vitroanti-cancer drug discovery assay of the National Cancer Institute(NCI), using a sulforhodamine B (SRB) dye binding assay essentiallyas described by Skehan et al., J. Natl. Cancer Inst. 82:1107-1112(1990). The 60 tumor cell lines employed in this study ("the NCIpanel"), as well as conditions for their maintenance and culture invitro have been described by Monks et al., J. Natl. Cancer Inst.83:757-766 (1991). The purpose of this screen is to initiallyevaluate the cytotoxic and/or cytostatic activity of the testcompounds against different types of tumors (Monks et al., supra;Boyd, Cancer: Princ. Pract. Oncol. Update 3(10):1-12 [1989]).

Cells from approximately 60 human tumor cell lines were harvestedwith trypsin/EDTA (Gibco), washed once, resuspended in IMEM andtheir viability was determined. The cell suspensions were added bypipet (100 .mu.L volume) into separate 96-well microtiter plates.The cell density for the 6-day incubation was less than for the2-day incubation to prevent overgrowth. Inoculates were allowed apreincubation period of 24 hours at 37.degree. C. forstabilization. Dilutions at twice the intended test concentrationwere added at time zero in 100 .mu.L aliquots to the microtiterplate wells (1:2 dilution). Test compounds were evaluated at fivehalf-log dilutions (1000 to 100,000-fold). Incubations took placefor two days and six days in a 5% CO.sub.2 atmosphere and 100%humidity.

After incubation, the medium was removed and the cells were fixedin 0.1 ml of 10% trichloroacetic acid at 40.degree. C. The plateswere rinsed five times with deionized water, dried, stained for 30minutes with 0.1 ml of 0.4% sulforhodamine B dye (Sigma) dissolvedin 1% acetic acid, rinsed four times with 1% acetic acid to removeunbound dye, dried, and the stain was extracted for five minuteswith 0.1 ml of 10 mM Tris base [tris(hydroxymethyl)aminomethane],pH 10.5. The absorbance (OD) of sulforhodamine B at 492 nm wasmeasured using a computer-interfaced, 96-well microtiter platereader.

A test sample is considered positive if it shows at least 50%growth inhibitory effect at one or more concentrations. PROpolypeptides testing positive in this assay are shown in Table 7,where the abbreviations are as follows: NSCL:=non-small cell lungcarcinoma CNS=central nervous system

TABLE-US-00066 TABLE 7 Test compound Tumor Cell Line Type Cell LineDesignation PRO211 NSCL HOP62 PRO211 Leukemia RPMI-8226 PRO211Leukemia HL-60 (TB) PRO211 NSCL NCI-H522 PRO211 CNS SF-539 PRO211Melanoma LOX IMVI PRO211 Breast MDA-MB-435 PRO211 Leukemia MOLT-4PRO211 CNS U251 PRO211 Breast MCF7 PRO211 Leukemia HT-60 (TB)PRO211 Leukemia MOLT-4 PRO211 NSCL EKVX PRO211 NSCL NCI-H23 PRO211NSCL NCI-H322M PRO211 NSCL NCI-H460 PRO211 Colon HCT-116 PRO211Colon HT29 PRO211 CNS SF-268 PRO211 CNS SF-295 PRO211 CNS SNB-19PRO211 CNS U251 PRO211 Melanoma LOX IMVI PRO211 Melanoma SK-MEL-5PRO211 Melanoma UACC-257 PRO211 Melanoma UACC-62 PRO211 OvarianOVCAR-8 PRO211 Renal RXF 393 PRO211 Breast MCF7 PRO211 BreastNCI/ADR-REHS 578T PRO211 Breast T-47D PRO211 Leukemia HL-60 (TB)PRO211 Leukemia SR PRO211 NSCL NCI-H23 PRO211 Colon HCT-116 PRO211Melanoma LOX-IMVI PRO211 Melanoma SK-MEL-5 PRO211 Breast T-47DPRO228 Leukemia MOLT-4 PRO228 NSCL EKVX PRO228 Colon KM12 PRO228Melanoma UACC-62 PRO228 Ovarian OVCAR-3 PRO228 Renal TK10 PRO228Renal SN12C PRO228 Breast MCF7 PRO228 Leukemia CCRF-CEM PRO228Leukemia HL-60 (TB) PRO228 Colon COLO 205 PRO228 Colon HCT-15PRO228 Colon KM12 PRO228 CNS SF-268 PRO228 CNS SNB-75 PRO228Melanoma LOX-IMVI PRO228 Melanoma SK-MEL2 PRO228 Melanoma UACC-257PRO228 Ovarian IGROV1 PRO228 Ovarian OVCAR-4 PRO228 Ovarian OVCAR-5PRO228 Ovarian OVCAR-8 PRO228 Renal 786-0 PRO228 Renal CAKI-1PRO228 Renal RXF 393 PRO228 Renal TK-10 PRO228 Renal UO-31 PRO228Prostate PC-3 PRO228 Prostate DU-145 PRO228 Breast MCF7 PRO228Breast NCI/ADR-REHS 578T PRO228 Breast MDA-MB-435MDA-N PRO228Breast T-47D PRO219 Leukemia SR PRO219 NSCL NCI-H5222 PRO219 BreastMCF7 PRO219 Leukemia K-562; RPMI-8226 PRO219 NSCL HOP-62; NCI-H322MPRO219 NSCL NCI-H460 PRO219 Colon HT29; KM12; HCT-116 PRO219 CNSSF-539; U251 PRO219 Prostate DU-145 PRO219 Breast MDA-N PRO219Ovarian IGROV1 PRO219 NSCL NCI-H226 PRO219 Leukemia MOLT-4 PRO219NSCL A549/ATCC; EKVX; NCI-H23 PRO219 Colon HCC-2998 PRO219 CNSSF-295; SNB-19 PRO219 Melanoma SK-MEL-2; SK-MEL-5 PRO219 MelanomaUACC-257; UACC-62 PRO219 Ovarian OCAR-4; SK-OV-3 PRO219 Renal786-0; ACHN; CAKI-1; SN12C PRO219 Renal TK-10; UO-31 PRO219 BreastNCI/ADR-RES; BT-549; T-47D PRO219 Breast MDA-MB-435 PRO221 LeukemiaCCRF-CEM PRO221 Leukemia MOLT-4 PRO221 NSCL HOP-62 PRO221 BreastMDA-N PRO221 Leukemia RPMI-8226; SR PRO221 NSCL NCI-H460 PRO221Colon HCC-2998 PRO221 Ovarian IGROVl PRO221 Renal TK-10 PRO221Breast MCF7 PRO221 Leukemia K-562 PRO221 Breast MDA-MB-435 PRO224Ovarian OVCAR-4 PRO224 Renal RXF 393 PRO224 Prostate DU-145 PRO224NSCL HOP-62; NCI-H322M PRO224 Melanoma LOX IMVI PRO224 OvarianOVCAR-8 PRO224 Leukemia SR PRO224 NSCL NCI-H460 PRO224 CNS SF-295PRO224 Leukemia RPMI-8226 PRO224 Breast BT-549 PRO224 LeukemiaCCRF-CEM; LH-60 (TB) PRO224 Colon HCT-116 PRO224 Breast MDA-MB-435PRO224 Leukemia HL-60 (TB) PRO224 Colon HCC-2998 PRO224 ProstatePC-3 PRO224 CNS U251 PRO224 Colon HCT-15 PRO224 CNS SF-539 PRO224Renal ACHN PRO328 Leukemia RPMI-8226 PRO328 NSCL A549/ATCC; EKVX;HOP-62 PRO328 NSCL NCI-H23; NCI-H322M PRO328 Colon HCT-15; KM12PRO328 CNS SF-295; SF-539; SNB-19; U251 PRO328 Melanoma M14;UACC-257; UCAA-62 PRO328 Renal 786-0; ACHN PRO328 Breast MCF7PRO328 Leukemia SR PRO328 Colon NCI-H23 PRO328 Melanoma SK-MEL-5PRO328 Prostate DU-145 PRO328 Melanoma LOX IMVI PRO328 BreastMDA-MB-435 PRO328 Ovarian OVCAR-3 PRO328 Breast T-47D PRO301 NSCLNCI-H322M PRO301 Leukemia MOLT-4; SR PRO301 NSCL A549/ATCC; EKVX;PRO301 NSCL NCI-H23; NCI-460; NCI-H226 PRO301 Colon COLO 205;HCC-2998; PRO301 Colon HCT-15; KM12; HT29; PRO301 Colon HCT-116PRO301 CNS SF-268; SF-295; SNB-19 PRO301 Melanoma MALME-3M;SK-MEL-2; PRO301 Melanoma SK-MEL-5; UACC-257 PRO301 MelanomaUACC-62 PRO301 Ovarian IGROV1; OVCAR-4 PRO301 Ovarian OVCAR-5PRO301 Ovarian OVCAR-8; SK0OV-3 PRO301 Renal ACHN; CAKI-1; TK-10;UO-31 PRO301 Prostate PC-3; DU-145 PRO301 Breast NCI/ADR-RES; HS578T PRO301 Breast MDA-MB-435; MDA-N; T-47D PRO301 Melanoma M14PRO301 Leukemia CCRF-CEM; HL-60(TB); K-562 PRO301 LeukemiaRPMI-8226 PRO301 Melanoma LOX IMVI PRO301 Renal 786-0; SN12C PRO301Breast MCF7; MDA-MB-231/ATCC PRO301 Breast BT-549 PRO301 NSCLHOP-62 PRO301 CNS SF-539 PRO301 Ovarian OVCAR-3 PRO326 NSCLNCI-H322M PRO326 CNS SF295 PRO326 CNS ST539 PRO326 CNS U251

The results of these assays demonstrate that the positive testingPRO polypeptides are useful for inhibiting neoplastic growth in anumber of different tumor cell types and may be usedtherapeutically therefor. Antibodies against these PRO polypeptidesare useful for affinity purification of these useful polypeptides.Nucleic acids encoding these PRO polypeptides are useful for therecombinant preparation of these polypeptides.

Example 92

Gene Amplification

This example shows that certain PRO polypeptide-encoding genes areamplified in the genome of certain human lung, colon and/or breastcancers and/or cell lines. Amplification is associated withoverexpression of the gene product, indicating that thepolypeptides are useful targets for therapeutic intervention incertain cancers such as colon, lung, breast and other cancers anddiagnostic determination of the presence of those cancers.Therapeutic agents may take the form of antagonists of the PROpolypeptide, for example, murine-human chimeric, humanized or humanantibodies against a PRO polypeptide.

The starting material for the screen was genomic DNA isolated froma variety cancers. The DNA is quantitated precisely, e.g.,fluorometrically. As a negative control, DNA was isolated from thecells of ten normal healthy individuals which was pooled and usedas assay controls for the gene copy in healthy individuals (notshown). The 5' nuclease assay (for example, TAQMAN.TM.) andreal-time quantitative PCR (for example, ABI PRIZM 7700 SEQUENCEDETECTION SYSTEM.TM. (Perkin Elmer, Applied Biosystems Division,Foster City, Calif.)), were used to find genes potentiallyamplified in certain cancers. The results were used to determinewhether the DNA encoding the PRO polypeptide is over-represented inany of the primary lung or colon cancers or cancer cell lines orbreast cancer cell lines that were screened. The primary lungcancers were obtained from individuals with tumors of the type andstage as indicated in Table 8. An explanation of the abbreviationsused for the designation of the primary tumors listed in Table 8and the primary tumors and cell lines referred to throughout thisexample are given below.

The results of the TAQMAN.TM. are reported in delta (.DELTA.) Ctunits. One unit corresponds to 1 PCR cycle or approximately a2-fold amplification relative to normal, two units corresponds to4-fold, 3 units to 8-fold amplification and so on. Quantitation wasobtained using primers and a TAQMAN.TM. fluorescent probe derivedfrom the PRO polypeptide-encoding gene. Regions of the PROpolypeptide-encoding gene which are most likely to contain uniquenucleic acid sequences and which are least likely to have splicedout introns are preferred for the primer and probe derivation,e.g., 3'-untranslated regions. The sequences for the primers andprobes (forward, reverse and probe) used for the PRO polypeptidegene amplification analysis were as follows:

TABLE-US-00067 PRO187 (DNA27864-1155) 27864.tm.p:5'-GCAGATTTTGAGGACAGCCACCTCCA-3' (SEQ ID NO: 381) 27864.tm.f:5'-GGCCTTGCAGACAACCGT-3' (SEQ ID NO: 382) 27864.tm.r:5'-CAGACTGAGGGAGATCCGAGA-3' (SEQ ID NO: 383) 27864.tm.p2:5'-CAGCTGCCCTTCCCCAACCA-3' (SEQ ID NO: 384) 27864.tm.f2:5'-CATCAAGCGCCTCTACCA-3' (SEQ ID NO: 385) 27864.tm.r2:5'-CACAAACTCGAACTGCTTCTG-3' (SEQ ID NO: 386) PRO214(DNA32286-1191): 32286.3utr-5: 5'-GGGCCATCACAGCTCCCT-3' (SEQ ID NO:387) 32286.3utr-3b: 5'-GGGATGTGGTGAACACAGAACA-3' (SEQ ID NO: 388)32286.3utr-probe: 5'-TGCCAGCTGCATGCTGCCAGTT-3' (SEQ ID NO: 389)PRO211 (DNA32292-1131): 32292.3utr-5: 5'-CAGAAGGATGTCCCGTGGAA-3'(SEQ ID NO: 390) 32292.3utr-3: 5'-GCCGCTGTCCACTGCAG-3' (SEQ ID NO:391) 32292.3utr-probe.rc: 5'-GACGGCATCCTCAGGGCCACA-3' (SEQ ID NO:392) PRO230 (DNA33223-1136): 33223.tm.p3:5'-ATGTCCTCCATGCCCACGCG-3' (SEQ ID NO: 393) 33223.tm.f3:5'-GAGTGCGACATCGAGAGCTT-3' (SEQ ID NO: 394) 33223.tm.r3:5'-CCGCAGCCTCAGTGATGA-3' (SEQ ID NO: 395) 33223.3utr-5:5'-GAAGAGCACAGCTGCAGATCC-3' (SEQ ID NO: 396) 33223.3utr-3:5'-GAGGTGTCCTGGCTTTGGTAGT-3' (SEQ ID NO: 397) 33223.3utr-probe:5'-CCTCTGGCGCCCCCACTCAA-3' (SEQ ID NO: 398) PRO317 (DNA33461-1199):33461.tm.f: 5'-CCAGGAGAGCTGGCGATG-3' (SEQ ID NO: 399) 33461.tm.r:5'-GCAAATTCAGGGCTCACTAGAGA-3' (SEQ ID NO: 400) 33461.tm.p:5'-CACAGAGCATTTGTCCATCAGCAGTTCAG- (SEQ ID NO: 401) 3' PRO246(DNA35639-1172): 35639.3utr-5: 5'-GGCAGAGACTTCCAGTCACTGA-3' (SEQ IDNO: 402) 35639.3utr-3: 5'-GCCAAGGGTGGTGTTAGATAGG-3' (SEQ ID NO:403) 35639.3utr-probe: 5'-CAGGCCCCCTTGATCTGTACCCCA-3' (SEQ ID NO:404) PRO533 (DNA49435-1219): 49435.tm.f:5'-GGGACGTGCTTCTACAAGAACAG-3' (SEQ ID NO: 405) 49435.tm.r:5'-CAGGCTTACAATGTTATGATCAGACA-3' (SEQ ID NO: 406) 49435.tm.p:5'-TATTCAGAGTTTTCCATTGGCAGTGCCAGT (SEQ ID NO: 407) T-3' PRO343(DNA43318-1217): 43318.tm.f1 5'-TCTACATCAGCCTCTCTGCGC-3' (SEQ IDNO: 408) 43318.tm.p1 5'-CGATCTTCTCCACCCAGGAGCGG-3' (SEQ ID NO: 409)43318.tm.r1 5'-GGAGCTGCACCCCTTGC-3' (SEQ ID NO: 237) PRO232(DNA34435-1140): 34435.3utr-5: 5'-GCCAGGCCTCACATTCGT-3' (SEQ ID NO:410) DNA34435.3utr-probe: 5'-CTCCCTGAATGGCAGCCTGAGCA-3' (SEQ ID NO:411) DNA34435.3utr-3: 5'-AGGTGTTTATTAAGGGCCTACGCT-3' (SEQ ID NO:412) PRO269 (DNA38260-1180): 38260.tm.f: 5'-CAGAGCAGAGGGTGCCTTG-3'(SEQ ID NO: 413 38260.tm.p: 5'-TGGCGGAGTCCCCTCTTGGCT-3' (SEQ ID NO:414) 38260.tm.r: 5'-CCCTGTTTCCCTATGCATCACT-3' (SEQ ID NO: 415)PRO304 (DNA39520-1217): 39520.tm.f: 5'-TCAACCCCTGACCCTTTCCTA-3'(SEQ ID NO: 416) 39520.tm.p: 5'-GGCAGGGGACAAGCCATCTCTCCT-3' (SEQ IDNO: 417) 39520.tm.r: 5'-GGGACTGAACTGCCAGCTTC-3' (SEQ ID NO: 418)PRO339 (DNA43466-1225): 43466.tm.f1: 5'-GGGCCCTAACCTCATTACCTTT-3'(SEQ ID NO: 419) 43466.tm.p1: 5'-TGTCTGCCTCAGCCCCAGGAAGG-3' (SEQ IDNO: 420) 43466.tm.r1: 5'-TCTGTCCACCATCTTGCCTTG-3' (SEQ ID NO:421)

The 5' nuclease assay reaction is a fluorescent PCR-based techniquewhich makes use of the 5' exonuclease activity of Taq DNApolymerase enzyme to monitor amplification in real time. Twooligonucleotide primers (forward [.f] and reverse [.r]) are used togenerate an amplicon typical of a PCR reaction. A thirdoligonucleotide, or probe (.p), is designed to detect nucleotidesequence located between the two PCR primers. The probe isnon-extendible by Taq DNA polymerase enzyme, and is labeled with areporter fluorescent dye and a quencher fluorescent dye. Anylaser-induced emission from the reporter dye is quenched by thequenching dye when the two dyes are located close together as theyare on the probe. During the amplification reaction, the Taq DNApolymerase enzyme cleaves the probe in a template-dependent manner.The resultant probe fragments disassociate in solution, and signalfrom the released reporter dye is free from the quenching effect ofthe second fluorophore. One molecule of reporter dye is liberatedfor each new molecule synthesized, and detection of the unquenchedreporter dye provides the basis for quantitative interpretation ofthe data.

The 5' nuclease procedure is run on a real-time quantitative PCRdevice such as the ABI PRIZM 7700 SEQUENCE DETECTION SYSTEM.TM..The system consists of a thermocycler, laser, charge-coupled device(CCD) camera and computer. The system amplifies samples in a96-well format on a thermocycler. During amplification,laser-induced fluorescent signal is collected in real-time throughfiber optics cables for all 96 wells, and detected at the CCD. Thesystem includes software for running the instrument and foranalyzing the data.

5' Nuclease assay data are initially expressed as Ct, or thethreshold cycle. This is defined as the cycle at which the reportersignal accumulates above the background level of fluorescence. The.DELTA.Ct values are used as quantitative measurement of therelative number of starting copies of a particular target sequencein a nucleic acid sample when comparing cancer DNA results tonormal human DNA results.

Table 8 describes the stage, T stage and N stage of various primarytumors which were used to screen the PRO polypeptide compounds ofthe invention.

TABLE-US-00068 TABLE 8 Primary Lung and Colon Tumor Profiles OtherDukes T N Primary Tumor Stage Stage Stage Stage Stage Stage Humanlung tumor AdenoCa (SRCC724) [LT1] IIA T1 N1 Human lung tumor SqCCa(SRCC725) [LT1a] IIB T3 N0 Human lung tumor AdenoCa (SRCC726) [LT2]IB T2 N0 Human lung tumor AdenoCa (SRCC727) [LT3] IIIA T1 N2 Humanlung tumor AdenoCa (SRCC728) [LT4] IB T2 N0 Human lung tumor SqCCa(SRCC729) [LT6] IB T2 N0 Human lung tumor Aden/SqCCa (SRCC730)[LT7] IA T1 N0 Human lung tumor AdenoCa (SRCC731) [LT9] IB T2 N0Human lung tumor SqCCa (SRCC732) [LT10] IIB T2 N1 Human lung tumorSqCCa (SRCC733) [LT11] IIA T1 N1 Human lung tumor AdenoCa (SRCC734)[LT12] IV T2 N0 Human lung tumor AdenoSqCCa (SRCC735) [LT13] IB T2N0 Human lung tumor SqCCa (SRCC736) [LT15] IB T2 N0 Human lungrumor SqCCa (SRCC737) [LT16] IB T2 N0 Human lung tumor SqCCa(SRCC738) [LT17] IIB T2 N1 Human lung tumor SqCCa (SRCC739) [LT18]IB T2 N0 Human lung tumor SqCCa (SRCC740) [LT19] IB T2 N0 Humanlung tumor LCCa (SRCC741) [LT21] IIB T3 N1 Human lung AdenoCa(SRCC811) [LT22] 1A T1 N0 Human colon AdenoCa (SRCC742) [CT2] M1 DpT4 N0 Human colon AdenoCa (SRCC743) [CT3] B pT3 N0 Human colonAdenoCa (SRCC744) [CT8] B T3 N0 Human colon AdenoCa (SRCC745)[CT10] A pT2 N0 Human colon AdenoCa (SRCC746) [CT12] MO, B T3 N0 R1Human colon AdenoCa (SRCC747) [CT14] pMO, B pT3 pN0 RO Human colonAdenoCa (SRCC748) [CT15] M1, D T4 N2 R2 Human colon AdenoCa(SRCC749) [CT16] pMO B pT3 pN0 Human colon AdenoCa (SRCC750) [CT17]C1 pT3 pN1 Human colon AdenoCa (SRCC751) [CT1] MO, B pT3 N0 R1Human colon AdenoCa (SRCC752) [CT4] B pT3 M0 Human colon AdenoCa(SRCC753) [CT5] G2 C1 pT3 pN0 Human colon AdenoCa (SRCC754) [CT6]pMO, B pT3 pN0 RO Human colon AdenoCa (SRCC755) [CT7] G1 A pT2 pN0Human colon AdenoCa (SRCC756) [CT9] G3 D pT4 pN2 Human colonAdenoCa (SRCC757) [CT11] B T3 N0 Human colon AdenoCa (SRCC758)[CT18] MO, B pT3 pN0 RO

DNA Preparation:

DNA was prepared from cultured cell lines, primary tumors, normalhuman blood. The isolation was performed using purification kit,buffer set and protease and all from Quiagen, according to themanufacturer's instructions and the description below.

Cell Culture Lysis:

Cells were washed and trypsinized at a concentration of7.5.times.10.sup.8 per tip and pelleted by centrifuging at 1000 rpmfor 5 minutes at 4.degree. C., followed by washing again with 1/2volume of PBS recentrifugation. The pellets were washed a thirdtime, the suspended cells collected and washed 2.times. with PBS.The cells were then suspended into 10 ml PBS. Buffer C1 wasequilibrated at 4.degree. C. Qiagen protease #19155 was dilutedinto 6.25 ml cold ddH.sub.2O to a final concentration of 20 mg/mland equilibrated at 4.degree. C. 10 ml of G2 Buffer was prepared bydiluting Qiagen RNAse A stock (100 mg/ml) to a final concentrationof 200 .mu.g/ml.

Buffer C1 (10 ml, 4.degree. C.) and ddH.sub.2O (40 ml, 4.degree.C.) were then added to the 10 ml of cell suspension, mixed byinverting and incubated on ice for 10 minutes. The cell nuclei werepelleted by centrifuging in a Beckman swinging bucket rotor at 2500rpm at 4.degree. C. for 15 minutes. The supernatant was discardedand the nuclei were suspended with a vortex into 2 ml Buffer C1 (at4.degree. C.) and 6 ml ddH.sub.2O, followed by a second 4.degree.C. centrifugation at 2500 rpm for 15 minutes. The nuclei were thenresuspended into the residual buffer using 200 .mu.l per tip. G2buffer (10 ml) was added to the suspended nuclei while gentlevortexing was applied. Upon completion of buffer addition, vigorousvortexing was applied for 30 seconds. Quiagen protease (200 .mu.l,prepared as indicated above) was added and incubated at 50.degree.C. for 60 minutes. The incubation and centrifugation was repeateduntil the lysates were clear (e.g., incubating additional 30-60minutes, pelleting at 3000.times. g for 10 min., 4.degree. C.).

Solid Human Tumor Sample Preparation and Lysis:

Tumor samples were weighed and placed into 50 ml conical tubes andheld on ice. Processing was limited to no more than 250 mg tissueper preparation (1 tip/preparation). The protease solution wasfreshly prepared by diluting into 6.25 ml cold ddH.sub.2O to afinal concentration of 20 mg/ml and stored at 4.degree. C. G2buffer (20 ml) was prepared by diluting DNAse A to a finalconcentration of 200 mg/ml (from 100 mg/ml stock). The tumor tissuewas homogenated in 19 ml G2 buffer for 60 seconds using the largetip of the polytron in a laminar-flow TC hood in order to avoidinhalation of aerosols, and held at room temperature. Betweensamples, the polytron was cleaned by spinning at 2.times.30 secondseach in 2L ddH.sub.2O, followed by G2 buffer (50 ml). If tissue wasstill present on the generator tip, the apparatus was disassembledand cleaned.

Quiagen protease (prepared as indicated above, 1.0 ml) was added,followed by vortexing and incubation at 50.degree. C. for 3 hours.The incubation and centrifugation was repeated until the lysateswere clear (e.g., incubating additional 30-60 minutes, pelleting at3000.times. g for 10 min., 4.degree. C.).

Human Blood Preparation and Lysis:

Blood was drawn from healthy volunteers using standard infectiousagent protocols and citrated into 10 ml samples per tip. Quiagenprotease was freshly prepared by dilution into 6.25 ml coldddH.sub.2O to a final concentration of 20 mg/ml and stored at4.degree. C. G2 buffer was prepared by diluting RNAse A to a finalconcentration of 200 .mu.g/ml from 100 mg/ml stock. The blood (10ml) was placed into a 50 ml conical tube and 10 ml C1 buffer and 30ml ddH.sub.2O (both previously equilibrated to 4.degree. C.) wereadded, and the components mixed by inverting and held on ice for 10minutes. The nuclei were pelleted with a Beckman swinging bucketrotor at 2500 rpm, 4.degree. C. for 15 minutes and the supernatantdiscarded. With a vortex, the nuclei were suspended into 2 ml C1buffer (4.degree. C.) and 6 ml ddH.sub.2O (4.degree. C.). Vortexingwas repeated until the pellet was white. The nuclei were thensuspended into the residual buffer using a 200 .mu.l tip. G2 buffer(10 ml) were added to the suspended nuclei while gently vortexing,followed by vigorous vortexing for 30 seconds. Quiagen protease wasadded (200 .mu.l) and incubated at 50.degree. C. for 60 minutes.The incubation and centrifugation was repeated until the lysateswere clear (e.g., incubating additional 30-60 minutes, pelleting at3000.times. g for 10 min., 4.degree. C.).

Purification of Cleared Lysates:

(1) Isolation of Genomic DNA:

Genomic DNA was equilibrated (1 sample per maxi tip preparation)with 10 ml QBT buffer. QF elution buffer was equilibrated at50.degree. C. The samples were vortexed for 30 seconds, then loadedonto equilibrated tips and drained by gravity. The tips were washedwith 2.times.15 ml QC buffer. The DNA was eluted into 30 mlsilanized, autoclaved 30 ml Corex tubes with 15 ml QF buffer(50.degree. C.). Isopropanol (10.5 ml) was added to each sample,the tubes covered with parafin and mixed by repeated inversionuntil the DNA precipitated. Samples were pelleted by centrifugationin the SS-34 rotor at 15,000 rpm for 10 minutes at 4.degree. C. Thepellet location was marked, the supernatant discarded, and 10 ml70% ethanol (4.degree. C.) was added. Samples were pelleted againby centrifugation on the SS-34 rotor at 10,000 rpm for 10 minutesat 4.degree. C. The pellet location was marked and the supernatantdiscarded. The tubes were then placed on their side in a dryingrack and dried 10 minutes at 37.degree. C., taking care not tooverdry the samples.

After drying, the pellets were dissolved into 1.0 ml TE (pH 8.5)and placed at 50.degree. C. for 1-2 hours. Samples were heldovernight at 4.degree. C. as dissolution continued. The DNAsolution was then transferred to 1.5 ml tubes with a 26 gaugeneedle on a tuberculin syringe. The transfer was repeated 5.times.in order to shear the DNA. Samples were then placed at 50.degree.C. for 1-2 hours.

(2) Quantitation of Genomic DNA and Preparation for GeneAmplification Assay:

The DNA levels in each tube were quantified by standard A.sub.260,A.sub.280 spectrophotometry on a 1:20 dilution (5 .mu.l DNA+95.mu.l ddH.sub.2O) using the 0.1 ml quartz cuvetts in the BeckmanDU640 spectrophotometer. A.sub.260/A.sub.280 ratios were in therange of 1.8-1.9. Each DNA samples was then diluted further toapproximately 200 ng/ml in TE (pH 8.5). If the original materialwas highly concentrated (about 700 ng/.mu.l), the material wasplaced at 50.degree. C. for several hours until resuspended.

Fluorometric DNA quantitation was then performed on the dilutedmaterial (20-600 ng/ml) using the manufacturer's guidelines asmodified below. This was accomplished by allowing a Hoeffer DyNAQuant 200 fluorometer to warm-up for about 15 minutes. The Hoechstdye working solution (#H33258, 10 .mu.l, prepared within 12 hoursof use) was diluted into 100 ml 1.times. TNE buffer. A 2 ml cuvettewas filled with the fluorometer solution, placed into the machine,and the machine was zeroed. pGEM 3Zf(+) (2 .mu.l, lot #360851026)was added to 2 ml of fluorometer solution and calibrated at 200units. An additional 2 .mu.l of pGEM 3Zf(+) DNA was then tested andthe reading confirmed at 400+/-10 units. Each sample was then readat least in triplicate. When 3 samples were found to be within 10%of each other, their average was taken and this value was used asthe quantification value.

The fluorometricly determined concentration was then used to diluteeach sample to 10 ng/.mu.l in ddH.sub.2O. This was donesimultaneously on all template samples for a single TAQMAN.TM.plate assay, and with enough material to run 500-1000 assays. Thesamples were tested in triplicate with TAQMAN.TM. primers and probeboth B-actin and GAPDH on a single plate with normal human DNA andno-template controls. The diluted samples were used provided thatthe CT value of normal human DNA subtracted from test DNA was +/-1Ct. The diluted, lot-qualified genomic DNA was stored in 1.0 mlaliquots at -80.degree. C. Aliquots which were subsequently to beused in the gene amplification assay were stored at 4.degree. C.Each 1 ml aliquot is enough for 8-9 plates or 64 tests.

Gene Amplification Assay:

The PRO polypeptide compounds of the invention were screened in thefollowing primary tumors and the resulting .DELTA.Ct values greaterthan or equal to 1.0 are reported in Table 9 below.

TABLE-US-00069 TABLE 9 .DELTA.Ct values in lung and colon primarytumors and cell line models Primary Tumors or Cell lines PRO187PRO533 PRO214 PRO343 PRO211 PRO230 LT7 LT13 2.74 1.85 2.71 1.883.42 2.98 1.83 2.23 2.26 3.22 2.44 2.84 2.15 2.75 2.53 1.82 LT31.57 1.97 LT4 1.17 LT9 1.42 LT12 2.70 1.38 2.23 1.51 2.86 2.90 1.491.50 1.27 2.96 2.27 2.92 1.25 2.68 2.28 1.34 LT30 1.67 2.13 1.36LT21 1.26 1.09 LT1-a 1.02 1.18 LT6 LT10 1.96 LT11 1.09 1.67 1.002:05 1.32 1.80 1.89 1.14 1.54 LT15 3.75 1.77 3.62 2.44 4.32 3.921.58 1.30 2.16 4.47 3.49 3.64 2.94 3.56 3.32 2.68 LT16 2.10 1.661.70 1.25 1.15 2.04 1.83 LT17 1.32 1.93 1.15 1.85 1.26 1.87 2.301.39 1.30 1.33 1.30 LT18 1.17 LT19 4.05 1.67 2.09 3.82 2.42 4.053.99 1.98 2.55 4.92 4.93 3.78 4.76 HF-000840 1.58 Calu-1 1.08 SW9001.86 CT2 3.56 2.49 1.95 1.42 3.49 CT3 2.06 1.15 1.34 CT8 1.01 1.481.29 1.58 CT10 1.81 1.84 1.88 1.00 1.49 CT12 1.81 1.74 1.13 CT141.82 2.48 2.33 1.72 CT15 1.63 2.06 1.41 CT16 1.95 1.78 1.40 CT172.04 2.40 1.74 CT1 1.24 1.22 1.27 1.25 1.34 1.46 1.14 CT4 1.36 1.771.33 1.32 1.42 1.02 CT5 2.96 1.56 2,68 1.76 2.27 2.99 2.76 1.64 CT61.10 1.33 1.01 1.14 CT7 1.40 1.66 1.39 CT9 1.39 1.16 CT11 2.22 2.051.55 2.01 1.75 2.26 1.85 1.83 HF000539 1.57 SW620 1.14 HF0006114.64 HF000733 1.93 2.33 HF000716 1.68 2.82 CT18 Primary Tumors orCell lines PRO246 PRO317 PRO232 PRO269 PRO304 PRO339 LT7 1.52 1.041.08 LT13 1.63 1.90 1.27 1.29 1.04 1.68 2.24 2.93 LT3 1.06 1.861.17 LT4 1.18 LT9 1.04 1.80 1.03 LT12 1.54 2.54 2.40 1.14 1.15 1.262.47 1.74 LT30 LT21 1.50 LT1-a 1.29 LT6 1.93 LT10 1.07 2.57 LT113.43 2.20 1.14 1.51 1.39 1.41 2.33 1.02 LT15 2.11 2.06 1.86 1.361.34 1.56 2.76 1.63 LT16 1.55 1.00 1.08 1.33 LT17 2.68 2.29 1.351.42 1.68 1.63 1.69 2.03 1.10 LT18 1.04 LT19 1.91 2.51 1.21 1.601.15 1.68 2.03 1.16 HF-000840 Calu-1 SW900 CT2 2.75 2.36 CT3 CT8CT10 1.88 1.55 CT12 CT14 1.36 1.24 CT15 1.33 1.04 CT16 CT17 CT12.41 CT4 1.10 1.17 2.05 CT5 1.33 1.59 2.39 CT6 CT7 1.00 CT9 1.091.24 1.13 CT11 1.48 1.92 1.12 HF000539 SW620 HF000611 HF000733HF000716 CT18 1.29

Summary

Because amplification of the various DNA's as described aboveoccurs in various tumors, it is likely associated with tumorformation and/or growth. As a result, antagonists (e.g.,antibodies) directed against these polypeptides would be expectedto be useful in cancer therapy.

Example 94

Detection of PRO Polypeptides That Affect Glucose or FFA Uptake byPrimary Rat Adipocytes (Assay 94)

This assay is designed to determine whether PRO polypeptides showthe ability to affect glucose or FFA uptake by adipocyte cells. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by adipocytes would bebeneficial including, for example, obesity, diabetes or hyper- orhypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added toprimary rat adipocytes, and allowed to incubate overnight. Samplesare taken at 4 and 16 hours and assayed for glycerol, glucose andFFA uptake. After the 16 hour incubation, insulin is added to themedia and allowed to incubate for 4 hours. At this time, a sampleis taken and glycerol, glucose and FFA uptake is measured. Mediacontaining insulin without the PRO polypeptide is used as apositive reference control. As the PRO polypeptide being tested mayeither stimulate or inhibit glucose and FFA uptake, results arescored as positive in the assay if greater than 1.5 times or lessthan 0.5 times the insulin control.

The following PRO polypeptides tested positive as stimulators ofglucose and/or FFA uptake in this assay: PRO221, PRO235, PRO245,PRO295, PRO301 and PRO332.

The following PRO polypeptides tested positive as inhibitors ofglucose and/or FFA uptake in this assay: PRO214, PRO219, PRO228,PRO222, PRO231 and PRO265.

Example 95

Chondrocyte Re-differentiation Assay (Assay 110)

This assay shows that certain polypeptides of the invention act toinduce redifferentiation of chondrocytes, therefore, are expectedto be useful for the treatment of various bone and/or cartilagedisorders such as, for example, sports injuries and arthritis. Theassay is performed as follows. Porcine chondrocytes are isolated byovernight collagenase digestion of articulary cartilage ofmetacarpophalangeal joints of 4-6 month old female pigs. Theisolated cells are then seeded at 25,000 cells/cm.sup.2 in Ham F-12containing 10% FBS and 4 .mu.g/ml gentamycin. The culture media ischanged every third day and the cells are then seeded in 96 wellplates at 5,000 cells/well in 100 .mu.l of the same media withoutserum and 100 .mu.l of the test PRO polypeptide, 5 nM staurosporin(positive control) or medium alone (negative control) is added togive a final volume of 200 .mu.L/well. After 5 days of incubationat 37.degree. C., a picture of each well is taken and thedifferentiation state of the chondrocytes is determined. A positiveresult in the assay occurs when the redifferentiation of thechondrocytes is determined to be more similar to the positivecontrol than the negative control.

The following polypeptide tested positive inthis assay: PRO214,PRO219, PRO229, PRO222, PRO224, PRO230, PRO257, PRO272 andPRO301.

Example 96

Fetal Hemoglobin Induction in an Erythroblastic Cell Line (Assay107)

This assay is useful for screening PRO polypeptides for the abilityto induce the switch from adult hemoglobin to fetal hemoglobin inan erythroblastic cell line. Molecules testing positive in thisassay are expected to be useful for therapeutically treatingvarious mammalian hemoglobin-associated disorders such as thevarious thalassemias. The assay is performed as follows.Erythroblastic cells are plated in standard growth medium at 1000cells/well in a 96 well format. PRO polypeptides are added to thegrowth medium at a concentration of 0.2% or 2% and the cells areincubated for 5 days at 37.degree. C. As a positive control, cellsare treated with 100 .mu.M hemin and as a negative control, thecells are untreated. After 5 days, cell lysates are prepared andanalyzed for the expression of gamma globin (a fetal marker). Apositive in the assay is a gamma globin level at least 2-fold abovethe negative control.

The following polypeptides tested positive in this assay: PRO221and PRO245.

Example 97

Mouse Kidney Mesangial Cell Proliferation Assay (Assay 92)

This assay shows that certain polypeptides of the invention act toinduce proliferation of mammalian kidney mesangial cells and,therefore, are useful for treating kidney disorders associated withdecreased mesangial cell function such as Berger disease or othernephropathies associated with Schonlein-Henoch purpura, celiacdisease, dermatitis herpetiformis or Crohn disease. The assay isperformed as follows. On day one, mouse kidney mesangial cells areplated on a 96 well plate in growth media (3:1 mixture ofDulbecco's modified Eagle's medium and Ham's F12 medium, 95% fetalbovine serum, 5% supplemented with 14 mM HEPES) and grownovernight. On day 2, PRO polypeptides are diluted at 2concentrations(1% and 0.1%) in serum-free medium and added to thecells. Control samples are serum-free medium alone. On day 4, 20.mu.l of the Cell Titer 96 Aqueous one solution reagent (Progema)was added to each well and the colormetric reaction was allowed toproceed for 2 hours. The absorbance (OD) is then measured at 490nm. A positive in the assay is anything that gives an absorbancereading which is at least 15% above the control reading.

The following polypeptide tested positive in this assay:PRO227.

Example 98

Proliferation of Rat Utricular Supporting Cells (Assay 54)

This assay shows that certain polypeptides of the invention act aspotent mitogens for inner ear supporting cells which are auditoryhair cell progenitors and, therefore, are useful for inducing theregeneration of auditory hair cells and treating hearing loss inmammals. The assay is performed as follows. Rat UEC-4 utricularepithelial cells are aliquoted into 96 well plates with a densityof 3000 cells/well in 200 .mu.l of serum-containing medium at33.degree. C. The cells are cultured overnight and are thenswitched to serun-free medium at 37.degree. C. Various dilutions ofPRO polypeptides (or nothing for a control) are then added to thecultures and the cells are incubated for 24 hours. After the 24hour incubation, .sup.3H-thymidine (1 .mu.Ci/well) is added and thecells are then cultured for an additional 24 hours. The culturesare then washed to remove unincorporated radiolabel, the cellsharvested and Cpm per well determined. Cpm of at least 30% orgreater in the PRO polypeptide treated cultures as compared to thecontrol cultures is considered a positive in the assay.

The following polypeptides tested positive in this assay: PRO310and PRO346.

Example 99

Chondrocyte Proliferation Assay (Assay 111)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to induce the proliferationand/or redifferentiation of chondrocytes in culture. PROpolypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of various bone and/orcartilage disorders such as, for example, sports injuries andarthritis.

Porcine chondrocytes are isolated by overnight collagenasedigestion of articular cartilage of the metacarpophalangeal jointof 4-6 month old female pigs. The isolated cells are then seeded at25,000 cells/cm.sup.2 in Ham F-12 containing 10% FBS and 4 .mu.g/mlgentamycin. The culture media is changed every third day and thecells are reseeded to 25,000 cells/cm.sup.2 every five days. On day12, the cells are seeded in 96 well plates at 5,000 cells/well in100 .mu.l of the same media without serum and 100 .mu.l of eitherserum-free medium (negative control), staurosporin (finalconcentration of 5 nM; positive control) or the test PROpolypeptide are added to give a final volume of 200 .mu.l/well.After 5 days at 37.degree. C., 20 .mu.l of Alamar blue is added toeach well and the plates are incubated for an additional 3 hours at37.degree. C. The fluorescence is then measured in each well(Ex:530 nm; Em: 590 nm). The fluorescence of a plate containing 200.mu.l of the serum-free medium is measured to obtain thebackground. A positive result in the assay is obtained when thefluorescence of the PRO polypeptide treated sample is more likethat of the positive control than the negative control.

The following PRO polypeptides tested positive in this assay:PRO219, PRO222, PRO317, PRO257, PRO265, PRO287, PRO272 andPRO533.

Example 100

Inhibition of Heart Neonatal Hypertrophy Induced by LIF+ET-1 (Assay74)

This assay is designed to determine whether PRO polypeptides of thepresent invention show the ability to inhibit neonatal hearthypertrophy induced by LIF and endothelin-1 (ET-1). A test compoundthat provides a positive response in the present assay would beuseful for the therapeutic treatment of cardiac insufficiencydiseases or disorders characterized or associated with an undesiredhypertrophy of the cardiac muscle.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats (180.mu.l at 7.5.times.10.sup.4/ml, serum <0.1, freshly isolated)are introduced on day 1 to 96-well plates previously coated withDMEM/F12+4%FCS. Test PRO polypeptide samples or growth medium alone(negative control) are then added directly to the wells on day 2 in20 .mu.l volume. LIF+ET-1 are then added to the wells on day 3. Thecells are stained after an additional 2 days in culture and arethen scored visually the next day. A positive in the assay occurswhen the PRO polypeptide treated myocytes are visually smaller onthe average or less numerous than the untreated myocytes.

The following PRO polypeptides tested positive in this assay:PRO238.

Example 101

Tissue Expression Distribution

Oligonucleotide probes were constructed from some of the PROpolypeptide-encoding nucleotide sequences shown in the accompanyingfigures for use in quantitative PCR amplification reactions. Theoligonucleotide probes were chosen so as to give an approximately200-600 base pair amplified fragment from the 3' end of itsassociated template in a standard PCR reaction. The oligonucleotideprobes were employed in standard quantitative PCR amplificationreactions with cDNA libraries isolated from different human adultand/or fetal tissue sources and analyzed by agarose gelelectrophoresis so as to obtain a quantitative determination of thelevel of expression of the PRO polypeptide-encoding nucleic acid inthe various tissues tested. Knowledge of the expression pattern orthe differential expression of the PRO polypeptide-encoding nucleicacid in various different human tissue types provides a diagnosticmarker useful for tissue typing, with or without othertissue-specific markers, for determining the primary tissue sourceof a metastatic tumor, and the like. These assays provided thefollowing results.

TABLE-US-00070 Tissues With Tissues Lacking DNA MoleculeSignificant Expression Significant Expression DNA34436-1238 lung,placenta, brain testis DNA35557-1137 lung, kidney, brain placentaDNA35599-1168 kidney, brain liver, placenta DNA35668-1171 liver,lung, kidney placenta, brain DNA36992-1168 liver, lung, kidney,brain placenta DNA39423-1182 kidney, brain liver DNA40603-1232liver brain, kidney, lung DNA40604-1187 liver brain, kidney, lungDNA41379-1236 lung, brain liver DNA33206-1165 heart, spleen,dendrocytes substantia nigra, hippocampus, cartilage, prostate,HUVEC DNA34431-1177 spleen, HUVEC, cartilage, brain, colon tumor,heart, uterus prostate, THP-1 macrophages DNA41225-1217 HUVEC,uterus, spleen, brain, heart, colon tumor, cartilage, IM-9lymphoblasts prostate

Example 102

In situ Hybridization

In situ hybridization is a powerful and versatile technique for thedetection and localization of nucleic acid sequences within cell ortissue preparations. It may be useful, for example, to identifysites of gene expression, analyze the tissue distribution oftranscription, identify and localize viral infection, followchanges in specific mRNA synthesis and aid in chromosomemapping.

In situ hybridization was performed following an optimized versionof the protocol by Lu and Gillett, Cell Vision 1: 169-176 (1994),using PCR-generated .sup.33P-labeled riboprobes. Briefly,formalin-fixed, paraffin-embedded human tissues were sectioned,deparaffinized, deproteinated in proteinase K (20 g/ml) for 15minutes at 37.degree. C., and further processed for in situhybridization as described by Lu and Gillett, supra. A [.sup.33-P]UTP-labeled antisense riboprobe was generated from a PCR productand hybridized at 55.degree. C. overnight. The slides were dippedin Kodak NTB2 nuclear track emulsion and exposed for 4 weeks.

.sup.33P-Riboprobe Synthesis

6.0 .mu.l (125 mCi) of .sup.33P-UTP (Amersham BF 1002, SA<2000Ci/mmol) were speed vac dried. To each tube containing dried.sup.33P-UTP, the following ingredients were added:

2.0 .mu.l 5.times. transcription buffer

1.0 .mu.l DTT (100 mM)

2.0 .mu.l NTP mix (2.5 mM: 10.mu.; each of 10 mM GTP, CTP &ATP+10 .mu.l H.sub.2O)

1.0 UTP (50 .mu.M)

1.0 .mu.l Rnasin

1.0 .mu.l DNA template (1 .mu.g)

1.0 .mu.l H.sub.2O

1.0 .mu.l RNA polymerase (for PCR products T3=AS, T7=S,usually)

The tubes were incubated at 37.degree. C. for one hour. 1.0 .mu.lRQ1 DNase were added, followed by incubation at 37.degree. C. for15 minutes. 90 .mu.l TE (10 mM Tris pH 7.6/1 mM EDTA pH 8.0) wereadded, and the mixture was pipetted onto DE81 paper. The remainingsolution was loaded in a Microcon-50 ultrafiltration unit, and spunusing program 10 (6 minutes). The filtration unit was inverted overa second tube and spun using program 2 (3 minutes). After the finalrecovery spin, 100 .mu.l TE were added. 1 .mu.l of the finalproduct was pipetted on DE81 paper and counted in 6 ml of BiofluorII.

The probe was run on a TBE/urea gel. 1-3 .mu.l of the probe or 5.mu.l of RNA Mrk III were added to 3 .mu.l of loading buffer. Afterheating on a 95.degree. C. heat block for three minutes, the gelwas immediately placed on ice. The wells of gel were flushed, thesample loaded, and run at 180-250 volts for 45 minutes. The gel waswrapped in saran wrap and exposed to XAR film with an intensifyingscreen in -70.degree. C. freezer one hour to overnight.

.sup.33P-Hybridization

A. Pretreatment of Frozen Sections

The slides were removed from the freezer, placed on aluminium traysand thawed at room temperature for 5 minutes. The trays were placedin 55.degree. C. incubator for five minutes to reduce condensation.The slides were fixed for 10 minutes in 4% paraformaldehyde on icein the fume hood, and washed in 0.5.times.SSC for 5 minutes, atroom temperature (25 ml 20.times.SSC+975 ml SQ H.sub.2O). Afterdeproteination in 0.5 .mu.g/ml proteinase K for 10 minutes at37.degree. C. (12.5 .mu.l of 10 mg/ml stock in 250 ml prewarmedRNase-free RNAse buffer), the sections were washed in 0.5.times.SSCfor 10 minutes at room temperature. The sections were dehydrated in70%, 95%, 100% ethanol, 2 minutes each.

B. Pretreatment of Paraffin-embedded Sections

The slides were deparaffinized, placed in SQ H.sub.2O, and rinsedtwice in 2.times.SSC at room temperature, for 5 minutes each time.The sections were deproteinated in 20 .mu.g/ml proteinase K (500.mu.l of 10 mg/ml in 250 ml RNase-free RNase buffer; 37.degree. C.,15 minutes)--human embryo, or 8.times. proteinase K (100 .mu.l in250 ml Rnase buffer, 37.degree. C., 30 minutes)--formalin tissues.Subsequent rinsing in 0.5.times.SSC and dehydration were performedas described above.

C. Prehybridization

The slides were laid out in a plastic box lined with Box buffer(4.times.SSC, 50% formamide)--saturated filter paper. The tissuewas covered with 50 .mu.l of hybridization buffer (3.75 g DextranSulfate+6 ml SQ H.sub.2O), vortexed and heated in the microwave for2 minutes with the cap loosened. After cooling on ice, 18.75 mlformamide, 3.75 ml 20.times.SSC and 9 ml SQ H.sub.2O were added,the tissue was vortexed well, and incubated at 42.degree. C. for1-4 hours.

D. Hybridization

1.0.times.10.sup.6 cpm probe and 1.0 .mu.l tRNA (50 mg/ml stock)per slide were heated at 95.degree. C. for 3 minutes. The slideswere cooled on ice, and 48 .mu.l hybridization buffer were addedper slide. After vortexing, 50 .mu.l .sup.33P mix were added to 50.mu.l prehybridization on slide. The slides were incubatedovernight at 55.degree. C.

E. Washes

Washing was done 2.times.10 minutes with 2.times.SSC, EDTA at roomtemperature (400 ml 20.times.SSC+16 ml 0.25M EDTA, V.sub.f=4L),followed by RNaseA treatment at 37.degree. C. for 30 minutes (500.mu.l of 10 mg/ml in 250 ml Rnase buffer=20 .mu.g/ml), The slideswere washed 2.times.10 minutes with 2.times.SSC, EDTA at roomtemperature. The stringency wash conditions were as follows: 2hours at 55.degree. C., 0.1.times.SSC, EDTA (20 ml 20.times.SSC+16ml EDTA, V.sub.f=4L).

F. Oligonucleotides

In situ analysis was performed on a variety of DNA sequencesdisclosed herein. The oligonucleotides employed for these analysesare as follows.

TABLE-US-00071 (1) DNA33094-1131 (PRO217) p15'-GGATTCTAATACGACTCACTATAGGGCTCAG (SEQ ID NO: 348)AAAAGCGCAACAGAGAA-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGATGTC (SEQ IDNO: 349) TTCCATGCCAACCTTC-3' (2) DNA33223-1136 (PRO230) p15'-GGATTCTAATACGACTCACTATAGGGCGGCG (SEQ ID NO: 350)ATGTCCACTGGGGCTAC-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGACGAG (SEQ IDNO: 351) GAAGATGGGCGGATGGT-3' (3) DNA34435-1140 (PRO232) p15'-GGATTCTAATACGACTCACTATAGGGCACCC (SEQ ID NO: 352)ACGCGTCCGGCTGCTT-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGACGGG (SEQ IDNO: 353) GGACACCACGGACCAGA-3' (4) DNA35639-1172 (PRO246) p15'-GGATTCTAATACGACTCACTATAGGGCTTGC (SEQ ID NO: 354)TGCGGTTTTTGTTCCTG-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGAGCTG (SEQ IDNO: 355) CCGATCCCACTGGTATT-3' (5) DNA49435-1219 (PRO533) p15'-GGATTCTAATACGACTCACTATAGGGCGGAT (SEQ ID NO: 356)CCTGGCCGGCCTCTG-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGAGCCC (SEQ IDNO: 357) GGGCATGGTCTCAGTTA-3' (6) DNA35638-1141 (PRO245) p15'-GGATTCTAATACGACTCACTATAGGGCGGGA (SEQ ID NO: 358)AGATGGCGAGGAGGAG-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGACCAA (SEQ IDNO: 359) GGCCACAAACGGAAATC-3' (7) DNA33089-1132 (PRO221) p15'-GGATTCTAATACGACTCACTATAGGGCTGTG (SEQ ID NO: 360)CTTTCATTCTGCCAGTA-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGAGGGT (SEQ IDNO: 361) ACAATTAAGGGGTGGAT-3' (8) DNA35918-1174 (PRO258) p15'-GGATTCTAATACGACTCACTATAGGGCCCGC (SEQ ID NO: 362)CTCGCTCCTGCTCCTG-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGAGGAT (SEQ IDNO: 363) TGCCGCGACCCTCACAG-3' (9) DNA32286-1191 (PRO214) p15'-GGATTCTAATACGACTCACTATAGGGCCCCT (SEQ ID NO: 364)CCTGCCTTCCCTGTCC-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGAGTGG (SEQ IDNO: 365) TGGCCGCGATTATCTGC-3' (10) DNA33221-1133 (PRO224) p15'-GGATTCTAATACGACTCACTATAGGGCGCAG (SEQ ID NO: 366)CGATGGCAGCGATGAGG-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGACAGA (SEQ IDNO: 367) CGGGGCAGAGGGAGTG-3' (11) DNA35557-1137 (PRO234) p15'-GGATTCTAATACGACTCACTATAGGGCCAGG (SEQ ID NO: 368)AGGCGTGAGGAGAAAC-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGAAAGA (SEQ IDNO: 369) CATGTCATCGGGAGTGG-3' (12) DNA33100-1159 (PRO229) p15'-GGATTCTAATACGACTCACTATAGGGCCGGG (SEQ ID NO: 370)TGGAGGTGGAACAGAAA-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGACACA (SEQ IDNO: 371) GACAGAGCCCCATACGC-3' (13) DNA34431-1177 (PRO263) p15'-GGATTCTAATACGACTCACTATAGGGCCAGG (SEQ ID NO: 372)GAAATCCGGATGTCTC-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGAGTAA (SEQ IDNO: 373) GGGGATGCCACCGAGTA-3' (14) DNA38268-1188 (PRO295) p15'-GGATTCTAATACGACTCACTATAGGGCCAGC (SEQ ID NO: 374)TACCCGCAGGAGGAGG-3' p2 5'-CTATGAAATTAACCCTCACTAAAGGGATCCC (SEQ IDNO: 375) AGGTGATGAGGTCCAGA-3'

G. Results

In situ analysis was performed on a variety of DNA sequencesdisclosed herein. The results from these analyses are asfollows.

(1) DNA33094-1131 (PRO217)

Highly distinctive expression pattern, that does not indicate anobvious biological function. In the human embryo it was expressedin outer smooth muscle layer of the GI tract, respiratirycartilage, branching respiratory epithelium, osteoblasts, tendons,gonad, in the optic nerve head and developing dermis. In the adultexpression was observed in the epidermal pegs of the chimp tongue,the basal epithelial/myoepithelial cells of the prostate andurinary bladder. Also expressed in the alveolar lining cells of theadult lung, mesenchymal cells juxtaposed to erectile tissue in thepenis and the cerebral cortex (probably glial cells). In thekidney, expression was only seen in disease, in cells surroundingthyroidized renal tubules. Human fetal tissues examined (E12-E16weeks) include: Placenta, umbilical cord, liver, kidney, adrenals,thyroid, lungs, heart, great vessels, oesophagus, stomach, smallintestine, spleen, thymus, pancreas, brain, eye, spinal cord, bodywall, pelvis and lower limb. Adult human tissues examined: Kidney(normal and end-stage), adrenal, myocardium, aorta, spleen, lymphnode, gall bladder, pancreas, lung, skin, eye (inc. retina),prostate, bladder, liver (normal, cirrhotic, acute failure).Non-human primate tissues examined:

(a) Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid,skin, thymus, ovary, lymph node.

(b) Rhesus Monkey Tissues: Cerebral cortex, hippocampus,cerebellum, penis.

(2) DNA33223-1136 (PRO230)

Sections show an intense signal associated with arterial and venousvessels in the fetus. In arteries the signal appeared to beconfined to smooth-muscle/pericytic cells. The signal is also seenin capillary vessels and in glomeruli. It is not clear whether ornot endothelial cells are expressing this mRNA. Expression is alsoobserved in epithelial cells in the fetal lens. Strong expressionwas also seen in cells within placental trophoblastic villi, thesecells lie between the trophoblast and the fibroblast-like cellsthat express HGF--uncertain histogenesis. In the adult, there wasno evidence of expression and the wall of the aorta and mostvessels appear to be negative. However, expression was seen overvascular channels in the normal prostate and in the epitheliumlining the gallbladder. Insurers expression was seen in the vesselsof the soft-tissue sarcoma and a renal cell carcinoma. In summary,this is a molecule that shows relatively specific vascularexpression in the fetus as well as in some adult organs. Expressionwas also observed in the fetal lens and the adult gallbladder.

In a secondary screen, vascular expression was observed, similar tothat observed above, seen in fetal blocks. Expression is onvascular smooth muscle, rather than endothelium. Expression alsoseen in smooth muscle of the developing oesophagus, so as reportedpreviously, this molecule is not vascular specific. Expression wasexamined in 4 lung and 4 breast carcinomas. Substantial expressionwas seen in vascular smooth muscle of at least 3/4 lung cancers and2/4 breast cancers. In addition, in one breast carcinoma,expression was observed in peritumoral stromal cells of uncertainhistogenesis (possibly myofibroblasts). No endothelial cellexpression was observed in this study.

(3) DNA34435-1140 (PRO232)

Strong expression in prostatic epithelium and bladder epithelium,lower level of expression in bronchial epithelium. Highbackground/low level expression seen in a number of sites,including among others, bone, blood, chondrosarcoma, adult heartand fetal liver. It is felt that this level of signal representsbackground, partly because signal at this level was seen over theblood. All other tissues negative. Human fetal tissues examined(E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney,adrenals, thyroid, lungs, heart, great vessels, oesophagus,stomach, small intestine, spleen, thymus, pancreas, brain, eye,spinal cord, body wall, pelvis, testis and lower limb. Adult humantissues examined: Kidney (normal and end-stage), adrenal, spleen,lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure). Non-human primate tissuesexamined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

In a secondary screen, expression was observed in the epithelium ofthe prostate, the superficial layers of the urethelium of theurinary bladder, the urethelium lining the renal pelvis and theurethelium of the ureter (1 out of 2 experiments). The urethra of arhesus monkey was negative; it is unclear whether this represents atrue lack of expression by the urethra, or if it is the result of afailure of the probe to cross react with rhesus tissue. Thefindings in the prostate and bladder are similar to thosepreviously described using an isotopic detection technique.Expression of the mRNA for this antigen is NOT prostate epithelialspecific. The antigen may serve as a useful marker for urethelialderived tissues. Expression in the superficial, post-mitotic cells,of the urinary tract epithelium also suggest that it is unlikely torepresent a specific stem cell marker, as this would be expected tobe expressed specifically in basal epithelium.

(4) DNA35639-1172 (PRO246)

Strongly expressed in fetal vascular endothelium, including tissuesof the CNS. Lower level of expression in adult vasculature,including the CNS. Not obviously expressed at higher levels intumor vascular endothelium. Signal also seen over bone matrix andadult spleen, not obviously cell associated, probably related tonon-specific background at these sites. Human fetal tissuesexamined (E12-E16 weeks) include: Placenta, umbilical cord, liver,kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus,stomach, small intestine, spleen, thymus, pancreas, brain, eye,spinal cord, body wall, pelvis, testis and lower limb. Adult humantissues examined: Kidney (normal and end-stage), adrenal, spleen,lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure). Non-human primate tissuesexamined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

(5) DNA49435-1219 (PRO533)

Moderate expression over cortical neurones in the fetal brain.Expression over the inner aspect of the fetal retina, possibleexpression in the developing lens. Expression over fetal skin,cartilage, small intestine, placental villi and umbilical cord. Inadult tissues there is an extremely high level of expression overthe gallbladder epithelium. Moderate expression over the adultkidney, gastric and colonic epithelia. Low-level expression wasobserved over many cell types in many tissues, this may be relatedto stickiness of the probe, these data should therefore beinterpreted with a degree of caution. Human fetal tissues examined(E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney,adrenals, thyroid, lungs, heart, great vessels, oesophagus,stomach, small intestine, spleen, thymus, pancreas, brain, eye,spinal cord, body wall, pelvis, testis and lower limb. Adult humantissues examined: Kidney (normal and end-stage), adrenal, spleen,lymph node, pancreas, lung, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure). Non-human primate tissuesexamined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus,cerebellum.

(6) DNA35638-1141 (PRO245)

Expression observed in the endothelium lining a subset of fetal andplacental vessels. Endothelial expression was confined to thesetissue blocks. Expression also observed over intermediatetrophoblast cells of placenta. Expression also observed tumorvasculature but not in the vasculature of normal tissues of thesame type. All other tissues negative. Fetal tissues examined(E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney,adrenals, thyroid, lungs, heart, great vessels, oesophagus,stomach, small intestine, spleen, thymus, pancreas, brain, eye,spinal cord, body wall, pelvis and lower limb. Adult tissuesexamined: Liver, kidney, adrenal, myocardium, aorta, spleen, lymphnode, pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm),cerebellum(rm), penis, eye, bladder, stomach, gastric carcinoma,colon, colonic carcinoma, thyroid (chimp), parathyroid (chimp)ovary (chimp) and chondrosarcoma. Acetominophen induced liverinjury and hepatic cirrhosis (7) DNA33089-1132 (PRO221)

Specific expression over fetal cerebral white and grey matter, aswell as over neurones in the spinal cord. Probe appears to crossreact with rat. Low level of expression over cerebellar neurones inadult rhesus brain. All other tissues negative. Fetal tissuesexamined (E12-E16 weeks) include: Placenta, umbilical cord, liver,kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus,stomach, small intestine, spleen, thymus, pancreas, brain, eye,spinal cord, body wall, pelvis and lower limb. Adult tissuesexamined: Liver, kidney, adrenal, myocardium, aorta, spleen, lymphnode, pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm),cerebellum(rm), penis, eye, bladder, stomach, gastric carcinoma,colon, colonic carcinoma and chondrosarcoma. Acetominophen inducedliver injury and hepatic cirrhosis (8) DNA35918-1174 (PRO258)

Strong expression in the nervous system. In the rhesus monkey brainexpression is observed in cortical, hippocampal and cerebellarneurones. Expression over spinal neurones in the fetal spinal cord,the developing brain and the inner aspects of the fetal retina.Expression over developing dorsal root and autonomic ganglia aswell as enteric nerves. Expression observed over ganglion cells inthe adult prostate. In the rat, there is strong expression over thedeveloping hind brain and spinal cord. Strong expression overinterstitial cells in the placental villi. All other tissues werenegative. Fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart,great vessels, oesophagus, stomach, small intestine, spleen,thymus, pancreas, brain, eye, spinal cord, body wall, pelvis andlower limb. Adult tissues examined: Liver, kidney, renal cellcarcinoma, adrenal, aorta, spleen, lymph node, pancreas, lung,myocardium, skin, cerebral cortex (rm), hippocampus(rm),cerebellum(rm), bladder, prostate, stomach, gastric carcinoma,colon, colonic carcinoma, thyroid (chimp), parathyroid (chimp)ovary (chimp) and chondrosarcoma. Acetominophen induced liverinjury and hepatic cirrhosis. (9) DNA32286-1191 (PRO214)

Fetal tissue: Low level throughout mesenchyme. Moderate expressionin placental stromal cells in membranous tissues and in thyroid.Low level expression in cortical neurones. Adult tissue: allnegative. Fetal tissues examined (E12-E16 weeks) include: Placenta,umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart,great vessels, oesophagus, stomach, small intestine, spleen,thymus, pancreas, brain, eye, spinal cord, body wall, pelvis andlower limb. Adult tissues examined include: Liver, kidney, adrenal,myocardium, aorta, spleen, lymph node, pancreas, lung and skin.(10) DNA33221-1133 (PRO224)

Expression limited to vascular endothelium in fetal spleen, adultspleen, fetal liver, adult thyroid and adult lymph node (chimp).Additional site of expression is the developing spinal ganglia. Allother tissues negative. Human fetal tissues examined (E12-E16weeks) include: Placenta, umbilical cord, liver, kidney, adrenals,thyroid, lungs, heart, great vessels, oesophagus, stomach, smallintestine, spleen, thymus, pancreas, brain, eye, spinal cord, bodywall, pelvis and lower limb. Adult human tissues examined: Kidney(normal and end-stage), adrenal, myocardium, aorta, spleen, lymphnode, pancreas, lung, skin, eye (inc. retina), bladder, liver(normal, cirrhotic, acute failure). Non-human primate tissuesexamined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum,penis.

(11) DNA35557-1137 (PRO234)

Specific expression over developing motor neurones in ventralaspect of the fetal spinal cord (will develop into ventral horns ofspinal cord). All other tissues negative. Possible role in growth,differentiation and/or development of spinal motor neurons. Fetaltissues examined (E12-E16 weeks) include: Placenta, umbilical cord,liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb. Adulttissues examined: Liver, kidney, adrenal, myocardium, aorta,spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm),hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach,gastric carcinoma, colon, colonic carcinoma and chondrosarcoma.Acetominophen induced liver injury and hepatic cirrhosis (12)DNA33100-1159 (PRO229)

Striking expression in mononuclear phagocytes (macrophages) offetal and adult spleen, liver, lymph node and adult thymus (intingible body macrophages). The highest expression is in thespleen. All other tissues negative. Localisation and homology areentirely consistent with a role as a scavenger receptor for cellsof the reticuloendothelial system. Expression also observed inplacental mononuclear cells. Human fetal tissues examined (E12-E16weeks) include: Placenta, umbilical cord, liver, kidney, adrenals,thyroid, lungs, heart, great vessels, oesophagus, stomach, smallintestine, spleen, thymus, pancreas, brain, eye, spinal cord, bodywall, pelvis and lower limb. Adult human tissues examined: Kidney(normal and end-stage), adrenal, myocardium, aorta, spleen, lymphnode, gall bladder, pancreas, lung, skin, eye (inc. retina),prostate, bladder, liver (normal, cirrhotic, acute failure).Non-human primate tissues examined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin,thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum,penis.

(13) DNA34431-1177 (PRO263)

Widepread expression in human fetal tissues and placenta overmononuclear cells, probably macrophages +/-lymphocytes. Thecellular distribution follows a perivascular pattern in manytissues. Strong expression also seen in epithelial cells of thefetal adrenal cortex. All adult tissues were negative. Fetaltissues examined (E12-E16 weeks) include: Placenta, umbilical cord,liver, kidney, adrenals, thyroid, lungs, heart, great vessels,oesophagus, stomach, small intestine, spleen, thymus, pancreas,brain, eye, spinal cord, body wall, pelvis and lower limb. Adulttissues examined: Liver, kidney, adrenal, spleen, lymph node,pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm),cerebellum(rm), bladder, stomach, colon and colonic carcinoma.Acetominophen induced liver injury and hepatic cirrhosis.

A secondary screen evidenced expression over stromal mononuclearcells probably histiocytes.

(14) DNA38268-1188 (PRO295)

High expression over ganglion cells in human fetal spinal gangliaand over large neurones in the anterior horns of the developingspinal cord. In the adult there is expression in the chimp adrenalmedulla (neural), neurones of the rhesus monkey brain (hippocampus[+++] and cerebral cortex) and neurones in ganglia in the normaladult human prostate (the only section that contains ganglioncells, expression in this cell type is presumed NOT to be confinedto the prostate). All other tissues negative. Human fetal tissuesexamined (E12-E16 weeks) include: Placenta, umbilical cord, liver,kidney, adrenals, thyroid, lungs, great vessels, stomach, smallintestine, spleen, thymus, pancreas, brain, eye, spinal cord, bodywall, pelvis, testis and lower limb. Adult human tissues examined:Kidney (normal and end-stage), adrenal, spleen, lymph node,pancreas, lung, eye (inc. retina), bladder, liver (normal,cirrhotic, acute failure). Non-human Primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus,cerebellum.

Example 103

Isolation of cDNA clones Encoding Human PRO1868

A consensus DNA sequence was assembled relative to other ESTsequences using phrap as described in Example 1 above. Thisconsensus sequence is herein designated DNA49803. Based up anobserved homology between the DNA49803 consensus sequence and anEST sequence contained within the Incyte EST clone no. 2994689,Incyte EST clone no. 2994689 was purchased and its insert obtainedand sequenced. The sequence of that insert is shown in FIG. 123 andis herein designated DNA77624-2515.

The entire nucleotide sequence of DNA77624-2515 is shown in FIG.123 (SEQ ID NO:422). Clone DNA77624-2515 contains a single openreading frame with an apparent translational initiation site atnucleotide positions 51-53 and ending at the stop codon atnucleotide positions 981-983 (FIG. 123). The predicted polypeptideprecursor is 310 amino acids long (FIG. 124). The full-lengthPRO1868 protein shown in FIG. 124 has an estimated molecular weightof about 35,020 daltons and a pI of about 7.90. Analysis of thefull-length PRO1868 sequence shown in FIG. 124 (SEQ ID NO:423)evidences the presence of the following: a signal peptide fromabout amino acid 1 to about amino acid 30, a transmembrane domainfrom about amino acid 243 to about amino acid 263, potentialN-glycosylation sites from about amino acid 104 to about amino acid107 and from about amino acid 192 to about amino acid 195, a cAMP-and cGMP-dependent protein kinase phosphorylation site from aboutamino acid 107 to about amino acid 110, casein kinase IIphosphorylation sites from about amino acid 106 to about amino acid109 and from about amino acid 296 to about amino acid 299, atyrosine kinase phosphorylation site from about amino acid 69 toabout amino acid 77 and potential N-myristolation sites from aboutamino acid 26 to about amino acid 31, from about amino acid 215 toabout amino acid 220, from about amino acid 226 to about amino acid231, from about amino acid 243 to about amino acid 248, from aboutamino acid 244 to about amino acid 249 and from about amino acid262 to about amino acid 267. Clone DNA77624-2515 has been depositedwith ATCC on Dec. 22, 1998 and is assigned ATCC deposit no.203553.

An analysis of the Dayhoff database (version 35.45 SwissProt 35),using a WU-BLAST2 sequence alignment analysis of the full-lengthsequence shown in FIG. 124 (SEQ ID NO:423), evidenced significanthomology between the PRO1868 amino acid sequence and the followingDayhoff sequences: HGS_RC75, P_W61379, A33_HUMAN, P_W14146,P_W14158, AMAL_DROME, P_R77437, I38346, NCM2_HUMAN andPTPD_HUMAN.

Example 104

Identification of Receptor/Ligand Interactions

In this assay, various PRO polypeptides are tested for ability tobind to a panel of potential receptor molecules for the purpose ofidentifying receptor/ligand interactions. The identification of aligand for a known receptor, a receptor for a known ligand or anovel receptor/ligand pair is useful for a variety of indicationsincluding, for example, targeting bioactive molecules (linked tothe ligand or receptor) to a cell known to express the receptor orligand, use of the receptor or ligand as a reagent to detect thepresence of the ligand or receptor in a composition suspected ofcontaining the same, wherein the composition may comprise cellssuspected of expressing the ligand or receptor, modulating thegrowth of or another biological or immunological activity of a cellknown to express or respond to the receptor or ligand, modulatingthe immune response of cells or toward cells that express thereceptor or ligand, allowing the preparaion of agonists,antagonists and/or antibodies directed against the receptor orligand which will modulate the growth of or a biological orimmunological activity of a cell expressing the receptor or ligand,and various other indications which will be readily apparent to theordinarily skilled artisan.

The assay is performed as follows. A PRO polypeptide of the presentinvention suspected of being a ligand for a receptor is expressedas a fusion protein containing the Fc domain of human IgG (animmunoadhesin). Receptor-ligand binding is detected by allowinginteraction of the immunoadhesin polypeptide with cells (e.g. Coscells) expressing candidate PRO polypeptide receptors andvisualization of bound immunoadhesin with fluorescent reagentsdirected toward the Fc fusion domain and examination by microscope.Cells expressing candidate receptors are produced by transienttransfection, in parallel, of defined subsets of a library of cDNAexpression vectors encoding PRO polypeptides that may function asreceptor molecules. Cells are then incubated for 1 hour in thepresence of the PRO polypeptide immunoadhesin being tested forpossible receptor binding. The cells are then washed and fixed withparaformaldehyde. The cells are then incubated with fluorescentconjugated antibody directed against the Fc portion of the PROpolypeptide immunoadhesin (e.g. FITC conjugated goat anti-human-Fcantibody). The cells are then washed again and examined bymicroscope. A positive interaction is judged by the presence offluorescent labeling of cells transfected with cDNA encoding aparticular PRO polypeptide receptor or pool of receptors and anabsence of similar fluorescent labeling of similarly prepared cellsthat have been transfected with other cDNA or pools of cDNA. If adefined pool of cDNA expression vectors is judged to be positivefor interaction with a PRO polypeptide immunoadhesin, theindividual cDNA species that comprise the pool are testedindividually (the pool is "broken down") to determine the specificcDNA that encodes a receptor able to interact with the PROpolypeptide immunoadhesin.

In another embodiment of this assay, an epitope-tagged potentialligand PRO polypeptide (e.g. 8 histidine "His" tag) is allowed tointeract with a panel of potential receptor PRO polypeptidemolecules that have been expressed as fusions with the Fc domain ofhuman IgG (immunoadhesins). Following a 1 hour co-incubation withthe epitope tagged PRO polypeptide, the candidate receptors areeach immunoprecipitated with protein A beads and the beads arewashed. Potential ligand interaction is determined by western blotanalysis of the immunoprecipitated complexes with antibody directedtowards the epitope tag. An interaction is judged to occur if aband of the anticipated molecular weight of the epitope taggedprotein is observed in the western blot analysis with a candidatereceptor, but is not observed to occur with the other members ofthe panel of potential receptors.

Using these assays, the following receptor/ligand interactions havebeen herein identified: PRO245 binds to PRO1868.

Deposit of Material

The following materials have been deposited with the American TypeCulture Collection, 10801 University Boulevard, Manassas. Va. USA(ATCC):

TABLE-US-00072 Material ATCC Dep. No. Deposit Date DNA32292-1131ATCC 209258 Sep. 16, 1997 DNA33094-1131 ATCC 209256 Sep. 16, 1997DNA33223-1136 ATCC 209264 Sep. 16, 1997 DNA34435-1140 ATCC 209250Sep. 16, 1997 DNA27864-1155 ATCC 209375 Oct. 16, 1997 DNA36350-1158ATCC 209378 Oct. 16, 1997 DNA32290-1164 ATCC 209384 Oct. 16, 1997DNA35639-1172 ATCC 209396 Oct. 17, 1997 DNA33092-1202 ATCC 209420Oct. 28, 1997 DNA49435-1219 ATCC 209480 Nov. 21, 1997 DNA35638-1141ATCC 209265 Sep. 16, 1997 DNA32298-1132 ATCC 209257 Sep. 16, 1997DNA33089-1132 ATCC 209262 Sep. 16, 1997 DNA33786-1132 ATCC 209253Sep. 16, 1997 DNA35918-1174 ATCC 209402 Oct. 17, 1997 DNA37150-1178ATCC 209401 Oct. 17, 1997 DNA38260-1180 ATCC 209397 Oct. 17, 1997DNA39969-1185 ATCC 209400 Oct. 17, 1997 DNA32286-1191 ATCC 209385Oct. 16, 1997 DNA33461-1199 ATCC 209367 Oct. 15, 1997 DNA40628-1216ATCC 209432 Nov. 7, 1997 DNA33221-1133 ATCC 209263 Sep. 16, 1997DNA33107-1135 ATCC 209251 Sep. 16, 1997 DNA35557-1137 ATCC 209255Sep. 16, 1997 DNA34434-1139 ATCC 209252 Sep. 16, 1997 DNA33100-1159ATCC 209373 Oct. 16, 1997 DNA35600-1162 ATCC 209370 Oct. 16, 1997DNA34436-1238 ATCC 209523 Dec. 10, 1997 DNA33206-1165 ATCC 209372Oct. 16, 1997 DNA35558-1167 ATCC 209374 Oct. 16, 1997 DNA35599-1168ATCC 209373 Oct. 16, 1997 DNA36992-1168 ATCC 209382 Oct. 16, 1997DNA34407-1169 ATCC 209383 Oct. 16, 1997 DNA35841-1173 ATCC 209403Oct. 17, 1997 DNA33470-1175 ATCC 209398 Oct. 17, 1997 DNA34431-1177ATCC 209399 Oct. 17, 1997 DNA39510-1181 ATCC 209392 Oct. 17, 1997DNA39423-1182 ATCC 209387 Oct. 17, 1997 DNA40620-1183 ATCC 209388Oct. 17, 1997 DNA40604-1187 ATCC 209394 Oct. 17, 1997 DNA38268-1188ATCC 209421 Oct. 28, 1997 DNA37151-1193 ATCC 209393 Oct. 17, 1997DNA35673-1201 ATCC 209418 Oct. 28, 1997 DNA40370-1217 ATCC 209485Nov. 21, 1997 DNA42551-1217 ATCC 209483 Nov. 21, 1997 DNA39520-1217ATCC 209482 Nov. 21, 1997 DNA41225-1217 ATCC 209491 Nov. 21, 1997DNA43318-1217 ATCC 209481 Nov. 21, 1997 DNA40587-1231 ATCC 209438Nov. 7, 1997 DNA41338-1234 ATCC 209927 Jun. 2, 1998 DNA40981-1234ATCC 209439 Nov. 7, 1997 DNA37140-1234 ATCC 209489 Nov. 21, 1997DNA40982-1235 ATCC 209433 Nov. 7, 1997 DNA41379-1236 ATCC 209488Nov. 21, 1997 DNA44167-1243 ATCC 209434 Nov. 7, 1997 DNA39427-1179ATCC 209395 Oct. 17, 1997 DNA40603-1232 ATCC 209486 Nov. 21, 1997DNA43466-1225 ATCC 209490 Nov. 21, 1997 DNA43046-1225 ATCC 209484Nov. 21, 1997 DNA35668-1171 ATCC 209371 Oct. 16, 1997 DNA77624-2515ATCC 203553 Dec. 22, 1998

These deposit were made under the provisions of the Budapest Treatyon the International Recognition of the Deposit of Microorganismsfor the Purpose of Patent Procedure and the Regulations thereunder(Budapest Treaty). This assures maintenance of a viable culture ofthe deposit for 30 years from the date of deposit. The depositswill be made available by ATCC under the terms of the BudapestTreaty, and subject to an agreement between Genentech, Inc. andATCC, which assures that all restrictions imposed by the depositoron the availability to the public of the deposited material will beirrevocably removed upon the granting of the pertinent U.S. patent,assures permanent and unrestricted availability of the progeny ofthe culture of the deposit to the public upon issuance of thepertinent U.S. patent or upon laying open to the public of any U.S.or foreign patent application, whichever comes first, and assuresavailability of the progeny to one determined by the U.S.Commissioner of Patents and Trademarks to be entitled theretoaccording to 35 USC .sctn. 122 and the Commissioner's rulespursuant thereto (including 37 CFR .sctn. 1.14 with particularreference to 886 OG 638).

The assignee of the present application has agreed that if aculture of the materials on deposit should die or be lost ordestroyed when cultivated under suitable conditions, the materialswill be promptly replaced on notification with another of the same.Availability of the deposited material is not to be construed as alicense to practice the invention in contravention of the rightsgranted under the authority of any government in accordance withits patent laws.

The foregoing written specification is considered to be sufficientto enable one skilled in the art to practice the invention. Thepresent invention is not to be limited in scope by the constructdeposited, since the deposited embodiment is intended as a singleillustration of certain aspects of the invention and any constructsthat are functionally equivalent are within the scope of thisinvention. The deposit of material herein does not constitute anadmission that the written description herein contained isinadequate to enable the practice of any aspect of the invention,including the best mode thereof, nor is it to be construed aslimiting the scope of the claims to the specific illustrations thatit represents. Indeed, various modifications of the invention inaddition to those shown and described herein will become apparentto those skilled in the art from the foregoing description and fallwithin the scope of the appended claims.

SEQUENCE LISTINGS

1

423 1 1825 DNA Homo sapiens 1 actgcacctc ggttctatcg attgaattccccggggatcc tctagagatc cctcgacctc 60 gacccacgcg tccgggccggagcagcacgg ccgcaggacc tggagctccg gctgcgtctt 120 cccgcagcgctacccgccat gcgcctgccg cgccgggccg cgctggggct cctgccgctt 180ctgctgctgc tgccgcccgc gccggaggcc gccaagaagc cgacgccctg ccaccggtgc240 cgggggctgg tggacaagtt taaccagggg atggtggaca ccgcaaagaagaactttggc 300 ggcgggaaca cggcttggga ggaaaagacg ctgtccaagtacgagtccag cgagattcgc 360 ctgctggaga tcctggaggg gctgtgcgagagcagcgact tcgaatgcaa tcagatgcta 420 gaggcgcagg aggagcacctggaggcctgg tggctgcagc tgaagagcga atatcctgac 480 ttattcgagtggttttgtgt gaagacactg aaagtgtgct gctctccagg aacctacggt 540cccgactgtc tcgcatgcca gggcggatcc cagaggccct gcagcgggaa tggccactgc600 agcggagatg ggagcagaca gggcgacggg tcctgccggt gccacatggggtaccagggc 660 ccgctgtgca ctgactgcat ggacggctac ttcagctcgctccggaacga gacccacagc 720 atctgcacag cctgtgacga gtcctgcaagacgtgctcgg gcctgaccaa cagagactgc 780 ggcgagtgtg aagtgggctgggtgctggac gagggcgcct gtgtggatgt ggacgagtgt 840 gcggccgagccgcctccctg cagcgctgcg cagttctgta agaacgccaa cggctcctac 900acgtgcgaag agtgtgactc cagctgtgtg ggctgcacag gggaaggccc aggaaactgt960 aaagagtgta tctctggcta cgcgagggag cacggacagt gtgcagatgtggacgagtgc 1020 tcactagcag aaaaaacctg tgtgaggaaa aacgaaaactgctacaatac tccagggagc 1080 tacgtctgtg tgtgtcctga cggcttcgaagaaacggaag atgcctgtgt gccgccggca 1140 gaggctgaag ccacagaaggagaaagcccg acacagctgc cctcccgcga agacctgtaa 1200 tgtgccggacttacccttta aattattcag aaggatgtcc cgtggaaaat gtggccctga 1260ggatgccgtc tcctgcagtg gacagcggcg gggagaggct gcctgctctc taacggttga1320 ttctcatttg tcccttaaac agctgcattt cttggttgtt cttaaacagacttgtatatt 1380 ttgatacagt tctttgtaat aaaattgacc attgtaggtaatcaggagga aaaaaaaaaa 1440 aaaaaaaaaa aaagggcggc cgcgactctagagtcgacct gcagaagctt ggccgccatg 1500 gcccaacttg tttattgcagcttataatgg ttacaaataa agcaatagca tcacaaattt 1560 cacaaataaagcattttttt cactgcattc tagttgtggt ttgtccaaac tcatcaatgt 1620atcttatcat gtctggatcg ggaattaatt cggcgcagca ccatggcctg aaataacctc1680 tgaaagagga acttggttag gtaccttctg aggcggaaag aaccagctgtggaatgtgtg 1740 tcagttaggg tgtggaaagt ccccaggctc cccagcaggcagaagtatgc aagcatgcat 1800 ctcaattagt cagcaaccca gtttt 1825 2 353PRT Homo sapiens 2 Met Arg Leu Pro Arg Arg Ala Ala Leu Gly Leu LeuPro Leu Leu Leu 1 5 10 15 Leu Leu Pro Pro Ala Pro Glu Ala Ala LysLys Pro Thr Pro Cys His 20 25 30 Arg Cys Arg Gly Leu Val Asp LysPhe Asn Gln Gly Met Val Asp Thr 35 40 45 Ala Lys Lys Asn Phe GlyGly Gly Asn Thr Ala Trp Glu Glu Lys Thr 50 55 60 Leu Ser Lys TyrGlu Ser Ser Glu Ile Arg Leu Leu Glu Ile Leu Glu 65 70 75 80 Gly LeuCys Glu Ser Ser Asp Phe Glu Cys Asn Gln Met Leu Glu Ala 85 90 95Gln Glu Glu His Leu Glu Ala Trp Trp Leu Gln Leu Lys Ser Glu Tyr 100105 110 Pro Asp Leu Phe Glu Trp Phe Cys Val Lys Thr Leu Lys Val CysCys 115 120 125 Ser Pro Gly Thr Tyr Gly Pro Asp Cys Leu Ala Cys GlnGly Gly Ser 130 135 140 Gln Arg Pro Cys Ser Gly Asn Gly His Cys SerGly Asp Gly Ser Arg 145 150 155 160 Gln Gly Asp Gly Ser Cys Arg CysHis Met Gly Tyr Gln Gly Pro Leu 165 170 175 Cys Thr Asp Cys Met AspGly Tyr Phe Ser Ser Leu Arg Asn Glu Thr 180 185 190 His Ser Ile CysThr Ala Cys Asp Glu Ser Cys Lys Thr Cys Ser Gly 195 200 205 Leu ThrAsn Arg Asp Cys Gly Glu Cys Glu Val Gly Trp Val Leu Asp 210 215 220Glu Gly Ala Cys Val Asp Val Asp Glu Cys Ala Ala Glu Pro Pro Pro 225230 235 240 Cys Ser Ala Ala Gln Phe Cys Lys Asn Ala Asn Gly Ser TyrThr Cys 245 250 255 Glu Glu Cys Asp Ser Ser Cys Val Gly Cys Thr GlyGlu Gly Pro Gly 260 265 270 Asn Cys Lys Glu Cys Ile Ser Gly Tyr AlaArg Glu His Gly Gln Cys 275 280 285 Ala Asp Val Asp Glu Cys Ser LeuAla Glu Lys Thr Cys Val Arg Lys 290 295 300 Asn Glu Asn Cys Tyr AsnThr Pro Gly Ser Tyr Val Cys Val Cys Pro 305 310 315 320 Asp Gly PheGlu Glu Thr Glu Asp Ala Cys Val Pro Pro Ala Glu Ala 325 330 335 GluAla Thr Glu Gly Glu Ser Pro Thr Gln Leu Pro Ser Arg Glu Asp 340 345350 Leu 3 2206 DNA Homo sapiens 3 caggtccaac tgcacctcgg ttctatcgattgaattcccc ggggatcctc tagagatccc 60 tcgacctcga cccacgcgtccgccaggccg ggaggcgacg cgcccagccg tctaaacggg 120 aacagccctggctgagggag ctgcagcgca gcagagtatc tgacggcgcc aggttgcgta 180ggtgcggcac gaggagtttt cccggcagcg aggaggtcct gagcagcatg gcccggagga240 gcgccttccc tgccgccgcg ctctggctct ggagcatcct cctgtgcctgctggcactgc 300 gggcggaggc cgggccgccg caggaggaga gcctgtacctatggatcgat gctcaccagg 360 caagagtact cataggattt gaagaagatatcctgattgt ttcagagggg aaaatggcac 420 cttttacaca tgatttcagaaaagcgcaac agagaatgcc agctattcct gtcaatatcc 480 attccatgaattttacctgg caagctgcag ggcaggcaga atacttctat gaattcctgt 540ccttgcgctc cctggataaa ggcatcatgg cagatccaac cgtcaatgtc cctctgctgg600 gaacagtgcc tcacaaggca tcagttgttc aagttggttt cccatgtcttggaaaacagg 660 atggggtggc agcatttgaa gtggatgtga ttgttatgaattctgaaggc aacaccattc 720 tccaaacacc tcaaaatgct atcttctttaaaacatgtca acaagctgag tgcccaggcg 780 ggtgccgaaa tggaggcttttgtaatgaaa gacgcatctg cgagtgtcct gatgggttcc 840 acggacctcactgtgagaaa gccctttgta ccccacgatg tatgaatggt ggactttgtg 900tgactcctgg tttctgcatc tgcccacctg gattctatgg agtgaactgt gacaaagcaa960 actgctcaac cacctgcttt aatggaggga cctgtttcta ccctggaaaatgtatttgcc 1020 ctccaggact agagggagag cagtgtgaaa tcagcaaatgcccacaaccc tgtcgaaatg 1080 gaggtaaatg cattggtaaa agcaaatgtaagtgttccaa aggttaccag ggagacctct 1140 gttcaaagcc tgtctgcgagcctggctgtg gtgcacatgg aacctgccat gaacccaaca 1200 aatgccaatgtcaagaaggt tggcatggaa gacactgcaa taaaaggtac gaagccagcc 1260tcatacatgc cctgaggcca gcaggcgccc agctcaggca gcacacgcct tcacttaaaa1320 aggccgagga gcggcgggat ccacctgaat ccaattacat ctggtgaactccgacatctg 1380 aaacgtttta agttacacca agttcatagc ctttgttaacctttcatgtg ttgaatgttc 1440 aaataatgtt cattacactt aagaatactggcctgaattt tattagcttc attataaatc 1500 actgagctga tatttactcttccttttaag ttttctaagt acgtctgtag catgatggta 1560 tagattttcttgtttcagtg ctttgggaca gattttatat tatgtcaatt gatcaggtta 1620aaattttcag tgtgtagttg gcagatattt tcaaaattac aatgcattta tggtgtctgg1680 gggcagggga acatcagaaa ggttaaattg ggcaaaaatg cgtaagtcacaagaatttgg 1740 atggtgcagt taatgttgaa gttacagcat ttcagattttattgtcagat atttagatgt 1800 ttgttacatt tttaaaaatt gctcttaatttttaaactct caatacaata tattttgacc 1860 ttaccattat tccagagattcagtattaaa aaaaaaaaaa ttacactgtg gtagtggcat 1920 ttaaacaatataatatattc taaacacaat gaaataggga atataatgta tgaacttttt 1980gcattggctt gaagcaatat aatatattgt aaacaaaaca cagctcttac ctaataaaca2040 ttttatactg tttgtatgta taaaataaag gtgctgcttt agttttttggaaaaaaaaaa 2100 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa gggcggccgcgactctagag tcgacctgca 2160 gaagcttggc cgccatggcc caacttgtttattgcagctt ataatg 2206 4 379 PRT Homo sapiens 4 Met Ala Arg Arg SerAla Phe Pro Ala Ala Ala Leu Trp Leu Trp Ser 1 5 10 15 Ile Leu LeuCys Leu Leu Ala Leu Arg Ala Glu Ala Gly Pro Pro Gln 20 25 30 GluGlu Ser Leu Tyr Leu Trp Ile Asp Ala His Gln Ala Arg Val Leu 35 4045 Ile Gly Phe Glu Glu Asp Ile Leu Ile Val Ser Glu Gly Lys Met Ala50 55 60 Pro Phe Thr His Asp Phe Arg Lys Ala Gln Gln Arg Met ProAla Ile 65 70 75 80 Pro Val Asn Ile His Ser Met Asn Phe Thr Trp GlnAla Ala Gly Gln 85 90 95 Ala Glu Tyr Phe Tyr Glu Phe Leu Ser LeuArg Ser Leu Asp Lys Gly 100 105 110 Ile Met Ala Asp Pro Thr Val AsnVal Pro Leu Leu Gly Thr Val Pro 115 120 125 His Lys Ala Ser Val ValGln Val Gly Phe Pro Cys Leu Gly Lys Gln 130 135 140 Asp Gly Val AlaAla Phe Glu Val Asp Val Ile Val Met Asn Ser Glu 145 150 155 160 GlyAsn Thr Ile Leu Gln Thr Pro Gln Asn Ala Ile Phe Phe Lys Thr 165 170175 Cys Gln Gln Ala Glu Cys Pro Gly Gly Cys Arg Asn Gly Gly Phe Cys180 185 190 Asn Glu Arg Arg Ile Cys Glu Cys Pro Asp Gly Phe His GlyPro His 195 200 205 Cys Glu Lys Ala Leu Cys Thr Pro Arg Cys Met AsnGly Gly Leu Cys 210 215 220 Val Thr Pro Gly Phe Cys Ile Cys Pro ProGly Phe Tyr Gly Val Asn 225 230 235 240 Cys Asp Lys Ala Asn Cys SerThr Thr Cys Phe Asn Gly Gly Thr Cys 245 250 255 Phe Tyr Pro Gly LysCys Ile Cys Pro Pro Gly Leu Glu Gly Glu Gln 260 265 270 Cys Glu IleSer Lys Cys Pro Gln Pro Cys Arg Asn Gly Gly Lys Cys 275 280 285 IleGly Lys Ser Lys Cys Lys Cys Ser Lys Gly Tyr Gln Gly Asp Leu 290 295300 Cys Ser Lys Pro Val Cys Glu Pro Gly Cys Gly Ala His Gly Thr Cys305 310 315 320 His Glu Pro Asn Lys Cys Gln Cys Gln Glu Gly Trp HisGly Arg His 325 330 335 Cys Asn Lys Arg Tyr Glu Ala Ser Leu Ile HisAla Leu Arg Pro Ala 340 345 350 Gly Ala Gln Leu Arg Gln His Thr ProSer Leu Lys Lys Ala Glu Glu 355 360 365 Arg Arg Asp Pro Pro Glu SerAsn Tyr Ile Trp 370 375 5 45 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 5 agggagcacggacagtgtgc agatgtggac gagtgctcac tagca 45 6 21 DNA ArtificialSequence Description of Artificial Sequence Syntheticoligonucleotide probe 6 agagtgtatc tctggctacg c 21 7 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 7 taagtccggc acattacagg tc 22 8 49 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 8 cccacgatgt atgaatggtg gactttgtgt gactcctggtttctgcatc 49 9 22 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 9 aaagacgcat ctgcgagtgt cc22 10 23 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 10 tgctgatttc acactgctct ccc 23 112197 DNA Homo sapiens 11 cggacgcgtg ggcgtccggc ggtcgcagagccaggaggcg gaggcgcgcg ggccagcctg 60 ggccccagcc cacaccttcaccagggccca ggagccacca tgtggcgatg tccactgggg 120 ctactgctgttgctgccgct ggctggccac ttggctctgg gtgcccagca gggtcgtggg 180cgccgggagc tagcaccggg tctgcacctg cggggcatcc gggacgcggg aggccggtac240 tgccaggagc aggacctgtg ctgccgcggc cgtgccgacg actgtgccctgccctacctg 300 ggcgccatct gttactgtga cctcttctgc aaccgcacggtctccgactg ctgccctgac 360 ttctgggact tctgcctcgg cgtgccacccccttttcccc cgatccaagg atgtatgcat 420 ggaggtcgta tctatccagtcttgggaacg tactgggaca actgtaaccg ttgcacctgc 480 caggagaacaggcagtggca tggtggatcc agacatgatc aaagccatca accagggcaa 540ctatggctgg caggctggga accacagcgc cttctggggc atgaccctgg atgagggcat600 tcgctaccgc ctgggcacca tccgcccatc ttcctcggtc atgaacatgcatgaaattta 660 tacagtgctg aacccagggg aggtgcttcc cacagccttcgaggcctctg agaagtggcc 720 caacctgatt catgagcctc ttgaccaaggcaactgtgca ggctcctggg ccttctccac 780 agcagctgtg gcatccgatcgtgtctcaat ccattctctg ggacacatga cgcctgtcct 840 gtcgccccagaacctgctgt cttgtgacac ccaccagcag cagggctgcc gcggtgggcg 900tctcgatggt gcctggtggt tcctgcgtcg ccgaggggtg gtgtctgacc actgctaccc960 cttctcgggc cgtgaacgag acgaggctgg ccctgcgccc ccctgtatgatgcacagccg 1020 agccatgggt cggggcaagc gccaggccac tgcccactgccccaacagct atgttaataa 1080 caatgacatc taccaggtca ctcctgtctaccgcctcggc tccaacgaca aggagatcat 1140 gaaggagctg atggagaatggccctgtcca agccctcatg gaggtgcatg aggacttctt 1200 cctatacaagggaggcatct acagccacac gccagtgagc cttgggaggc cagagagata 1260ccgccggcat gggacccact cagtcaagat cacaggatgg ggagaggaga cgctgccaga1320 tggaaggacg ctcaaatact ggactgcggc caactcctgg ggcccagcctggggcgagag 1380 gggccacttc cgcatcgtgc gcggcgtcaa tgagtgcgacatcgagagct tcgtgctggg 1440 cgtctggggc cgcgtgggca tggaggacatgggtcatcac tgaggctgcg ggcaccacgc 1500 ggggtccggc ctgggatccaggctaagggc cggcggaaga ggccccaatg gggcggtgac 1560 cccagcctcgcccgacagag cccggggcgc aggcgggcgc cagggcgcta atcccggcgc 1620gggttccgct gacgcagcgc cccgcctggg agccgcgggc aggcgagact ggcggagccc1680 ccagacctcc cagtggggac ggggcagggc ctggcctggg aagagcacagctgcagatcc 1740 caggcctctg gcgcccccac tcaagactac caaagccaggacacctcaag tctccagccc 1800 caatacccca ccccaatccc gtattctttttttttttttt ttagacaggg tcttgctccg 1860 ttgcccaggt tggagtgcagtggcccatca gggctcactg taacctccga ctcctgggtt 1920 caagtgaccctcccacctca gcctctcaag tagctgggac tacaggtgca ccaccacacc 1980tggctaattt ttgtattttt tgtaaagagg ggggtctcac tgtgttgccc aggctggttt2040 cgaactcctg ggctcaagcg gtccacctgc ctccgcctcc caaagtgctgggattgcagg 2100 catgagccac tgcacccagc cctgtattct tattcttcagatatttattt ttcttttcac 2160 tgttttaaaa taaaaccaaa gtattgataa aaaaaaa2197 12 164 PRT Homo sapiens 12 Met Trp Arg Cys Pro Leu Gly Leu LeuLeu Leu Leu Pro Leu Ala Gly 1 5 10 15 His Leu Ala Leu Gly Ala GlnGln Gly Arg Gly Arg Arg Glu Leu Ala 20 25 30 Pro Gly Leu His LeuArg Gly Ile Arg Asp Ala Gly Gly Arg Tyr Cys 35 40 45 Gln Glu GlnAsp Leu Cys Cys Arg Gly Arg Ala Asp Asp Cys Ala Leu 50 55 60 ProTyr Leu Gly Ala Ile Cys Tyr Cys Asp Leu Phe Cys Asn Arg Thr 65 7075 80 Val Ser Asp Cys Cys Pro Asp Phe Trp Asp Phe Cys Leu Gly ValPro 85 90 95 Pro Pro Phe Pro Pro Ile Gln Gly Cys Met His Gly GlyArg Ile Tyr 100 105 110 Pro Val Leu Gly Thr Tyr Trp Asp Asn Cys AsnArg Cys Thr Cys Gln 115 120 125 Glu Asn Arg Gln Trp His Gly Gly SerArg His Asp Gln Ser His Gln 130 135 140 Pro Gly Gln Leu Trp Leu AlaGly Trp Glu Pro Gln Arg Leu Leu Gly 145 150 155 160 His Asp Pro Gly13 533 DNA Homo sapiens modified_base (33)..(33) a, t, c or g 13aggctccttg gccctttttc cacagcaagc ttntgcnatc ccgattcgtt gtctcaaatc60 caattctctt gggacacatn acgcctgtcc tttngcccca gaacctgctgtcttgtacac 120 ccaccagcag cagggctgcc gcgntgggcg tctcgatggtgcctggtggt tcctgcgtcg 180 ccgagggntg gtgtctgacc actgctaccccttctcgggc cgtgaacgag acgaggctgg 240 ccctgcgccc ccctgtatgatgcacagccg agccatgggt cggggcaagc gccaggccac 300 tgcccactgccccaacagct atgttaataa caatgacatc taccaggtca ctcctgtcta 360ccgcctcggc tccaacgaca aggagatcat gaaggagctg atggagaatg gccctgtcca420 agccctcatg gaggtgcatg aggacttctt cctatacaag ggaggcatctacagccacac 480 gccagtgagc cttgggaggc cagagagata ccgccggcatgggacccact cag 533 14 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 14 ttcgaggcctctgagaagtg gccc 24 15 22 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 15 ggcggtatctctctggcctc cc 22 16 50 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 16 ttctccacagcagctgtggc atccgatcgt gtctcaatcc attctctggg 50 17 960 DNA Homosapiens 17 gctgcttgcc ctgttgatgg caggcttggc cctgcagcca ggcactgccctgctgtgcta 60 ctcctgcaaa gcccaggtga gcaacgagga ctgcctgcaggtggagaact gcacccagct 120 gggggagcag tgctggaccg cgcgcatccgcgcagttggc ctcctgaccg tcatcagcaa 180 aggctgcagc ttgaactgcgtggatgactc acaggactac tacgtgggca agaagaacat 240 cacgtgctgtgacaccgact tgtgcaacgc cagcggggcc catgccctgc agccggctgc 300cgccatcctt gcgctgctcc ctgcactcgg cctgctgctc tggggacccg gccagctata360 ggctctgggg ggccccgctg cagcccacac tgggtgtggt gccccaggcctctgtgccac 420 tcctcacaga cctggcccag tgggagcctg tcctggttcctgaggcacat cctaacgcaa 480 gtctgaccat gtatgtctgc acccctgtcccccaccctga ccctcccatg gccctctcca 540 ggactcccac ccggcagatcagctctagtg acacagatcc gcctgcagat ggcccctcca 600 accctctctgctgctgtttc catggcccag cattctccac ccttaaccct gtgctcaggc 660acctcttccc ccaggaagcc ttccctgccc accccatcta tgacttgagc caggtctggt720 ccgtggtgtc ccccgcaccc agcaggggac aggcactcag gagggcccagtaaaggctga 780 gatgaagtgg actgagtaga actggaggac aagagtcgacgtgagttcct gggagtctcc 840 agagatgggg cctggaggcc tggaggaaggggccaggcct cacattcgtg gggctccctg 900 aatggcagcc tgagcacagcgtaggccctt aataaacacc tgttggataa gccaaaaaaa 960 18 189 PRT Homosapiens 18 Met Thr His Arg Thr Thr Thr Trp Ala Arg Arg Thr Ser ArgAla Val 1 5 10 15 Thr Pro Thr Cys Ala Thr Pro Ala Gly Pro Met ProCys Ser Arg Leu

20 25 30 Pro Pro Ser Leu Arg Cys Ser Leu His Ser Ala Cys Cys SerGly Asp 35 40 45 Pro Ala Ser Tyr Arg Leu Trp Gly Ala Pro Leu GlnPro Thr Leu Gly 50 55 60 Val Val Pro Gln Ala Ser Val Pro Leu LeuThr Asp Leu Ala Gln Trp 65 70 75 80 Glu Pro Val Leu Val Pro Glu AlaHis Pro Asn Ala Ser Leu Thr Met 85 90 95 Tyr Val Cys Thr Pro ValPro His Pro Asp Pro Pro Met Ala Leu Ser 100 105 110 Arg Thr Pro ThrArg Gln Ile Ser Ser Ser Asp Thr Asp Pro Pro Ala 115 120 125 Asp GlyPro Ser Asn Pro Leu Cys Cys Cys Phe His Gly Pro Ala Phe 130 135 140Ser Thr Leu Asn Pro Val Leu Arg His Leu Phe Pro Gln Glu Ala Phe 145150 155 160 Pro Ala His Pro Ile Tyr Asp Leu Ser Gln Val Trp Ser ValVal Ser 165 170 175 Pro Ala Pro Ser Arg Gly Gln Ala Leu Arg Arg AlaGln 180 185 19 24 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 19 tgctgtgcta ctcctgcaaagccc 24 20 24 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 20 tgcacaagtc ggtgtcacagcacg 24 21 44 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 21 agcaacgagg actgcctgcaggtggagaac tgcacccagc tggg 44 22 1200 DNA Homo sapiens 22cccacgcgtc cgaacctctc cagcgatggg agccgcccgc ctgctgccca acctcactct60 gtgcttacag ctgctgattc tctgctgtca aactcagtac gtgagggaccagggcgccat 120 gaccgaccag ctgagcaggc ggcagatccg cgagtaccaactctacagca ggaccagtgg 180 caagcacgtg caggtcaccg ggcgtcgcatctccgccacc gccgaggacg gcaacaagtt 240 tgccaagctc atagtggagacggacacgtt tggcagccgg gttcgcatca aaggggctga 300 gagtgagaagtacatctgta tgaacaagag gggcaagctc atcgggaagc ccagcgggaa 360gagcaaagac tgcgtgttca cggagatcgt gctggagaac aactatacgg ccttccagaa420 cgcccggcac gagggctggt tcatggcctt cacgcggcag gggcggccccgccaggcttc 480 ccgcagccgc cagaaccagc gcgaggccca cttcatcaagcgcctctacc aaggccagct 540 gcccttcccc aaccacgccg agaagcagaagcagttcgag tttgtgggct ccgcccccac 600 ccgccggacc aagcgcacacggcggcccca gcccctcacg tagtctggga ggcagggggc 660 agcagcccctgggccgcctc cccacccctt tcccttctta atccaaggac tgggctgggg 720tggcgggagg ggagccagat ccccgaggga ggaccctgag ggccgcgaag catccgagcc780 cccagctggg aaggggcagg ccggtgcccc aggggcggct ggcacagtgcccccttcccg 840 gacgggtggc aggccctgga gaggaactga gtgtcaccctgatctcaggc caccagcctc 900 tgccggcctc ccagccgggc tcctgaagcccgctgaaagg tcagcgactg aaggccttgc 960 agacaaccgt ctggaggtggctgtcctcaa aatctgcttc tcggatctcc ctcagtctgc 1020 ccccagcccccaaactcctc ctggctagac tgtaggaagg gacttttgtt tgtttgtttg 1080tttcaggaaa aaagaaaggg agagagagga aaatagaggg ttgtccactc ctcacattcc1140 acgacccagg cctgcacccc acccccaact cccagccccg gaataaaaccattttcctgc 1200 23 205 PRT Homo sapiens 23 Met Gly Ala Ala Arg LeuLeu Pro Asn Leu Thr Leu Cys Leu Gln Leu 1 5 10 15 Leu Ile Leu CysCys Gln Thr Gln Tyr Val Arg Asp Gln Gly Ala Met 20 25 30 Thr AspGln Leu Ser Arg Arg Gln Ile Arg Glu Tyr Gln Leu Tyr Ser 35 40 45Arg Thr Ser Gly Lys His Val Gln Val Thr Gly Arg Arg Ile Ser Ala 5055 60 Thr Ala Glu Asp Gly Asn Lys Phe Ala Lys Leu Ile Val Glu ThrAsp 65 70 75 80 Thr Phe Gly Ser Arg Val Arg Ile Lys Gly Ala Glu SerGlu Lys Tyr 85 90 95 Ile Cys Met Asn Lys Arg Gly Lys Leu Ile GlyLys Pro Ser Gly Lys 100 105 110 Ser Lys Asp Cys Val Phe Thr Glu IleVal Leu Glu Asn Asn Tyr Thr 115 120 125 Ala Phe Gln Asn Ala Arg HisGlu Gly Trp Phe Met Ala Phe Thr Arg 130 135 140 Gln Gly Arg Pro ArgGln Ala Ser Arg Ser Arg Gln Asn Gln Arg Glu 145 150 155 160 Ala HisPhe Ile Lys Arg Leu Tyr Gln Gly Gln Leu Pro Phe Pro Asn 165 170 175His Ala Glu Lys Gln Lys Gln Phe Glu Phe Val Gly Ser Ala Pro Thr 180185 190 Arg Arg Thr Lys Arg Thr Arg Arg Pro Gln Pro Leu Thr 195 200205 24 28 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 24 cagtacgtga gggaccagggcgccatga 28 25 24 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 25 ccggtgacct gcacgtgcttgcca 24 26 41 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 26 gcggatctgc cgcctgctcanctggtcggt catggcgccc t 41 27 2479 DNA Homo sapiens 27 acttgccatcacctgttgcc agtgtggaaa aattctccct gttgaatttt ttgcacatgg 60aggacagcag caaagagggc aacacaggct gataagacca gagacagcag ggagattatt120 ttaccatacg ccctcaggac gttccctcta gctggagttc tggacttcaacagaacccca 180 tccagtcatt ttgattttgc tgtttatttt ttttttctttttctttttcc caccacattg 240 tattttattt ccgtacttca gaaatgggcctacagaccac aaagtggccc agccatgggg 300 cttttttcct gaagtcttggcttatcattt ccctggggct ctactcacag gtgtccaaac 360 tcctggcctgccctagtgtg tgccgctgcg acaggaactt tgtctactgt aatgagcgaa 420gcttgacctc agtgcctctt gggatcccgg agggcgtaac cgtactctac ctccacaaca480 accaaattaa taatgctgga tttcctgcag aactgcacaa tgtacagtcggtgcacacgg 540 tctacctgta tggcaaccaa ctggacgaat tccccatgaaccttcccaag aatgtcagag 600 ttctccattt gcaggaaaac aatattcagaccatttcacg ggctgctctt gcccagctct 660 tgaagcttga agagctgcacctggatgaca actccatatc cacagtgggg gtggaagacg 720 gggccttccgggaggctatt agcctcaaat tgttgttttt gtctaagaat cacctgagca 780gtgtgcctgt tgggcttcct gtggacttgc aagagctgag agtggatgaa aatcgaattg840 ctgtcatatc cgacatggcc ttccagaatc tcacgagctt ggagcgtcttattgtggacg 900 ggaacctcct gaccaacaag ggtatcgccg agggcaccttcagccatctc accaagctca 960 aggaattttc aattgtacgt aattcgctgtcccaccctcc tcccgatctc ccaggtacgc 1020 atctgatcag gctctatttgcaggacaacc agataaacca cattcctttg acagccttct 1080 caaatctgcgtaagctggaa cggctggata tatccaacaa ccaactgcgg atgctgactc 1140aaggggtttt tgataatctc tccaacctga agcagctcac tgctcggaat aacccttggt1200 tttgtgactg cagtattaaa tgggtcacag aatggctcaa atatatcccttcatctctca 1260 acgtgcgggg tttcatgtgc caaggtcctg aacaagtccgggggatggcc gtcagggaat 1320 taaatatgaa tcttttgtcc tgtcccaccacgacccccgg cctgcctctc ttcaccccag 1380 ccccaagtac agcttctccgaccactcagc ctcccaccct ctctattcca aaccctagca 1440 gaagctacacgcctccaact cctaccacat cgaaacttcc cacgattcct gactgggatg 1500gcagagaaag agtgacccca cctatttctg aacggatcca gctctctatc cattttgtga1560 atgatacttc cattcaagtc agctggctct ctctcttcac cgtgatggcatacaaactca 1620 catgggtgaa aatgggccac agtttagtag ggggcatcgttcaggagcgc atagtcagcg 1680 gtgagaagca acacctgagc ctggttaacttagagccccg atccacctat cggatttgtt 1740 tagtgccact ggatgcttttaactaccgcg cggtagaaga caccatttgt tcagaggcca 1800 ccacccatgcctcctatctg aacaacggca gcaacacagc gtccagccat gagcagacga 1860cgtcccacag catgggctcc ccctttctgc tggcgggctt gatcgggggc gcggtgatat1920 ttgtgctggt ggtcttgctc agcgtctttt gctggcatat gcacaaaaaggggcgctaca 1980 cctcccagaa gtggaaatac aaccggggcc ggcggaaagatgattattgc gaggcaggca 2040 ccaagaagga caactccatc ctggagatgacagaaaccag ttttcagatc gtctccttaa 2100 ataacgatca actccttaaaggagatttca gactgcagcc catttacacc ccaaatgggg 2160 gcattaattacacagactgc catatcccca acaacatgcg atactgcaac agcagcgtgc 2220cagacctgga gcactgccat acgtgacagc cagaggccca gcgttatcaa ggcggacaat2280 tagactcttg agaacacact cgtgtgtgca cataaagaca cgcagattacatttgataaa 2340 tgttacacag atgcatttgt gcatttgaat actctgtaatttatacggtg tactatataa 2400 tgggatttaa aaaaagtgct atcttttctatttcaagtta attacaaaca gttttgtaac 2460 tctttgcttt ttaaatctt 2479 28660 PRT Homo sapiens 28 Met Gly Leu Gln Thr Thr Lys Trp Pro Ser HisGly Ala Phe Phe Leu 1 5 10 15 Lys Ser Trp Leu Ile Ile Ser Leu GlyLeu Tyr Ser Gln Val Ser Lys 20 25 30 Leu Leu Ala Cys Pro Ser ValCys Arg Cys Asp Arg Asn Phe Val Tyr 35 40 45 Cys Asn Glu Arg SerLeu Thr Ser Val Pro Leu Gly Ile Pro Glu Gly 50 55 60 Val Thr ValLeu Tyr Leu His Asn Asn Gln Ile Asn Asn Ala Gly Phe 65 70 75 80 ProAla Glu Leu His Asn Val Gln Ser Val His Thr Val Tyr Leu Tyr 85 9095 Gly Asn Gln Leu Asp Glu Phe Pro Met Asn Leu Pro Lys Asn Val Arg100 105 110 Val Leu His Leu Gln Glu Asn Asn Ile Gln Thr Ile Ser ArgAla Ala 115 120 125 Leu Ala Gln Leu Leu Lys Leu Glu Glu Leu His LeuAsp Asp Asn Ser 130 135 140 Ile Ser Thr Val Gly Val Glu Asp Gly AlaPhe Arg Glu Ala Ile Ser 145 150 155 160 Leu Lys Leu Leu Phe Leu SerLys Asn His Leu Ser Ser Val Pro Val 165 170 175 Gly Leu Pro Val AspLeu Gln Glu Leu Arg Val Asp Glu Asn Arg Ile 180 185 190 Ala Val IleSer Asp Met Ala Phe Gln Asn Leu Thr Ser Leu Glu Arg 195 200 205 LeuIle Val Asp Gly Asn Leu Leu Thr Asn Lys Gly Ile Ala Glu Gly 210 215220 Thr Phe Ser His Leu Thr Lys Leu Lys Glu Phe Ser Ile Val Arg Asn225 230 235 240 Ser Leu Ser His Pro Pro Pro Asp Leu Pro Gly Thr HisLeu Ile Arg 245 250 255 Leu Tyr Leu Gln Asp Asn Gln Ile Asn His IlePro Leu Thr Ala Phe 260 265 270 Ser Asn Leu Arg Lys Leu Glu Arg LeuAsp Ile Ser Asn Asn Gln Leu 275 280 285 Arg Met Leu Thr Gln Gly ValPhe Asp Asn Leu Ser Asn Leu Lys Gln 290 295 300 Leu Thr Ala Arg AsnAsn Pro Trp Phe Cys Asp Cys Ser Ile Lys Trp 305 310 315 320 Val ThrGlu Trp Leu Lys Tyr Ile Pro Ser Ser Leu Asn Val Arg Gly 325 330 335Phe Met Cys Gln Gly Pro Glu Gln Val Arg Gly Met Ala Val Arg Glu 340345 350 Leu Asn Met Asn Leu Leu Ser Cys Pro Thr Thr Thr Pro Gly LeuPro 355 360 365 Leu Phe Thr Pro Ala Pro Ser Thr Ala Ser Pro Thr ThrGln Pro Pro 370 375 380 Thr Leu Ser Ile Pro Asn Pro Ser Arg Ser TyrThr Pro Pro Thr Pro 385 390 395 400 Thr Thr Ser Lys Leu Pro Thr IlePro Asp Trp Asp Gly Arg Glu Arg 405 410 415 Val Thr Pro Pro Ile SerGlu Arg Ile Gln Leu Ser Ile His Phe Val 420 425 430 Asn Asp Thr SerIle Gln Val Ser Trp Leu Ser Leu Phe Thr Val Met 435 440 445 Ala TyrLys Leu Thr Trp Val Lys Met Gly His Ser Leu Val Gly Gly 450 455 460Ile Val Gln Glu Arg Ile Val Ser Gly Glu Lys Gln His Leu Ser Leu 465470 475 480 Val Asn Leu Glu Pro Arg Ser Thr Tyr Arg Ile Cys Leu ValPro Leu 485 490 495 Asp Ala Phe Asn Tyr Arg Ala Val Glu Asp Thr IleCys Ser Glu Ala 500 505 510 Thr Thr His Ala Ser Tyr Leu Asn Asn GlySer Asn Thr Ala Ser Ser 515 520 525 His Glu Gln Thr Thr Ser His SerMet Gly Ser Pro Phe Leu Leu Ala 530 535 540 Gly Leu Ile Gly Gly AlaVal Ile Phe Val Leu Val Val Leu Leu Ser 545 550 555 560 Val Phe CysTrp His Met His Lys Lys Gly Arg Tyr Thr Ser Gln Lys 565 570 575 TrpLys Tyr Asn Arg Gly Arg Arg Lys Asp Asp Tyr Cys Glu Ala Gly 580 585590 Thr Lys Lys Asp Asn Ser Ile Leu Glu Met Thr Glu Thr Ser Phe Gln595 600 605 Ile Val Ser Leu Asn Asn Asp Gln Leu Leu Lys Gly Asp PheArg Leu 610 615 620 Gln Pro Ile Tyr Thr Pro Asn Gly Gly Ile Asn TyrThr Asp Cys His 625 630 635 640 Ile Pro Asn Asn Met Arg Tyr Cys AsnSer Ser Val Pro Asp Leu Glu 645 650 655 His Cys His Thr 660 29 21DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 29 cggtctacct gtatggcaac c 21 30 22DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 30 gcaggacaac cagataaacc ac 22 3122 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 31 acgcagattt gagaaggctg tc 22 3246 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 32 ttcacgggct gctcttgccc agctcttgaagcttgaagag ctgcac 46 33 3449 DNA Homo sapiens 33 acttggagcaagcggcggcg gcggagacag aggcagaggc agaagctggg gctccgtcct 60cgcctcccac gagcgatccc cgaggagagc cgcggccctc ggcgaggcga agaggccgac120 gaggaagacc cgggtggctg cgcccctgcc tcgcttccca ggcgccggcggctgcagcct 180 tgcccctctt gctcgccttg aaaatggaaa agatgctcgcaggctgcttt ctgctgatcc 240 tcggacagat cgtcctcctc cctgccgaggccagggagcg gtcacgtggg aggtccatct 300 ctaggggcag acacgctcggacccacccgc agacggccct tctggagagt tcctgtgaga 360 acaagcgggcagacctggtt ttcatcattg acagctctcg cagtgtcaac acccatgact 420atgcaaaggt caaggagttc atcgtggaca tcttgcaatt cttggacatt ggtcctgatg480 tcacccgagt gggcctgctc caatatggca gcactgtcaa gaatgagttctccctcaaga 540 ccttcaagag gaagtccgag gtggagcgtg ctgtcaagaggatgcggcat ctgtccacgg 600 gcaccatgac tgggctggcc atccagtatgccctgaacat cgcattctca gaagcagagg 660 gggcccggcc cctgagggagaatgtgccac gggtcataat gatcgtgaca gatgggagac 720 ctcaggactccgtggccgag gtggctgcta aggcacggga cacgggcatc ctaatctttg 780ccattggtgt gggccaggta gacttcaaca ccttgaagtc cattgggagt gagccccatg840 aggaccatgt cttccttgtg gccaatttca gccagattga gacgctgacctccgtgttcc 900 agaagaagtt gtgcacggcc cacatgtgca gcaccctggagcataactgt gcccacttct 960 gcatcaacat ccctggctca tacgtctgcaggtgcaaaca aggctacatt ctcaactcgg 1020 atcagacgac ttgcagaatccaggatctgt gtgccatgga ggaccacaac tgtgagcagc 1080 tctgtgtgaatgtgccgggc tccttcgtct gccagtgcta cagtggctac gccctggctg 1140aggatgggaa gaggtgtgtg gctgtggact actgtgcctc agaaaaccac ggatgtgaac1200 atgagtgtgt aaatgctgat ggctcctacc tttgccagtg ccatgaaggatttgctctta 1260 acccagatga aaaaacgtgc acaaggatca actactgtgcactgaacaaa ccgggctgtg 1320 agcatgagtg cgtcaacatg gaggagagctactactgccg ctgccaccgt ggctacactc 1380 tggaccccaa tggcaaaacctgcagccgag tggaccactg tgcacagcag gaccatggct 1440 gtgagcagctgtgtctgaac acggaggatt ccttcgtctg ccagtgctca gaaggcttcc 1500tcatcaacga ggacctcaag acctgctccc gggtggatta ctgcctgctg agtgaccatg1560 gttgtgaata ctcctgtgtc aacatggaca gatcctttgc ctgtcagtgtcctgagggac 1620 acgtgctccg cagcgatggg aagacgtgtg caaaattggactcttgtgct ctgggggacc 1680 acggttgtga acattcgtgt gtaagcagtgaagattcgtt tgtgtgccag tgctttgaag 1740 gttatatact ccgtgaagatggaaaaacct gcagaaggaa agatgtctgc caagctatag 1800 accatggctgtgaacacatt tgtgtgaaca gtgacgactc atacacgtgc gagtgcttgg 1860agggattccg gctcgctgag gatgggaaac gctgccgaag gaaggatgtc tgcaaatcaa1920 cccaccatgg ctgcgaacac atttgtgtta ataatgggaa ttcctacatctgcaaatgct 1980 cagagggatt tgttctagct gaggacggaa gacggtgcaagaaatgcact gaaggcccaa 2040 ttgacctggt ctttgtgatc gatggatccaagagtcttgg agaagagaat tttgaggtcg 2100 tgaagcagtt tgtcactggaattatagatt ccttgacaat ttcccccaaa gccgctcgag 2160 tggggctgctccagtattcc acacaggtcc acacagagtt cactctgaga aacttcaact 2220cagccaaaga catgaaaaaa gccgtggccc acatgaaata catgggaaag ggctctatga2280 ctgggctggc cctgaaacac atgtttgaga gaagttttac ccaaggagaaggggccaggc 2340 ccctttccac aagggtgccc agagcagcca ttgtgttcaccgacggacgg gctcaggatg 2400 acgtctccga gtgggccagt aaagccaaggccaatggtat cactatgtat gctgttgggg 2460 taggaaaagc cattgaggaggaactacaag agattgcctc tgagcccaca aacaagcatc 2520 tcttctatgccgaagacttc agcacaatgg atgagataag tgaaaaactc aagaaaggca 2580tctgtgaagc tctagaagac tccgatggaa gacaggactc tccagcaggg gaactgccaa2640 aaacggtcca acagccaaca gaatctgagc cagtcaccat aaatatccaagacctacttt 2700 cctgttctaa ttttgcagtg caacacagat atctgtttgaagaagacaat cttttacggt 2760 ctacacaaaa gctttcccat tcaacaaaaccttcaggaag ccctttggaa gaaaaacacg 2820 atcaatgcaa atgtgaaaaccttataatgt tccagaacct tgcaaacgaa gaagtaagaa 2880 aattaacacagcgcttagaa gaaatgacac agagaatgga agccctggaa aatcgcctga 2940gatacagatg aagattagaa atcgcgacac atttgtagtc attgtatcac ggattacaat3000 gaacgcagtg cagagcccca aagctcaggc tattgttaaa tcaataatgttgtgaagtaa 3060 aacaatcagt actgagaaac ctggtttgcc acagaacaaagacaagaagt atacactaac 3120 ttgtataaat ttatctagga aaaaaatccttcagaattct aagatgaatt taccaggtga 3180 gaatgaataa gctatgcaaggtattttgta atatactgtg gacacaactt gcttctgcct 3240 catcctgccttagtgtgcaa tctcatttga ctatacgata aagtttgcac agtcttactt 3300ctgtagaaca ctggccatag gaaatgctgt ttttttgtac tggactttac cttgatatat3360 gtatatggat

gtatgcataa aatcatagga catatgtact tgtggaacaa gttggatttt 3420ttatacaata ttaaaattca ccacttcag 3449 34 915 PRT Homo sapiens 34 MetGlu Lys Met Leu Ala Gly Cys Phe Leu Leu Ile Leu Gly Gln Ile 1 5 1015 Val Leu Leu Pro Ala Glu Ala Arg Glu Arg Ser Arg Gly Arg Ser Ile20 25 30 Ser Arg Gly Arg His Ala Arg Thr His Pro Gln Thr Ala LeuLeu Glu 35 40 45 Ser Ser Cys Glu Asn Lys Arg Ala Asp Leu Val PheIle Ile Asp Ser 50 55 60 Ser Arg Ser Val Asn Thr His Asp Tyr AlaLys Val Lys Glu Phe Ile 65 70 75 80 Val Asp Ile Leu Gln Phe Leu AspIle Gly Pro Asp Val Thr Arg Val 85 90 95 Gly Leu Leu Gln Tyr GlySer Thr Val Lys Asn Glu Phe Ser Leu Lys 100 105 110 Thr Phe Lys ArgLys Ser Glu Val Glu Arg Ala Val Lys Arg Met Arg 115 120 125 His LeuSer Thr Gly Thr Met Thr Gly Leu Ala Ile Gln Tyr Ala Leu 130 135 140Asn Ile Ala Phe Ser Glu Ala Glu Gly Ala Arg Pro Leu Arg Glu Asn 145150 155 160 Val Pro Arg Val Ile Met Ile Val Thr Asp Gly Arg Pro GlnAsp Ser 165 170 175 Val Ala Glu Val Ala Ala Lys Ala Arg Asp Thr GlyIle Leu Ile Phe 180 185 190 Ala Ile Gly Val Gly Gln Val Asp Phe AsnThr Leu Lys Ser Ile Gly 195 200 205 Ser Glu Pro His Glu Asp His ValPhe Leu Val Ala Asn Phe Ser Gln 210 215 220 Ile Glu Thr Leu Thr SerVal Phe Gln Lys Lys Leu Cys Thr Ala His 225 230 235 240 Met Cys SerThr Leu Glu His Asn Cys Ala His Phe Cys Ile Asn Ile 245 250 255 ProGly Ser Tyr Val Cys Arg Cys Lys Gln Gly Tyr Ile Leu Asn Ser 260 265270 Asp Gln Thr Thr Cys Arg Ile Gln Asp Leu Cys Ala Met Glu Asp His275 280 285 Asn Cys Glu Gln Leu Cys Val Asn Val Pro Gly Ser Phe ValCys Gln 290 295 300 Cys Tyr Ser Gly Tyr Ala Leu Ala Glu Asp Gly LysArg Cys Val Ala 305 310 315 320 Val Asp Tyr Cys Ala Ser Glu Asn HisGly Cys Glu His Glu Cys Val 325 330 335 Asn Ala Asp Gly Ser Tyr LeuCys Gln Cys His Glu Gly Phe Ala Leu 340 345 350 Asn Pro Asp Glu LysThr Cys Thr Arg Ile Asn Tyr Cys Ala Leu Asn 355 360 365 Lys Pro GlyCys Glu His Glu Cys Val Asn Met Glu Glu Ser Tyr Tyr 370 375 380 CysArg Cys His Arg Gly Tyr Thr Leu Asp Pro Asn Gly Lys Thr Cys 385 390395 400 Ser Arg Val Asp His Cys Ala Gln Gln Asp His Gly Cys Glu GlnLeu 405 410 415 Cys Leu Asn Thr Glu Asp Ser Phe Val Cys Gln Cys SerGlu Gly Phe 420 425 430 Leu Ile Asn Glu Asp Leu Lys Thr Cys Ser ArgVal Asp Tyr Cys Leu 435 440 445 Leu Ser Asp His Gly Cys Glu Tyr SerCys Val Asn Met Asp Arg Ser 450 455 460 Phe Ala Cys Gln Cys Pro GluGly His Val Leu Arg Ser Asp Gly Lys 465 470 475 480 Thr Cys Ala LysLeu Asp Ser Cys Ala Leu Gly Asp His Gly Cys Glu 485 490 495 His SerCys Val Ser Ser Glu Asp Ser Phe Val Cys Gln Cys Phe Glu 500 505 510Gly Tyr Ile Leu Arg Glu Asp Gly Lys Thr Cys Arg Arg Lys Asp Val 515520 525 Cys Gln Ala Ile Asp His Gly Cys Glu His Ile Cys Val Asn SerAsp 530 535 540 Asp Ser Tyr Thr Cys Glu Cys Leu Glu Gly Phe Arg LeuAla Glu Asp 545 550 555 560 Gly Lys Arg Cys Arg Arg Lys Asp Val CysLys Ser Thr His His Gly 565 570 575 Cys Glu His Ile Cys Val Asn AsnGly Asn Ser Tyr Ile Cys Lys Cys 580 585 590 Ser Glu Gly Phe Val LeuAla Glu Asp Gly Arg Arg Cys Lys Lys Cys 595 600 605 Thr Glu Gly ProIle Asp Leu Val Phe Val Ile Asp Gly Ser Lys Ser 610 615 620 Leu GlyGlu Glu Asn Phe Glu Val Val Lys Gln Phe Val Thr Gly Ile 625 630 635640 Ile Asp Ser Leu Thr Ile Ser Pro Lys Ala Ala Arg Val Gly Leu Leu645 650 655 Gln Tyr Ser Thr Gln Val His Thr Glu Phe Thr Leu Arg AsnPhe Asn 660 665 670 Ser Ala Lys Asp Met Lys Lys Ala Val Ala His MetLys Tyr Met Gly 675 680 685 Lys Gly Ser Met Thr Gly Leu Ala Leu LysHis Met Phe Glu Arg Ser 690 695 700 Phe Thr Gln Gly Glu Gly Ala ArgPro Leu Ser Thr Arg Val Pro Arg 705 710 715 720 Ala Ala Ile Val PheThr Asp Gly Arg Ala Gln Asp Asp Val Ser Glu 725 730 735 Trp Ala SerLys Ala Lys Ala Asn Gly Ile Thr Met Tyr Ala Val Gly 740 745 750 ValGly Lys Ala Ile Glu Glu Glu Leu Gln Glu Ile Ala Ser Glu Pro 755 760765 Thr Asn Lys His Leu Phe Tyr Ala Glu Asp Phe Ser Thr Met Asp Glu770 775 780 Ile Ser Glu Lys Leu Lys Lys Gly Ile Cys Glu Ala Leu GluAsp Ser 785 790 795 800 Asp Gly Arg Gln Asp Ser Pro Ala Gly Glu LeuPro Lys Thr Val Gln 805 810 815 Gln Pro Thr Glu Ser Glu Pro Val ThrIle Asn Ile Gln Asp Leu Leu 820 825 830 Ser Cys Ser Asn Phe Ala ValGln His Arg Tyr Leu Phe Glu Glu Asp 835 840 845 Asn Leu Leu Arg SerThr Gln Lys Leu Ser His Ser Thr Lys Pro Ser 850 855 860 Gly Ser ProLeu Glu Glu Lys His Asp Gln Cys Lys Cys Glu Asn Leu 865 870 875 880Ile Met Phe Gln Asn Leu Ala Asn Glu Glu Val Arg Lys Leu Thr Gln 885890 895 Arg Leu Glu Glu Met Thr Gln Arg Met Glu Ala Leu Glu Asn ArgLeu 900 905 910 Arg Tyr Arg 915 35 23 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe35 gtgaccctgg ttgtgaatac tcc 23 36 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe36 acagccatgg tctatagctt gg 22 37 45 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe37 gcctgtcagt gtcctgaggg acacgtgctc cgcagcgatg ggaag 45 38 1813 DNAHomo sapiens 38 ggagccgccc tgggtgtcag cggctcggct cccgcgcacgctccggccgt cgcgcagcct 60 cggcacctgc aggtccgtgc gtcccgcggctggcgcccct gactccgtcc cggccaggga 120 gggccatgat ttccctcccggggcccctgg tgaccaactt gctgcggttt ttgttcctgg 180 ggctgagtgccctcgcgccc ccctcgcggg cccagctgca actgcacttg cccgccaacc 240ggttgcaggc ggtggaggga ggggaagtgg tgcttccagc gtggtacacc ttgcacgggg300 aggtgtcttc atcccagcca tgggaggtgc cctttgtgat gtggttcttcaaacagaaag 360 aaaaggagga tcaggtgttg tcctacatca atggggtcacaacaagcaaa cctggagtat 420 ccttggtcta ctccatgccc tcccggaacctgtccctgcg gctggagggt ctccaggaga 480 aagactctgg cccctacagctgctccgtga atgtgcaaga caaacaaggc aaatctaggg 540 gccacagcatcaaaacctta gaactcaatg tactggttcc tccagctcct ccatcctgcc 600gtctccaggg tgtgccccat gtgggggcaa acgtgaccct gagctgccag tctccaagga660 gtaagcccgc tgtccaatac cagtgggatc ggcagcttcc atccttccagactttctttg 720 caccagcatt agatgtcatc cgtgggtctt taagcctcaccaacctttcg tcttccatgg 780 ctggagtcta tgtctgcaag gcccacaatgaggtgggcac tgcccaatgt aatgtgacgc 840 tggaagtgag cacagggcctggagctgcag tggttgctgg agctgttgtg ggtaccctgg 900 ttggactggggttgctggct gggctggtcc tcttgtacca ccgccggggc aaggccctgg 960aggagccagc caatgatatc aaggaggatg ccattgctcc ccggaccctg ccctggccca1020 agagctcaga cacaatctcc aagaatggga ccctttcctc tgtcacctccgcacgagccc 1080 tccggccacc ccatggccct cccaggcctg gtgcattgacccccacgccc agtctctcca 1140 gccaggccct gccctcacca agactgcccacgacagatgg ggcccaccct caaccaatat 1200 cccccatccc tggtggggtttcttcctctg gcttgagccg catgggtgct gtgcctgtga 1260 tggtgcctgcccagagtcaa gctggctctc tggtatgatg accccaccac tcattggcta 1320aaggatttgg ggtctctcct tcctataagg gtcacctcta gcacagaggc ctgagtcatg1380 ggaaagagtc acactcctga cccttagtac tctgccccca cctctctttactgtgggaaa 1440 accatctcag taagacctaa gtgtccagga gacagaaggagaagaggaag tggatctgga 1500 attgggagga gcctccaccc acccctgactcctccttatg aagccagctg ctgaaattag 1560 ctactcacca agagtgaggggcagagactt ccagtcactg agtctcccag gcccccttga 1620 tctgtaccccacccctatct aacaccaccc ttggctccca ctccagctcc ctgtattgat 1680ataacctgtc aggctggctt ggttaggttt tactggggca gaggataggg aatctcttat1740 taaaactaac atgaaatatg tgttgttttc atttgcaaat ttaaataaagatacataatg 1800 tttgtatgaa aaa 1813 39 390 PRT Homo sapiens 39 MetIle Ser Leu Pro Gly Pro Leu Val Thr Asn Leu Leu Arg Phe Leu 1 5 1015 Phe Leu Gly Leu Ser Ala Leu Ala Pro Pro Ser Arg Ala Gln Leu Gln20 25 30 Leu His Leu Pro Ala Asn Arg Leu Gln Ala Val Glu Gly GlyGlu Val 35 40 45 Val Leu Pro Ala Trp Tyr Thr Leu His Gly Glu ValSer Ser Ser Gln 50 55 60 Pro Trp Glu Val Pro Phe Val Met Trp PhePhe Lys Gln Lys Glu Lys 65 70 75 80 Glu Asp Gln Val Leu Ser Tyr IleAsn Gly Val Thr Thr Ser Lys Pro 85 90 95 Gly Val Ser Leu Val TyrSer Met Pro Ser Arg Asn Leu Ser Leu Arg 100 105 110 Leu Glu Gly LeuGln Glu Lys Asp Ser Gly Pro Tyr Ser Cys Ser Val 115 120 125 Asn ValGln Asp Lys Gln Gly Lys Ser Arg Gly His Ser Ile Lys Thr 130 135 140Leu Glu Leu Asn Val Leu Val Pro Pro Ala Pro Pro Ser Cys Arg Leu 145150 155 160 Gln Gly Val Pro His Val Gly Ala Asn Val Thr Leu Ser CysGln Ser 165 170 175 Pro Arg Ser Lys Pro Ala Val Gln Tyr Gln Trp AspArg Gln Leu Pro 180 185 190 Ser Phe Gln Thr Phe Phe Ala Pro Ala LeuAsp Val Ile Arg Gly Ser 195 200 205 Leu Ser Leu Thr Asn Leu Ser SerSer Met Ala Gly Val Tyr Val Cys 210 215 220 Lys Ala His Asn Glu ValGly Thr Ala Gln Cys Asn Val Thr Leu Glu 225 230 235 240 Val Ser ThrGly Pro Gly Ala Ala Val Val Ala Gly Ala Val Val Gly 245 250 255 ThrLeu Val Gly Leu Gly Leu Leu Ala Gly Leu Val Leu Leu Tyr His 260 265270 Arg Arg Gly Lys Ala Leu Glu Glu Pro Ala Asn Asp Ile Lys Glu Asp275 280 285 Ala Ile Ala Pro Arg Thr Leu Pro Trp Pro Lys Ser Ser AspThr Ile 290 295 300 Ser Lys Asn Gly Thr Leu Ser Ser Val Thr Ser AlaArg Ala Leu Arg 305 310 315 320 Pro Pro His Gly Pro Pro Arg Pro GlyAla Leu Thr Pro Thr Pro Ser 325 330 335 Leu Ser Ser Gln Ala Leu ProSer Pro Arg Leu Pro Thr Thr Asp Gly 340 345 350 Ala His Pro Gln ProIle Ser Pro Ile Pro Gly Gly Val Ser Ser Ser 355 360 365 Gly Leu SerArg Met Gly Ala Val Pro Val Met Val Pro Ala Gln Ser 370 375 380 GlnAla Gly Ser Leu Val 385 390 40 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe40 agggtctcca ggagaaagac tc 22 41 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe41 attgtgggcc ttgcagacat agac 24 42 50 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe42 ggccacagca tcaaaacctt agaactcaat gtactggttc ctccagctcc 50 43 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 43 gtgtgacaca gcgtgggc 18 44 18 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 44 gaccggcagg cttctgcg 18 45 25 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 45 cagcagcttc agccaccagg agtgg 25 46 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 46 ctgagccgtg ggctgcagtc tcgc 24 47 45 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 47 ccgactacga ctggttcttc atcatgcaggatgacacata tgtgc 45 48 2822 DNA Homo sapiens 48 cgccaccactgcggccaccg ccaatgaaac gcctcccgct cctagtggtt ttttccactt 60tgttgaattg ttcctatact caaaattgca ccaagacacc ttgtctccca aatgcaaaat120 gtgaaatacg caatggaatt gaagcctgct attgcaacat gggattttcaggaaatggtg 180 tcacaatttg tgaagatgat aatgaatgtg gaaatttaactcagtcctgt ggcgaaaatg 240 ctaattgcac taacacagaa ggaagttattattgtatgtg tgtacctggc ttcagatcca 300 gcagtaacca agacaggtttatcactaatg atggaaccgt ctgtatagaa aatgtgaatg 360 caaactgccatttagataat gtctgtatag ctgcaaatat taataaaact ttaacaaaaa 420tcagatccat aaaagaacct gtggctttgc tacaagaagt ctatagaaat tctgtgacag480 atctttcacc aacagatata attacatata tagaaatatt agctgaatcatcttcattac 540 taggttacaa gaacaacact atctcagcca aggacaccctttctaactca actcttactg 600 aatttgtaaa aaccgtgaat aattttgttcaaagggatac atttgtagtt tgggacaagt 660 tatctgtgaa tcataggagaacacatctta caaaactcat gcacactgtt gaacaagcta 720 ctttaaggatatcccagagc ttccaaaaga ccacagagtt tgatacaaat tcaacggata 780tagctctcaa agttttcttt tttgattcat ataacatgaa acatattcat cctcatatga840 atatggatgg agactacata aatatatttc caaagagaaa agctgcatatgattcaaatg 900 gcaatgttgc agttgcattt ttatattata agagtattggtcctttgctt tcatcatctg 960 acaacttctt attgaaacct caaaattatgataattctga agaggaggaa agagtcatat 1020 cttcagtaat ttcagtctcaatgagctcaa acccacccac attatatgaa cttgaaaaaa 1080 taacatttacattaagtcat cgaaaggtca cagataggta taggagtcta tgtgcatttt 1140ggaattactc acctgatacc atgaatggca gctggtcttc agagggctgt gagctgacat1200 actcaaatga gacccacacc tcatgccgct gtaatcacct gacacattttgcaattttga 1260 tgtcctctgg tccttccatt ggtattaaag attataatattcttacaagg atcactcaac 1320 taggaataat tatttcactg atttgtcttgccatatgcat ttttaccttc tggttcttca 1380 gtgaaattca aagcaccaggacaacaattc acaaaaatct ttgctgtagc ctatttcttg 1440 ctgaacttgtttttcttgtt gggatcaata caaatactaa taagctcttc tgttcaatca 1500ttgccggact gctacactac ttctttttag ctgcttttgc atggatgtgc attgaaggca1560 tacatctcta tctcattgtt gtgggtgtca tctacaacaa gggatttttgcacaagaatt 1620 tttatatctt tggctatcta agcccagccg tggtagttggattttcggca gcactaggat 1680 acagatatta tggcacaacc aaagtatgttggcttagcac cgaaaacaac tttatttgga 1740 gttttatagg accagcatgcctaatcattc ttgttaatct cttggctttt ggagtcatca 1800 tatacaaagtttttcgtcac actgcagggt tgaaaccaga agttagttgc tttgagaaca 1860taaggtcttg tgcaagagga gccctcgctc ttctgttcct tctcggcacc acctggatct1920 ttggggttct ccatgttgtg cacgcatcag tggttacagc ttacctcttcacagtcagca 1980 atgctttcca ggggatgttc atttttttat tcctgtgtgttttatctaga aagattcaag 2040 aagaatatta cagattgttc aaaaatgtcccctgttgttt tggatgttta aggtaaacat 2100 agagaatggt ggataattacaactgcacaa aaataaaaat tccaagctgt ggatgaccaa 2160 tgtataaaaatgactcatca aattatccaa ttattaacta ctagacaaaa agtattttaa 2220atcagttttt ctgtttatgc tataggaact gtagataata aggtaaaatt atgtatcata2280 tagatatact atgtttttct atgtgaaata gttctgtcaa aaatagtattgcagatattt 2340 ggaaagtaat tggtttctca ggagtgatat cactgcacccaaggaaagat tttctttcta 2400 acacgagaag tatatgaatg tcctgaaggaaaccactggc ttgatatttc tgtgactcgt 2460 gttgcctttg aaactagtcccctaccacct cggtaatgag ctccattaca gaaagtggaa 2520 cataagagaatgaaggggca gaatatcaaa cagtgaaaag ggaatgataa gatgtatttt 2580gaatgaactg ttttttctgt agactagctg agaaattgtt gacataaaat aaagaattga2640 agaaacacat tttaccattt tgtgaattgt tctgaactta aatgtccactaaaacaactt 2700 agacttctgt ttgctaaatc tgtttctttt tctaatattctaaaaaaaaa aaaaaggttt 2760 acctccacaa attgaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2820 aa 2822 49 690 PRT Homosapiens 49 Met Lys Arg Leu Pro Leu Leu Val Val Phe Ser Thr Leu LeuAsn Cys 1 5 10 15 Ser Tyr Thr Gln Asn Cys Thr Lys Thr Pro Cys LeuPro Asn Ala Lys 20 25 30 Cys Glu Ile Arg Asn Gly Ile Glu Ala CysTyr Cys Asn Met Gly Phe 35 40 45 Ser Gly Asn Gly Val Thr Ile CysGlu Asp Asp Asn Glu Cys Gly Asn 50 55 60 Leu Thr Gln Ser Cys

Gly Glu Asn Ala Asn Cys Thr Asn Thr Glu Gly 65 70 75 80 Ser Tyr TyrCys Met Cys Val Pro Gly Phe Arg Ser Ser Ser Asn Gln 85 90 95 AspArg Phe Ile Thr Asn Asp Gly Thr Val Cys Ile Glu Asn Val Asn 100 105110 Ala Asn Cys His Leu Asp Asn Val Cys Ile Ala Ala Asn Ile Asn Lys115 120 125 Thr Leu Thr Lys Ile Arg Ser Ile Lys Glu Pro Val Ala LeuLeu Gln 130 135 140 Glu Val Tyr Arg Asn Ser Val Thr Asp Leu Ser ProThr Asp Ile Ile 145 150 155 160 Thr Tyr Ile Glu Ile Leu Ala Glu SerSer Ser Leu Leu Gly Tyr Lys 165 170 175 Asn Asn Thr Ile Ser Ala LysAsp Thr Leu Ser Asn Ser Thr Leu Thr 180 185 190 Glu Phe Val Lys ThrVal Asn Asn Phe Val Gln Arg Asp Thr Phe Val 195 200 205 Val Trp AspLys Leu Ser Val Asn His Arg Arg Thr His Leu Thr Lys 210 215 220 LeuMet His Thr Val Glu Gln Ala Thr Leu Arg Ile Ser Gln Ser Phe 225 230235 240 Gln Lys Thr Thr Glu Phe Asp Thr Asn Ser Thr Asp Ile Ala LeuLys 245 250 255 Val Phe Phe Phe Asp Ser Tyr Asn Met Lys His Ile HisPro His Met 260 265 270 Asn Met Asp Gly Asp Tyr Ile Asn Ile Phe ProLys Arg Lys Ala Ala 275 280 285 Tyr Asp Ser Asn Gly Asn Val Ala ValAla Phe Leu Tyr Tyr Lys Ser 290 295 300 Ile Gly Pro Leu Leu Ser SerSer Asp Asn Phe Leu Leu Lys Pro Gln 305 310 315 320 Asn Tyr Asp AsnSer Glu Glu Glu Glu Arg Val Ile Ser Ser Val Ile 325 330 335 Ser ValSer Met Ser Ser Asn Pro Pro Thr Leu Tyr Glu Leu Glu Lys 340 345 350Ile Thr Phe Thr Leu Ser His Arg Lys Val Thr Asp Arg Tyr Arg Ser 355360 365 Leu Cys Ala Phe Trp Asn Tyr Ser Pro Asp Thr Met Asn Gly SerTrp 370 375 380 Ser Ser Glu Gly Cys Glu Leu Thr Tyr Ser Asn Glu ThrHis Thr Ser 385 390 395 400 Cys Arg Cys Asn His Leu Thr His Phe AlaIle Leu Met Ser Ser Gly 405 410 415 Pro Ser Ile Gly Ile Lys Asp TyrAsn Ile Leu Thr Arg Ile Thr Gln 420 425 430 Leu Gly Ile Ile Ile SerLeu Ile Cys Leu Ala Ile Cys Ile Phe Thr 435 440 445 Phe Trp Phe PheSer Glu Ile Gln Ser Thr Arg Thr Thr Ile His Lys 450 455 460 Asn LeuCys Cys Ser Leu Phe Leu Ala Glu Leu Val Phe Leu Val Gly 465 470 475480 Ile Asn Thr Asn Thr Asn Lys Leu Phe Cys Ser Ile Ile Ala Gly Leu485 490 495 Leu His Tyr Phe Phe Leu Ala Ala Phe Ala Trp Met Cys IleGlu Gly 500 505 510 Ile His Leu Tyr Leu Ile Val Val Gly Val Ile TyrAsn Lys Gly Phe 515 520 525 Leu His Lys Asn Phe Tyr Ile Phe Gly TyrLeu Ser Pro Ala Val Val 530 535 540 Val Gly Phe Ser Ala Ala Leu GlyTyr Arg Tyr Tyr Gly Thr Thr Lys 545 550 555 560 Val Cys Trp Leu SerThr Glu Asn Asn Phe Ile Trp Ser Phe Ile Gly 565 570 575 Pro Ala CysLeu Ile Ile Leu Val Asn Leu Leu Ala Phe Gly Val Ile 580 585 590 IleTyr Lys Val Phe Arg His Thr Ala Gly Leu Lys Pro Glu Val Ser 595 600605 Cys Phe Glu Asn Ile Arg Ser Cys Ala Arg Gly Ala Leu Ala Leu Leu610 615 620 Phe Leu Leu Gly Thr Thr Trp Ile Phe Gly Val Leu His ValVal His 625 630 635 640 Ala Ser Val Val Thr Ala Tyr Leu Phe Thr ValSer Asn Ala Phe Gln 645 650 655 Gly Met Phe Ile Phe Leu Phe Leu CysVal Leu Ser Arg Lys Ile Gln 660 665 670 Glu Glu Tyr Tyr Arg Leu PheLys Asn Val Pro Cys Cys Phe Gly Cys 675 680 685 Leu Arg 690 50 589DNA Homo sapiens modified_base (61)..(61) a, t, c or g 50tggaaacata tcctccctca tatgaatatg gatggagact acataaatat atttccaaag60 ngaaaagccg gcatatggat tcaaatggca atgttgcagt tgcatttttatattataaga 120 gtattggtcc ctttgctttc atcatctgac aacttcttattgaaacctca aaattatgat 180 aattctgaag aggaggaaag agtcatatcttcagtaattt cagtctcaat gagctcaaac 240 ccacccacat tatatgaacttgaaaaaata acatttacat taagtcatcg aaaggtcaca 300 gataggtataggagtctatg tggcattttg gaatactcac ctgataccat gaatggcagc 360tggtcttcag agggctgtga gctgacatac tcaaatgaga cccacacctc atgccgctgt420 aatcacctga cacattttgc aattttgatg tcctctggtc cttccattggtattaaagat 480 tataatattc ttacaaggat cactcaacta ggaataattatttcactgat ttgtcttgcc 540 atatgcattt ttaccttctg gttcttcagtgaaattcaaa gcaccagga 589 51 20 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 51ggtaatgagc tccattacag 20 52 18 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 52ggagtagaaa gcgcatgg 18 53 22 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 53 cacctgataccatgaatggc ag 22 54 18 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 54 cgagctcgaattaattcg 18 55 18 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 55 ggatctcctg agctcagg 1856 23 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 56 cctagttgag tgatccttgt aag 23 5750 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 57 atgagaccca cacctcatgc cgctgtaatcacctgacaca ttttgcaatt 50 58 2137 DNA Homo sapiens 58 gctcccagccaagaacctcg gggccgctgc gcggtgggga ggagttcccc gaaacccggc 60cgctaagcga ggcctcctcc tcccgcagat ccgaacggcc tgggcggggt caccccggct120 gggacaagaa gccgccgcct gcctgcccgg gcccggggag ggggctggggctggggccgg 180 aggcggggtg tgagtgggtg tgtgcggggg gcggaggcttgatgcaatcc cgataagaaa 240 tgctcgggtg tcttgggcac ctacccgtggggcccgtaag gcgctactat ataaggctgc 300 cggcccggag ccgccgcgccgtcagagcag gagcgctgcg tccaggatct agggccacga 360 ccatcccaacccggcactca cagccccgca gcgcatcccg gtcgccgccc agcctcccgc 420acccccatcg ccggagctgc gccgagagcc ccagggaggt gccatgcgga gcgggtgtgt480 ggtggtccac gtatggatcc tggccggcct ctggctggcc gtggccgggcgccccctcgc 540 cttctcggac gcggggcccc acgtgcacta cggctggggcgaccccatcc gcctgcggca 600 cctgtacacc tccggccccc acgggctctccagctgcttc ctgcgcatcc gtgccgacgg 660 cgtcgtggac tgcgcgcggggccagagcgc gcacagtttg ctggagatca aggcagtcgc 720 tctgcggaccgtggccatca agggcgtgca cagcgtgcgg tacctctgca tgggcgccga 780cggcaagatg caggggctgc ttcagtactc ggaggaagac tgtgctttcg aggaggagat840 ccgcccagat ggctacaatg tgtaccgatc cgagaagcac cgcctcccggtctccctgag 900 cagtgccaaa cagcggcagc tgtacaagaa cagaggctttcttccactct ctcatttcct 960 gcccatgctg cccatggtcc cagaggagcctgaggacctc aggggccact tggaatctga 1020 catgttctct tcgcccctggagaccgacag catggaccca tttgggcttg tcaccggact 1080 ggaggccgtgaggagtccca gctttgagaa gtaactgaga ccatgcccgg gcctcttcac 1140tgctgccagg ggctgtggta cctgcagcgt gggggacgtg cttctacaag aacagtcctg1200 agtccacgtt ctgtttagct ttaggaagaa acatctagaa gttgtacatattcagagttt 1260 tccattggca gtgccagttt ctagccaata gacttgtctgatcataacat tgtaagcctg 1320 tagcttgccc agctgctgcc tgggcccccattctgctccc tcgaggttgc tggacaagct 1380 gctgcactgt ctcagttctgcttgaatacc tccatcgatg gggaactcac ttcctttgga 1440 aaaattcttatgtcaagctg aaattctcta attttttctc atcacttccc caggagcagc 1500cagaagacag gcagtagttt taatttcagg aacaggtgat ccactctgta aaacagcagg1560 taaatttcac tcaaccccat gtgggaattg atctatatct ctacttccagggaccatttg 1620 cccttcccaa atccctccag gccagaactg actggagcaggcatggccca ccaggcttca 1680 ggagtagggg aagcctggag ccccactccagccctgggac aacttgagaa ttccccctga 1740 ggccagttct gtcatggatgctgtcctgag aataacttgc tgtcccggtg tcacctgctt 1800 ccatctcccagcccaccagc cctctgccca cctcacatgc ctccccatgg attggggcct 1860cccaggcccc ccaccttatg tcaacctgca cttcttgttc aaaaatcagg aaaagaaaag1920 atttgaagac cccaagtctt gtcaataact tgctgtgtgg aagcagcgggggaagaccta 1980 gaaccctttc cccagcactt ggttttccaa catgatatttatgagtaatt tattttgata 2040 tgtacatctc ttattttctt acattatttatgcccccaaa ttatatttat gtatgtaagt 2100 gaggtttgtt ttgtatattaaaatggagtt tgtttgt 2137 59 216 PRT Homo sapiens 59 Met Arg Ser GlyCys Val Val Val His Val Trp Ile Leu Ala Gly Leu 1 5 10 15 Trp LeuAla Val Ala Gly Arg Pro Leu Ala Phe Ser Asp Ala Gly Pro 20 25 30His Val His Tyr Gly Trp Gly Asp Pro Ile Arg Leu Arg His Leu Tyr 3540 45 Thr Ser Gly Pro His Gly Leu Ser Ser Cys Phe Leu Arg Ile ArgAla 50 55 60 Asp Gly Val Val Asp Cys Ala Arg Gly Gln Ser Ala HisSer Leu Leu 65 70 75 80 Glu Ile Lys Ala Val Ala Leu Arg Thr Val AlaIle Lys Gly Val His 85 90 95 Ser Val Arg Tyr Leu Cys Met Gly AlaAsp Gly Lys Met Gln Gly Leu 100 105 110 Leu Gln Tyr Ser Glu Glu AspCys Ala Phe Glu Glu Glu Ile Arg Pro 115 120 125 Asp Gly Tyr Asn ValTyr Arg Ser Glu Lys His Arg Leu Pro Val Ser 130 135 140 Leu Ser SerAla Lys Gln Arg Gln Leu Tyr Lys Asn Arg Gly Phe Leu 145 150 155 160Pro Leu Ser His Phe Leu Pro Met Leu Pro Met Val Pro Glu Glu Pro 165170 175 Glu Asp Leu Arg Gly His Leu Glu Ser Asp Met Phe Ser Ser ProLeu 180 185 190 Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr GlyLeu Glu Ala 195 200 205 Val Arg Ser Pro Ser Phe Glu Lys 210 215 6026 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 60 atccgcccag atggctacaa tgtgta 2661 42 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 61 gcctcccggt ctccctgagc agtgccaaacagcggcagtg ta 42 62 22 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 62 ccagtccggtgacaagccca aa 22 63 1295 DNA Homo sapiens 63 cccagaagtt caagggcccccggcctcctg cgctcctgcc gccgggaccc tcgacctcct 60 cagagcagccggctgccgcc ccgggaagat ggcgaggagg agccgccacc gcctcctcct 120gctgctgctg cgctacctgg tggtcgccct gggctatcat aaggcctatg ggttttctgc180 cccaaaagac caacaagtag tcacagcagt agagtaccaa gaggctattttagcctgcaa 240 aaccccaaag aagactgttt cctccagatt agagtggaagaaactgggtc ggagtgtctc 300 ctttgtctac tatcaacaga ctcttcaaggtgattttaaa aatcgagctg agatgataga 360 tttcaatatc cggatcaaaaatgtgacaag aagtgatgcg gggaaatatc gttgtgaagt 420 tagtgccccatctgagcaag gccaaaacct ggaagaggat acagtcactc tggaagtatt 480agtggctcca gcagttccat catgtgaagt accctcttct gctctgagtg gaactgtggt540 agagctacga tgtcaagaca aagaagggaa tccagctcct gaatacacatggtttaagga 600 tggcatccgt ttgctagaaa atcccagact tggctcccaaagcaccaaca gctcatacac 660 aatgaataca aaaactggaa ctctgcaatttaatactgtt tccaaactgg acactggaga 720 atattcctgt gaagcccgcaattctgttgg atatcgcagg tgtcctggga aacgaatgca 780 agtagatgatctcaacataa gtggcatcat agcagccgta gtagttgtgg ccttagtgat 840ttccgtttgt ggccttggtg tatgctatgc tcagaggaaa ggctactttt caaaagaaac900 ctccttccag aagagtaatt cttcatctaa agccacgaca atgagtgaaaatgtgcagtg 960 gctcacgcct gtaatcccag cactttggaa ggccgcggcgggcggatcac gaggtcagga 1020 gttctagacc agtctggcca atatggtgaaaccccatctc tactaaaata caaaaattag 1080 ctgggcatgg tggcatgtgcctgcagttcc agctgcttgg gagacaggag aatcacttga 1140 acccgggaggcggaggttgc agtgagctga gatcacgcca ctgcagtcca gcctgggtaa 1200cagagcaaga ttccatctca aaaaataaaa taaataaata aataaatact ggtttttacc1260 tgtagaattc ttacaataaa tatagcttga tattc 1295 64 312 PRT Homosapiens 64 Met Ala Arg Arg Ser Arg His Arg Leu Leu Leu Leu Leu LeuArg Tyr 1 5 10 15 Leu Val Val Ala Leu Gly Tyr His Lys Ala Tyr GlyPhe Ser Ala Pro 20 25 30 Lys Asp Gln Gln Val Val Thr Ala Val GluTyr Gln Glu Ala Ile Leu 35 40 45 Ala Cys Lys Thr Pro Lys Lys ThrVal Ser Ser Arg Leu Glu Trp Lys 50 55 60 Lys Leu Gly Arg Ser ValSer Phe Val Tyr Tyr Gln Gln Thr Leu Gln 65 70 75 80 Gly Asp Phe LysAsn Arg Ala Glu Met Ile Asp Phe Asn Ile Arg Ile 85 90 95 Lys AsnVal Thr Arg Ser Asp Ala Gly Lys Tyr Arg Cys Glu Val Ser 100 105 110Ala Pro Ser Glu Gln Gly Gln Asn Leu Glu Glu Asp Thr Val Thr Leu 115120 125 Glu Val Leu Val Ala Pro Ala Val Pro Ser Cys Glu Val Pro SerSer 130 135 140 Ala Leu Ser Gly Thr Val Val Glu Leu Arg Cys Gln AspLys Glu Gly 145 150 155 160 Asn Pro Ala Pro Glu Tyr Thr Trp Phe LysAsp Gly Ile Arg Leu Leu 165 170 175 Glu Asn Pro Arg Leu Gly Ser GlnSer Thr Asn Ser Ser Tyr Thr Met 180 185 190 Asn Thr Lys Thr Gly ThrLeu Gln Phe Asn Thr Val Ser Lys Leu Asp 195 200 205 Thr Gly Glu TyrSer Cys Glu Ala Arg Asn Ser Val Gly Tyr Arg Arg 210 215 220 Cys ProGly Lys Arg Met Gln Val Asp Asp Leu Asn Ile Ser Gly Ile 225 230 235240 Ile Ala Ala Val Val Val Val Ala Leu Val Ile Ser Val Cys Gly Leu245 250 255 Gly Val Cys Tyr Ala Gln Arg Lys Gly Tyr Phe Ser Lys GluThr Ser 260 265 270 Phe Gln Lys Ser Asn Ser Ser Ser Lys Ala Thr ThrMet Ser Glu Asn 275 280 285 Val Gln Trp Leu Thr Pro Val Ile Pro AlaLeu Trp Lys Ala Ala Ala 290 295 300 Gly Gly Ser Arg Gly Gln Glu Phe305 310 65 22 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 65 atcgttgtga agttagtgcccc 22 66 23 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 66 acctgcgata tccaacagaattg 23 67 48 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 67 ggaagaggat acagtcactctggaagtatt agtggctcca gcagttcc 48 68 2639 DNA Homo sapiens 68gacatcggag gtgggctagc actgaaactg cttttcaaga cgaggaagag gaggagaaag60 agaaagaaga ggaagatgtt gggcaacatt tatttaacat gctccacagcccggaccctg 120 gcatcatgct gctattcctg caaatactga agaagcatgggatttaaata ttttacttct 180 aaataaatga attactcaat ctcctatgaccatctataca tactccacct tcaaaaagta 240 catcaatatt atatcattaaggaaatagta accttctctt ctccaatatg catgacattt 300 ttggacaatgcaattgtggc actggcactt atttcagtga agaaaaactt tgtggttcta 360tggcattcat catttgacaa atgcaagcat cttccttatc aatcagctcc tattgaactt420 actagcactg actgtggaat ccttaagggc ccattacatt tctgaagaagaaagctaaga 480 tgaaggacat gccactccga attcatgtgc tacttggcctagctatcact acactagtac 540 aagctgtaga taaaaaagtg gattgtccacggttatgtac gtgtgaaatc aggccttggt 600 ttacacccag atccatttatatggaagcat ctacagtgga ttgtaatgat ttaggtcttt 660 taactttcccagccagattg ccagctaaca cacagattct tctcctacag actaacaata 720ttgcaaaaat tgaatactcc acagactttc cagtaaacct tactggcctg gatttatctc780 aaaacaattt atcttcagtc accaatatta atgtaaaaaa gatgcctcagctcctttctg 840 tgtacctaga ggaaaacaaa cttactgaac tgcctgaaaaatgtctgtcc gaactgagca 900 acttacaaga actctatatt aatcacaacttgctttctac aatttcacct ggagccttta 960 ttggcctaca taatcttcttcgacttcatc tcaattcaaa tagattgcag atgatcaaca 1020 gtaagtggtttgatgctctt ccaaatctag agattctgat gattggggaa aatccaatta 1080tcagaatcaa agacatgaac tttaagcctc ttatcaatct tcgcagcctg gttatagctg1140 gtataaacct cacagaaata ccagataacg ccttggttgg actggaaaacttagaaagca 1200 tctcttttta cgataacagg cttattaaag taccccatgttgctcttcaa aaagttgtaa 1260 atctcaaatt tttggatcta aataaaaatcctattaatag aatacgaagg ggtgatttta 1320 gcaatatgct acacttaaaagagttgggga taaataatat gcctgagctg atttccatcg 1380 atagtcttgctgtggataac ctgccagatt taagaaaaat agaagctact aacaacccta 1440gattgtctta cattcacccc aatgcatttt tcagactccc caagctggaa tcactcatgc1500 tgaacagcaa tgctctcagt gccctgtacc atggtaccat tgagtctctgccaaacctca 1560 aggaaatcag catacacagt aaccccatca ggtgtgactgtgtcatccgt tggatgaaca 1620 tgaacaaaac caacattcga ttcatggagccagattcact gttttgcgtg gacccacctg 1680 aattccaagg tcagaatgttcggcaagtgc atttcaggga catgatggaa atttgtctcc 1740

ctcttatagc tcctgagagc tttccttcta atctaaatgt agaagctggg agctatgttt1800 cctttcactg tagagctact gcagaaccac agcctgaaat ctactggataacaccttctg 1860 gtcaaaaact cttgcctaat accctgacag acaagttctatgtccattct gagggaacac 1920 tagatataaa tggcgtaact cccaaagaagggggtttata tacttgtata gcaactaacc 1980 tagttggcgc tgacttgaagtctgttatga tcaaagtgga tggatctttt ccacaagata 2040 acaatggctctttgaatatt aaaataagag atattcaggc caattcagtt ttggtgtcct 2100ggaaagcaag ttctaaaatt ctcaaatcta gtgttaaatg gacagccttt gtcaagactg2160 aaaattctca tgctgcgcaa agtgctcgaa taccatctga tgtcaaggtatataatctta 2220 ctcatctgaa tccatcaact gagtataaaa tttgtattgatattcccacc atctatcaga 2280 aaaacagaaa aaaatgtgta aatgtcaccaccaaaggttt gcaccctgat caaaaagagt 2340 atgaaaagaa taataccacaacacttatgg cctgtcttgg aggccttctg gggattattg 2400 gtgtgatatgtcttatcagc tgcctctctc cagaaatgaa ctgtgatggt ggacacagct 2460atgtgaggaa ttacttacag aaaccaacct ttgcattagg tgagctttat cctcctctga2520 taaatctctg ggaagcagga aaagaaaaaa gtacatcact gaaagtaaaagcaactgtta 2580 taggtttacc aacaaatatg tcctaaaaac caccaaggaaacctactcca aaaatgaac 2639 69 708 PRT Homo sapiens 69 Met Lys AspMet Pro Leu Arg Ile His Val Leu Leu Gly Leu Ala Ile 1 5 10 15 ThrThr Leu Val Gln Ala Val Asp Lys Lys Val Asp Cys Pro Arg Leu 20 2530 Cys Thr Cys Glu Ile Arg Pro Trp Phe Thr Pro Arg Ser Ile Tyr Met35 40 45 Glu Ala Ser Thr Val Asp Cys Asn Asp Leu Gly Leu Leu ThrPhe Pro 50 55 60 Ala Arg Leu Pro Ala Asn Thr Gln Ile Leu Leu LeuGln Thr Asn Asn 65 70 75 80 Ile Ala Lys Ile Glu Tyr Ser Thr Asp PhePro Val Asn Leu Thr Gly 85 90 95 Leu Asp Leu Ser Gln Asn Asn LeuSer Ser Val Thr Asn Ile Asn Val 100 105 110 Lys Lys Met Pro Gln LeuLeu Ser Val Tyr Leu Glu Glu Asn Lys Leu 115 120 125 Thr Glu Leu ProGlu Lys Cys Leu Ser Glu Leu Ser Asn Leu Gln Glu 130 135 140 Leu TyrIle Asn His Asn Leu Leu Ser Thr Ile Ser Pro Gly Ala Phe 145 150 155160 Ile Gly Leu His Asn Leu Leu Arg Leu His Leu Asn Ser Asn Arg Leu165 170 175 Gln Met Ile Asn Ser Lys Trp Phe Asp Ala Leu Pro Asn LeuGlu Ile 180 185 190 Leu Met Ile Gly Glu Asn Pro Ile Ile Arg Ile LysAsp Met Asn Phe 195 200 205 Lys Pro Leu Ile Asn Leu Arg Ser Leu ValIle Ala Gly Ile Asn Leu 210 215 220 Thr Glu Ile Pro Asp Asn Ala LeuVal Gly Leu Glu Asn Leu Glu Ser 225 230 235 240 Ile Ser Phe Tyr AspAsn Arg Leu Ile Lys Val Pro His Val Ala Leu 245 250 255 Gln Lys ValVal Asn Leu Lys Phe Leu Asp Leu Asn Lys Asn Pro Ile 260 265 270 AsnArg Ile Arg Arg Gly Asp Phe Ser Asn Met Leu His Leu Lys Glu 275 280285 Leu Gly Ile Asn Asn Met Pro Glu Leu Ile Ser Ile Asp Ser Leu Ala290 295 300 Val Asp Asn Leu Pro Asp Leu Arg Lys Ile Glu Ala Thr AsnAsn Pro 305 310 315 320 Arg Leu Ser Tyr Ile His Pro Asn Ala Phe PheArg Leu Pro Lys Leu 325 330 335 Glu Ser Leu Met Leu Asn Ser Asn AlaLeu Ser Ala Leu Tyr His Gly 340 345 350 Thr Ile Glu Ser Leu Pro AsnLeu Lys Glu Ile Ser Ile His Ser Asn 355 360 365 Pro Ile Arg Cys AspCys Val Ile Arg Trp Met Asn Met Asn Lys Thr 370 375 380 Asn Ile ArgPhe Met Glu Pro Asp Ser Leu Phe Cys Val Asp Pro Pro 385 390 395 400Glu Phe Gln Gly Gln Asn Val Arg Gln Val His Phe Arg Asp Met Met 405410 415 Glu Ile Cys Leu Pro Leu Ile Ala Pro Glu Ser Phe Pro Ser AsnLeu 420 425 430 Asn Val Glu Ala Gly Ser Tyr Val Ser Phe His Cys ArgAla Thr Ala 435 440 445 Glu Pro Gln Pro Glu Ile Tyr Trp Ile Thr ProSer Gly Gln Lys Leu 450 455 460 Leu Pro Asn Thr Leu Thr Asp Lys PheTyr Val His Ser Glu Gly Thr 465 470 475 480 Leu Asp Ile Asn Gly ValThr Pro Lys Glu Gly Gly Leu Tyr Thr Cys 485 490 495 Ile Ala Thr AsnLeu Val Gly Ala Asp Leu Lys Ser Val Met Ile Lys 500 505 510 Val AspGly Ser Phe Pro Gln Asp Asn Asn Gly Ser Leu Asn Ile Lys 515 520 525Ile Arg Asp Ile Gln Ala Asn Ser Val Leu Val Ser Trp Lys Ala Ser 530535 540 Ser Lys Ile Leu Lys Ser Ser Val Lys Trp Thr Ala Phe Val LysThr 545 550 555 560 Glu Asn Ser His Ala Ala Gln Ser Ala Arg Ile ProSer Asp Val Lys 565 570 575 Val Tyr Asn Leu Thr His Leu Asn Pro SerThr Glu Tyr Lys Ile Cys 580 585 590 Ile Asp Ile Pro Thr Ile Tyr GlnLys Asn Arg Lys Lys Cys Val Asn 595 600 605 Val Thr Thr Lys Gly LeuHis Pro Asp Gln Lys Glu Tyr Glu Lys Asn 610 615 620 Asn Thr Thr ThrLeu Met Ala Cys Leu Gly Gly Leu Leu Gly Ile Ile 625 630 635 640 GlyVal Ile Cys Leu Ile Ser Cys Leu Ser Pro Glu Met Asn Cys Asp 645 650655 Gly Gly His Ser Tyr Val Arg Asn Tyr Leu Gln Lys Pro Thr Phe Ala660 665 670 Leu Gly Glu Leu Tyr Pro Pro Leu Ile Asn Leu Trp Glu AlaGly Lys 675 680 685 Glu Lys Ser Thr Ser Leu Lys Val Lys Ala Thr ValIle Gly Leu Pro 690 695 700 Thr Asn Met Ser 705 70 1305 DNA Homosapiens 70 gcccgggact ggcgcaaggt gcccaagcaa ggaaagaaat aatgaagagacacatgtgtt 60 agctgcagcc ttttgaaaca cgcaagaagg aaatcaatagtgtggacagg gctggaacct 120 ttaccacgct tgttggagta gatgaggaatgggctcgtga ttatgctgac attccagcat 180 gaatctggta gacctgtggttaacccgttc cctctccatg tgtctcctcc tacaaagttt 240 tgttcttatgatactgtgct ttcattctgc cagtatgtgt cccaagggct gtctttgttc 300ttcctctggg ggtttaaatg tcacctgtag caatgcaaat ctcaaggaaa tacctagaga360 tcttcctcct gaaacagtct tactgtatct ggactccaat cagatcacatctattcccaa 420 tgaaattttt aaggacctcc atcaactgag agttctcaacctgtccaaaa atggcattga 480 gtttatcgat gagcatgcct tcaaaggagtagctgaaacc ttgcagactc tggacttgtc 540 cgacaatcgg attcaaagtgtgcacaaaaa tgccttcaat aacctgaagg ccagggccag 600 aattgccaacaacccctggc actgcgactg tactctacag caagttctga ggagcatggc 660gtccaatcat gagacagccc acaacgtgat ctgtaaaacg tccgtgttgg atgaacatgc720 tggcagacca ttcctcaatg ctgccaacga cgctgacctt tgtaacctccctaaaaaaac 780 taccgattat gccatgctgg tcaccatgtt tggctggttcactatggtga tctcatatgt 840 ggtatattat gtgaggcaaa atcaggaggatgcccggaga cacctcgaat acttgaaatc 900 cctgccaagc aggcagaagaaagcagatga acctgatgat attagcactg tggtatagtg 960 tccaaactgactgtcattga gaaagaaaga aagtagtttg cgattgcagt agaaataagt 1020ggtttacttc tcccatccat tgtaaacatt tgaaactttg tatttcagtt ttttttgaat1080 tatgccactg ctgaactttt aacaaacact acaacataaa taatttgagtttaggtgatc 1140 caccccttaa ttgtaccccc gatggtatat ttctgagtaagctactatct gaacattagt 1200 tagatccatc tcactattta ataatgaaatttattttttt aatttaaaag caaataaaag 1260 cttaactttg aaccatgggaaaaaaaaaaa aaaaaaaaaa aaaca 1305 71 259 PRT Homo sapiens 71 Met AsnLeu Val Asp Leu Trp Leu Thr Arg Ser Leu Ser Met Cys Leu 1 5 10 15Leu Leu Gln Ser Phe Val Leu Met Ile Leu Cys Phe His Ser Ala Ser 2025 30 Met Cys Pro Lys Gly Cys Leu Cys Ser Ser Ser Gly Gly Leu AsnVal 35 40 45 Thr Cys Ser Asn Ala Asn Leu Lys Glu Ile Pro Arg AspLeu Pro Pro 50 55 60 Glu Thr Val Leu Leu Tyr Leu Asp Ser Asn GlnIle Thr Ser Ile Pro 65 70 75 80 Asn Glu Ile Phe Lys Asp Leu His GlnLeu Arg Val Leu Asn Leu Ser 85 90 95 Lys Asn Gly Ile Glu Phe IleAsp Glu His Ala Phe Lys Gly Val Ala 100 105 110 Glu Thr Leu Gln ThrLeu Asp Leu Ser Asp Asn Arg Ile Gln Ser Val 115 120 125 His Lys AsnAla Phe Asn Asn Leu Lys Ala Arg Ala Arg Ile Ala Asn 130 135 140 AsnPro Trp His Cys Asp Cys Thr Leu Gln Gln Val Leu Arg Ser Met 145 150155 160 Ala Ser Asn His Glu Thr Ala His Asn Val Ile Cys Lys Thr SerVal 165 170 175 Leu Asp Glu His Ala Gly Arg Pro Phe Leu Asn Ala AlaAsn Asp Ala 180 185 190 Asp Leu Cys Asn Leu Pro Lys Lys Thr Thr AspTyr Ala Met Leu Val 195 200 205 Thr Met Phe Gly Trp Phe Thr Met ValIle Ser Tyr Val Val Tyr Tyr 210 215 220 Val Arg Gln Asn Gln Glu AspAla Arg Arg His Leu Glu Tyr Leu Lys 225 230 235 240 Ser Leu Pro SerArg Gln Lys Lys Ala Asp Glu Pro Asp Asp Ile Ser 245 250 255 Thr ValVal 72 2290 DNA Homo sapiens 72 accgagccga gcggaccgaa ggcgcgcccgagatgcaggt gagcaagagg atgctggcgg 60 ggggcgtgag gagcatgcccagccccctcc tggcctgctg gcagcccatc ctcctgctgg 120 tgctgggctcagtgctgtca ggctcggcca cgggctgccc gccccgctgc gagtgctccg 180cccaggaccg cgctgtgctg tgccaccgca agtgctttgt ggcagtcccc gagggcatcc240 ccaccgagac gcgcctgctg gacctaggca agaaccgcat caaaacgctcaaccaggacg 300 agttcgccag cttcccgcac ctggaggagc tggagctcaacgagaacatc gtgagcgccg 360 tggagcccgg cgccttcaac aacctcttcaacctccggac gctgggtctc cgcagcaacc 420 gcctgaagct catcccgctaggcgtcttca ctggcctcag caacctgacc aagcaggaca 480 tcagcgagaacaagatcgtt atcctactgg actacatgtt tcaggacctg tacaacctca 540agtcactgga ggttggcgac aatgacctcg tctacatctc tcaccgcgcc ttcagcggcc600 tcaacagcct ggagcagctg acgctggaga aatgcaacct gacctccatccccaccgagg 660 cgctgtccca cctgcacggc ctcatcgtcc tgaggctccggcacctcaac atcaatgcca 720 tccgggacta ctccttcaag aggctgtaccgactcaaggt cttggagatc tcccactggc 780 cctacttgga caccatgacacccaactgcc tctacggcct caacctgacg tccctgtcca 840 tcacacactgcaatctgacc gctgtgccct acctggccgt ccgccaccta gtctatctcc 900gcttcctcaa cctctcctac aaccccatca gcaccattga gggctccatg ttgcatgagc960 tgctccggct gcaggagatc cagctggtgg gcgggcagct ggccgtggtggagccctatg 1020 ccttccgcgg cctcaactac ctgcgcgtgc tcaatgtctctggcaaccag ctgaccacac 1080 tggaggaatc agtcttccac tcggtgggcaacctggagac actcatcctg gactccaacc 1140 cgctggcctg cgactgtcggctcctgtggg tgttccggcg ccgctggcgg ctcaacttca 1200 accggcagcagcccacgtgc gccacgcccg agtttgtcca gggcaaggag ttcaaggact 1260tccctgatgt gctactgccc aactacttca cctgccgccg cgcccgcatc cgggaccgca1320 aggcccagca ggtgtttgtg gacgagggcc acacggtgca gtttgtgtgccgggccgatg 1380 gcgacccgcc gcccgccatc ctctggctct caccccgaaagcacctggtc tcagccaaga 1440 gcaatgggcg gctcacagtc ttccctgatggcacgctgga ggtgcgctac gcccaggtac 1500 aggacaacgg cacgtacctgtgcatcgcgg ccaacgcggg cggcaacgac tccatgcccg 1560 cccacctgcatgtgcgcagc tactcgcccg actggcccca tcagcccaac aagaccttcg 1620ctttcatctc caaccagccg ggcgagggag aggccaacag cacccgcgcc actgtgcctt1680 tccccttcga catcaagacc ctcatcatcg ccaccaccat gggcttcatctctttcctgg 1740 gcgtcgtcct cttctgcctg gtgctgctgt ttctctggagccggggcaag ggcaacacaa 1800 agcacaacat cgagatcgag tatgtgccccgaaagtcgga cgcaggcatc agctccgccg 1860 acgcgccccg caagttcaacatgaagatga tatgaggccg gggcgggggg cagggacccc 1920 cgggcggccgggcaggggaa ggggcctggt cgccacctgc tcactctcca gtccttccca 1980cctcctccct acccttctac acacgttctc tttctccctc ccgcctccgt cccctgctgc2040 cccccgccag ccctcaccac ctgccctcct tctaccagga cctcagaagcccagacctgg 2100 ggaccccacc tacacagggg cattgacaga ctggagttgaaagccgacga accgacacgc 2160 ggcagagtca ataattcaat aaaaaagttacgaactttct ctgtaacttg ggtttcaata 2220 attatggatt tttatgaaaacttgaaataa taaaaagaga aaaaaactaa aaaaaaaaaa 2280 aaaaaaaaaa 2290 73620 PRT Homo sapiens 73 Met Gln Val Ser Lys Arg Met Leu Ala Gly GlyVal Arg Ser Met Pro 1 5 10 15 Ser Pro Leu Leu Ala Cys Trp Gln ProIle Leu Leu Leu Val Leu Gly 20 25 30 Ser Val Leu Ser Gly Ser AlaThr Gly Cys Pro Pro Arg Cys Glu Cys 35 40 45 Ser Ala Gln Asp ArgAla Val Leu Cys His Arg Lys Cys Phe Val Ala 50 55 60 Val Pro GluGly Ile Pro Thr Glu Thr Arg Leu Leu Asp Leu Gly Lys 65 70 75 80 AsnArg Ile Lys Thr Leu Asn Gln Asp Glu Phe Ala Ser Phe Pro His 85 9095 Leu Glu Glu Leu Glu Leu Asn Glu Asn Ile Val Ser Ala Val Glu Pro100 105 110 Gly Ala Phe Asn Asn Leu Phe Asn Leu Arg Thr Leu Gly LeuArg Ser 115 120 125 Asn Arg Leu Lys Leu Ile Pro Leu Gly Val Phe ThrGly Leu Ser Asn 130 135 140 Leu Thr Lys Gln Asp Ile Ser Glu Asn LysIle Val Ile Leu Leu Asp 145 150 155 160 Tyr Met Phe Gln Asp Leu TyrAsn Leu Lys Ser Leu Glu Val Gly Asp 165 170 175 Asn Asp Leu Val TyrIle Ser His Arg Ala Phe Ser Gly Leu Asn Ser 180 185 190 Leu Glu GlnLeu Thr Leu Glu Lys Cys Asn Leu Thr Ser Ile Pro Thr 195 200 205 GluAla Leu Ser His Leu His Gly Leu Ile Val Leu Arg Leu Arg His 210 215220 Leu Asn Ile Asn Ala Ile Arg Asp Tyr Ser Phe Lys Arg Leu Tyr Arg225 230 235 240 Leu Lys Val Leu Glu Ile Ser His Trp Pro Tyr Leu AspThr Met Thr 245 250 255 Pro Asn Cys Leu Tyr Gly Leu Asn Leu Thr SerLeu Ser Ile Thr His 260 265 270 Cys Asn Leu Thr Ala Val Pro Tyr LeuAla Val Arg His Leu Val Tyr 275 280 285 Leu Arg Phe Leu Asn Leu SerTyr Asn Pro Ile Ser Thr Ile Glu Gly 290 295 300 Ser Met Leu His GluLeu Leu Arg Leu Gln Glu Ile Gln Leu Val Gly 305 310 315 320 Gly GlnLeu Ala Val Val Glu Pro Tyr Ala Phe Arg Gly Leu Asn Tyr 325 330 335Leu Arg Val Leu Asn Val Ser Gly Asn Gln Leu Thr Thr Leu Glu Glu 340345 350 Ser Val Phe His Ser Val Gly Asn Leu Glu Thr Leu Ile Leu AspSer 355 360 365 Asn Pro Leu Ala Cys Asp Cys Arg Leu Leu Trp Val PheArg Arg Arg 370 375 380 Trp Arg Leu Asn Phe Asn Arg Gln Gln Pro ThrCys Ala Thr Pro Glu 385 390 395 400 Phe Val Gln Gly Lys Glu Phe LysAsp Phe Pro Asp Val Leu Leu Pro 405 410 415 Asn Tyr Phe Thr Cys ArgArg Ala Arg Ile Arg Asp Arg Lys Ala Gln 420 425 430 Gln Val Phe ValAsp Glu Gly His Thr Val Gln Phe Val Cys Arg Ala 435 440 445 Asp GlyAsp Pro Pro Pro Ala Ile Leu Trp Leu Ser Pro Arg Lys His 450 455 460Leu Val Ser Ala Lys Ser Asn Gly Arg Leu Thr Val Phe Pro Asp Gly 465470 475 480 Thr Leu Glu Val Arg Tyr Ala Gln Val Gln Asp Asn Gly ThrTyr Leu 485 490 495 Cys Ile Ala Ala Asn Ala Gly Gly Asn Asp Ser MetPro Ala His Leu 500 505 510 His Val Arg Ser Tyr Ser Pro Asp Trp ProHis Gln Pro Asn Lys Thr 515 520 525 Phe Ala Phe Ile Ser Asn Gln ProGly Glu Gly Glu Ala Asn Ser Thr 530 535 540 Arg Ala Thr Val Pro PhePro Phe Asp Ile Lys Thr Leu Ile Ile Ala 545 550 555 560 Thr Thr MetGly Phe Ile Ser Phe Leu Gly Val Val Leu Phe Cys Leu 565 570 575 ValLeu Leu Phe Leu Trp Ser Arg Gly Lys Gly Asn Thr Lys His Asn 580 585590 Ile Glu Ile Glu Tyr Val Pro Arg Lys Ser Asp Ala Gly Ile Ser Ser595 600 605 Ala Asp Ala Pro Arg Lys Phe Asn Met Lys Met Ile 610 615620 74 22 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 74 tcacctggag cctttattggcc 22 75 23 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 75 ataccagcta taaccaggctgcg 23 76 52 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 76 caacagtaag tggtttgatgctcttccaaa tctagagatt ctgatgattg 50 gg 52 77 22 DNA ArtificialSequence Description of Artificial Sequence Syntheticoligonucleotide probe 77 ccatgtgtct cctcctacaa ag

22 78 23 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 78 gggaatagat gtgatctgat tgg 23 7950 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 79 cacctgtagc aatgcaaatc tcaaggaaatacctagagat cttcctcctg 50 80 22 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 80agcaaccgcc tgaagctcat cc 22 81 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe81 aaggcgcggt gaaagatgta gacg 24 82 50 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe82 gactacatgt ttcaggacct gtacaacctc aagtcactgg aggttggcga 50 831685 DNA Homo sapiens 83 cccacgcgtc cgcacctcgg ccccgggctccgaagcggct cgggggcgcc ctttcggtca 60 acatcgtagt ccaccccctccccatcccca gcccccgggg attcaggctc gccagcgccc 120 agccagggagccggccggga agcgcgatgg gggccccagc cgcctcgctc ctgctcctgc 180tcctgctgtt cgcctgctgc tgggcgcccg gcggggccaa cctctcccag gacgacagcc240 agccctggac atctgatgaa acagtggtgg ctggtggcac cgtggtgctcaagtgccaag 300 tgaaagatca cgaggactca tccctgcaat ggtctaaccctgctcagcag actctctact 360 ttggggagaa gagagccctt cgagataatcgaattcagct ggttacctct acgccccacg 420 agctcagcat cagcatcagcaatgtggccc tggcagacga gggcgagtac acctgctcaa 480 tcttcactatgcctgtgcga actgccaagt ccctcgtcac tgtgctagga attccacaga 540agcccatcat cactggttat aaatcttcat tacgggaaaa agacacagcc accctaaact600 gtcagtcttc tgggagcaag cctgcagccc ggctcacctg gagaaagggtgaccaagaac 660 tccacggaga accaacccgc atacaggaag atcccaatggtaaaaccttc actgtcagca 720 gctcggtgac attccaggtt acccgggaggatgatggggc gagcatcgtg tgctctgtga 780 accatgaatc tctaaagggagctgacagat ccacctctca acgcattgaa gttttataca 840 caccaactgcgatgattagg ccagaccctc cccatcctcg tgagggccag aagctgttgc 900tacactgtga gggtcgcggc aatccagtcc cccagcagta cctatgggag aaggagggca960 gtgtgccacc cctgaagatg acccaggaga gtgccctgat cttccctttcctcaacaaga 1020 gtgacagtgg cacctacggc tgcacagcca ccagcaacatgggcagctac aaggcctact 1080 acaccctcaa tgttaatgac cccagtccggtgccctcctc ctccagcacc taccacgcca 1140 tcatcggtgg gatcgtggctttcattgtct tcctgctgct catcatgctc atcttccttg 1200 gccactacttgatccggcac aaaggaacct acctgacaca tgaggcaaaa ggctccgacg 1260atgctccaga cgcggacacg gccatcatca atgcagaagg cgggcagtca ggaggggacg1320 acaagaagga atatttcatc tagaggcgcc tgcccacttc ctgcgccccccaggggccct 1380 gtggggactg ctggggccgt caccaacccg gacttgtacagagcaaccgc agggccgccc 1440 ctcccgcttg ctccccagcc cacccacccccctgtacaga atgtctgctt tgggtgcggt 1500 tttgtactcg gtttggaatggggagggagg agggcggggg gaggggaggg ttgccctcag 1560 ccctttccgtggcttctctg catttgggtt attattattt ttgtaacaat cccaaatcaa 1620atctgtctcc aggctggaga ggcaggagcc ctggggtgag aaaagcaaaa aacaaacaaa1680 aaaca 1685 84 398 PRT Homo sapiens 84 Met Gly Ala Pro Ala AlaSer Leu Leu Leu Leu Leu Leu Leu Phe Ala 1 5 10 15 Cys Cys Trp AlaPro Gly Gly Ala Asn Leu Ser Gln Asp Asp Ser Gln 20 25 30 Pro TrpThr Ser Asp Glu Thr Val Val Ala Gly Gly Thr Val Val Leu 35 40 45Lys Cys Gln Val Lys Asp His Glu Asp Ser Ser Leu Gln Trp Ser Asn 5055 60 Pro Ala Gln Gln Thr Leu Tyr Phe Gly Glu Lys Arg Ala Leu ArgAsp 65 70 75 80 Asn Arg Ile Gln Leu Val Thr Ser Thr Pro His Glu LeuSer Ile Ser 85 90 95 Ile Ser Asn Val Ala Leu Ala Asp Glu Gly GluTyr Thr Cys Ser Ile 100 105 110 Phe Thr Met Pro Val Arg Thr Ala LysSer Leu Val Thr Val Leu Gly 115 120 125 Ile Pro Gln Lys Pro Ile IleThr Gly Tyr Lys Ser Ser Leu Arg Glu 130 135 140 Lys Asp Thr Ala ThrLeu Asn Cys Gln Ser Ser Gly Ser Lys Pro Ala 145 150 155 160 Ala ArgLeu Thr Trp Arg Lys Gly Asp Gln Glu Leu His Gly Glu Pro 165 170 175Thr Arg Ile Gln Glu Asp Pro Asn Gly Lys Thr Phe Thr Val Ser Ser 180185 190 Ser Val Thr Phe Gln Val Thr Arg Glu Asp Asp Gly Ala Ser IleVal 195 200 205 Cys Ser Val Asn His Glu Ser Leu Lys Gly Ala Asp ArgSer Thr Ser 210 215 220 Gln Arg Ile Glu Val Leu Tyr Thr Pro Thr AlaMet Ile Arg Pro Asp 225 230 235 240 Pro Pro His Pro Arg Glu Gly GlnLys Leu Leu Leu His Cys Glu Gly 245 250 255 Arg Gly Asn Pro Val ProGln Gln Tyr Leu Trp Glu Lys Glu Gly Ser 260 265 270 Val Pro Pro LeuLys Met Thr Gln Glu Ser Ala Leu Ile Phe Pro Phe 275 280 285 Leu AsnLys Ser Asp Ser Gly Thr Tyr Gly Cys Thr Ala Thr Ser Asn 290 295 300Met Gly Ser Tyr Lys Ala Tyr Tyr Thr Leu Asn Val Asn Asp Pro Ser 305310 315 320 Pro Val Pro Ser Ser Ser Ser Thr Tyr His Ala Ile Ile GlyGly Ile 325 330 335 Val Ala Phe Ile Val Phe Leu Leu Leu Ile Met LeuIle Phe Leu Gly 340 345 350 His Tyr Leu Ile Arg His Lys Gly Thr TyrLeu Thr His Glu Ala Lys 355 360 365 Gly Ser Asp Asp Ala Pro Asp AlaAsp Thr Ala Ile Ile Asn Ala Glu 370 375 380 Gly Gly Gln Ser Gly GlyAsp Asp Lys Lys Glu Tyr Phe Ile 385 390 395 85 22 DNA ArtificialSequence Description of Artificial Sequence Syntheticoligonucleotide probe 85 gctaggaatt ccacagaagc cc 22 86 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 86 aacctggaat gtcaccgagc tg 22 87 26 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 87 cctagcacag tgacgaggga cttggc 26 88 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 88 aagacacagc caccctaaac tgtcagtcttctgggagcaa gcctgcagcc 50 89 50 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 89gccctggcag acgagggcga gtacacctgc tcaatcttca ctatgcctgt 50 90 2755DNA Homo sapiens 90 gggggttagg gaggaaggaa tccaccccca cccccccaaacccttttctt ctcctttcct 60 ggcttcggac attggagcac taaatgaacttgaattgtgt ctgtggcgag caggatggtc 120 gctgttactt tgtgatgagatcggggatga attgctcgct ttaaaaatgc tgctttggat 180 tctgttgctggagacgtctc tttgttttgc cgctggaaac gttacagggg acgtttgcaa 240agagaagatc tgttcctgca atgagataga aggggaccta cacgtagact gtgaaaaaaa300 gggcttcaca agtctgcagc gtttcactgc cccgacttcc cagttttaccatttatttct 360 gcatggcaat tccctcactc gacttttccc taatgagttcgctaactttt ataatgcggt 420 tagtttgcac atggaaaaca atggcttgcatgaaatcgtt ccgggggctt ttctggggct 480 gcagctggtg aaaaggctgcacatcaacaa caacaagatc aagtcttttc gaaagcagac 540 ttttctggggctggacgatc tggaatatct ccaggctgat tttaatttat tacgagatat 600agacccgggg gccttccagg acttgaacaa gctggaggtg ctcattttaa atgacaatct660 catcagcacc ctacctgcca acgtgttcca gtatgtgccc atcacccacctcgacctccg 720 gggtaacagg ctgaaaacgc tgccctatga ggaggtcttggagcaaatcc ctggtattgc 780 ggagatcctg ctagaggata acccttgggactgcacctgt gatctgctct ccctgaaaga 840 atggctggaa aacattcccaagaatgccct gatcggccga gtggtctgcg aagcccccac 900 cagactgcagggtaaagacc tcaatgaaac caccgaacag gacttgtgtc ctttgaaaaa 960ccgagtggat tctagtctcc cggcgccccc tgcccaagaa gagacctttg ctcctggacc1020 cctgccaact cctttcaaga caaatgggca agaggatcat gccacaccagggtctgctcc 1080 aaacggaggt acaaagatcc caggcaactg gcagatcaaaatcagaccca cagcagcgat 1140 agcgacgggt agctccagga acaaacccttagctaacagt ttaccctgcc ctgggggctg 1200 cagctgcgac cacatcccagggtcgggttt aaagatgaac tgcaacaaca ggaacgtgag 1260 cagcttggctgatttgaagc ccaagctctc taacgtgcag gagcttttcc tacgagataa 1320caagatccac agcatccgaa aatcgcactt tgtggattac aagaacctca ttctgttgga1380 tctgggcaac aataacatcg ctactgtaga gaacaacact ttcaagaaccttttggacct 1440 caggtggcta tacatggata gcaattacct ggacacgctgtcccgggaga aattcgcggg 1500 gctgcaaaac ctagagtacc tgaacgtggagtacaacgct atccagctca tcctcccggg 1560 cactttcaat gccatgcccaaactgaggat cctcattctc aacaacaacc tgctgaggtc 1620 cctgcctgtggacgtgttcg ctggggtctc gctctctaaa ctcagcctgc acaacaatta 1680cttcatgtac ctcccggtgg caggggtgct ggaccagtta acctccatca tccagataga1740 cctccacgga aacccctggg agtgctcctg cacaattgtg cctttcaagcagtgggcaga 1800 acgcttgggt tccgaagtgc tgatgagcga cctcaagtgtgagacgccgg tgaacttctt 1860 tagaaaggat ttcatgctcc tctccaatgacgagatctgc cctcagctgt acgctaggat 1920 ctcgcccacg ttaacttcgcacagtaaaaa cagcactggg ttggcggaga ccgggacgca 1980 ctccaactcctacctagaca ccagcagggt gtccatctcg gtgttggtcc cgggactgct 2040gctggtgttt gtcacctccg ccttcaccgt ggtgggcatg ctcgtgttta tcctgaggaa2100 ccgaaagcgg tccaagagac gagatgccaa ctcctccgcg tccgagattaattccctaca 2160 gacagtctgt gactcttcct actggcacaa tgggccttacaacgcagatg gggcccacag 2220 agtgtatgac tgtggctctc actcgctctcagactaagac cccaacccca ataggggagg 2280 gcagagggaa ggcgatacatccttccccac cgcaggcacc ccgggggctg gaggggcgtg 2340 tacccaaatccccgcgccat cagcctggat gggcataagt agataaataa ctgtgagctc 2400gcacaaccga aagggcctga ccccttactt agctccctcc ttgaaacaaa gagcagactg2460 tggagagctg ggagagcgca gccagctcgc tctttgctga gagccccttttgacagaaag 2520 cccagcacga ccctgctgga agaactgaca gtgccctcgccctcggcccc ggggcctgtg 2580 gggttggatg ccgcggttct atacatatatacatatatcc acatctatat agagagatag 2640 atatctattt ttcccctgtggattagcccc gtgatggctc cctgttggct acgcagggat 2700 gggcagttgcacgaaggcat gaatgtattg taaataagta actttgactt ctgac 2755 91 696 PRTHomo sapiens 91 Met Leu Leu Trp Ile Leu Leu Leu Glu Thr Ser Leu CysPhe Ala Ala 1 5 10 15 Gly Asn Val Thr Gly Asp Val Cys Lys Glu LysIle Cys Ser Cys Asn 20 25 30 Glu Ile Glu Gly Asp Leu His Val AspCys Glu Lys Lys Gly Phe Thr 35 40 45 Ser Leu Gln Arg Phe Thr AlaPro Thr Ser Gln Phe Tyr His Leu Phe 50 55 60 Leu His Gly Asn SerLeu Thr Arg Leu Phe Pro Asn Glu Phe Ala Asn 65 70 75 80 Phe Tyr AsnAla Val Ser Leu His Met Glu Asn Asn Gly Leu His Glu 85 90 95 IleVal Pro Gly Ala Phe Leu Gly Leu Gln Leu Val Lys Arg Leu His 100 105110 Ile Asn Asn Asn Lys Ile Lys Ser Phe Arg Lys Gln Thr Phe Leu Gly115 120 125 Leu Asp Asp Leu Glu Tyr Leu Gln Ala Asp Phe Asn Leu LeuArg Asp 130 135 140 Ile Asp Pro Gly Ala Phe Gln Asp Leu Asn Lys LeuGlu Val Leu Ile 145 150 155 160 Leu Asn Asp Asn Leu Ile Ser Thr LeuPro Ala Asn Val Phe Gln Tyr 165 170 175 Val Pro Ile Thr His Leu AspLeu Arg Gly Asn Arg Leu Lys Thr Leu 180 185 190 Pro Tyr Glu Glu ValLeu Glu Gln Ile Pro Gly Ile Ala Glu Ile Leu 195 200 205 Leu Glu AspAsn Pro Trp Asp Cys Thr Cys Asp Leu Leu Ser Leu Lys 210 215 220 GluTrp Leu Glu Asn Ile Pro Lys Asn Ala Leu Ile Gly Arg Val Val 225 230235 240 Cys Glu Ala Pro Thr Arg Leu Gln Gly Lys Asp Leu Asn Glu ThrThr 245 250 255 Glu Gln Asp Leu Cys Pro Leu Lys Asn Arg Val Asp SerSer Leu Pro 260 265 270 Ala Pro Pro Ala Gln Glu Glu Thr Phe Ala ProGly Pro Leu Pro Thr 275 280 285 Pro Phe Lys Thr Asn Gly Gln Glu AspHis Ala Thr Pro Gly Ser Ala 290 295 300 Pro Asn Gly Gly Thr Lys IlePro Gly Asn Trp Gln Ile Lys Ile Arg 305 310 315 320 Pro Thr Ala AlaIle Ala Thr Gly Ser Ser Arg Asn Lys Pro Leu Ala 325 330 335 Asn SerLeu Pro Cys Pro Gly Gly Cys Ser Cys Asp His Ile Pro Gly 340 345 350Ser Gly Leu Lys Met Asn Cys Asn Asn Arg Asn Val Ser Ser Leu Ala 355360 365 Asp Leu Lys Pro Lys Leu Ser Asn Val Gln Glu Leu Phe Leu ArgAsp 370 375 380 Asn Lys Ile His Ser Ile Arg Lys Ser His Phe Val AspTyr Lys Asn 385 390 395 400 Leu Ile Leu Leu Asp Leu Gly Asn Asn AsnIle Ala Thr Val Glu Asn 405 410 415 Asn Thr Phe Lys Asn Leu Leu AspLeu Arg Trp Leu Tyr Met Asp Ser 420 425 430 Asn Tyr Leu Asp Thr LeuSer Arg Glu Lys Phe Ala Gly Leu Gln Asn 435 440 445 Leu Glu Tyr LeuAsn Val Glu Tyr Asn Ala Ile Gln Leu Ile Leu Pro 450 455 460 Gly ThrPhe Asn Ala Met Pro Lys Leu Arg Ile Leu Ile Leu Asn Asn 465 470 475480 Asn Leu Leu Arg Ser Leu Pro Val Asp Val Phe Ala Gly Val Ser Leu485 490 495 Ser Lys Leu Ser Leu His Asn Asn Tyr Phe Met Tyr Leu ProVal Ala 500 505 510 Gly Val Leu Asp Gln Leu Thr Ser Ile Ile Gln IleAsp Leu His Gly 515 520 525 Asn Pro Trp Glu Cys Ser Cys Thr Ile ValPro Phe Lys Gln Trp Ala 530 535 540 Glu Arg Leu Gly Ser Glu Val LeuMet Ser Asp Leu Lys Cys Glu Thr 545 550 555 560 Pro Val Asn Phe PheArg Lys Asp Phe Met Leu Leu Ser Asn Asp Glu 565 570 575 Ile Cys ProGln Leu Tyr Ala Arg Ile Ser Pro Thr Leu Thr Ser His 580 585 590 SerLys Asn Ser Thr Gly Leu Ala Glu Thr Gly Thr His Ser Asn Ser 595 600605 Tyr Leu Asp Thr Ser Arg Val Ser Ile Ser Val Leu Val Pro Gly Leu610 615 620 Leu Leu Val Phe Val Thr Ser Ala Phe Thr Val Val Gly MetLeu Val 625 630 635 640 Phe Ile Leu Arg Asn Arg Lys Arg Ser Lys ArgArg Asp Ala Asn Ser 645 650 655 Ser Ala Ser Glu Ile Asn Ser Leu GlnThr Val Cys Asp Ser Ser Tyr 660 665 670 Trp His Asn Gly Pro Tyr AsnAla Asp Gly Ala His Arg Val Tyr Asp 675 680 685 Cys Gly Ser His SerLeu Ser Asp 690 695 92 22 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 92 gttggatctgggcaacaata ac 22 93 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 93 attgttgtgcaggctgagtt taag 24 94 45 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 94 ggtggctatacatggatagc aattacctgg acacgctgtc ccggg 45 95 2226 DNA Homo sapiens95 agtcgactgc gtcccctgta cccggcgcca gctgtgttcc tgaccccagaataactcagg 60 gctgcaccgg gcctggcagc gctccgcaca catttcctgtcgcggcctaa gggaaactgt 120 tggccgctgg gcccgcgggg ggattcttggcagttggggg gtccgtcggg agcgagggcg 180 gaggggaagg gagggggaaccgggttgggg aagccagctg tagagggcgg tgaccgcgct 240 ccagacacagctctgcgtcc tcgagcggga cagatccaag ttgggagcag ctctgcgtgc 300ggggcctcag agaatgaggc cggcgttcgc cctgtgcctc ctctggcagg cgctctggcc360 cgggccgggc ggcggcgaac accccactgc cgaccgtgct ggctgctcggcctcgggggc 420 ctgctacagc ctgcaccacg ctaccatgaa gcggcaggcggccgaggagg cctgcatcct 480 gcgaggtggg gcgctcagca ccgtgcgtgcgggcgccgag ctgcgcgctg tgctcgcgct 540 cctgcgggca ggcccagggcccggaggggg ctccaaagac ctgctgttct gggtcgcact 600 ggagcgcaggcgttcccact gcaccctgga gaacgagcct ttgcggggtt tctcctggct 660gtcctccgac cccggcggtc tcgaaagcga cacgctgcag tgggtggagg agccccaacg720 ctcctgcacc gcgcggagat gcgcggtact ccaggccacc ggtggggtcgagcccgcagg 780 ctggaaggag atgcgatgcc acctgcgcgc caacggctacctgtgcaagt accagtttga 840 ggtcttgtgt cctgcgccgc gccccggggccgcctctaac ttgagctatc gcgcgccctt 900 ccagctgcac agcgccgctctggacttcag tccacctggg accgaggtga gtgcgctctg 960 ccggggacagctcccgatct cagttacttg catcgcggac gaaatcggcg ctcgctggga 1020caaactctcg ggcgatgtgt tgtgtccctg ccccgggagg tacctccgtg ctggcaaatg1080 cgcagagctc cctaactgcc tagacgactt gggaggcttt gcctgcgaatgtgctacggg 1140 cttcgagctg gggaaggacg gccgctcttg tgtgaccagtggggaaggac agccgaccct 1200 tggggggacc ggggtgccca ccaggcgcccgccggccact gcaaccagcc ccgtgccgca 1260 gagaacatgg ccaatcagggtcgacgagaa gctgggagag acaccacttg tccctgaaca 1320 agacaattcagtaacatcta ttcctgagat tcctcgatgg ggatcacaga gcacgatgtc 1380tacccttcaa atgtcccttc aagccgagtc aaaggccact atcaccccat cagggagcgt1440 gatttccaag tttaattcta cgacttcctc tgccactcct caggctttcgactcctcctc 1500 tgccgtggtc ttcatatttg tgagcacagc agtagtagtgttggtgatct tgaccatgac 1560 agtactgggg cttgtcaagc tctgctttcacgaaagcccc tcttcccagc caaggaagga 1620 gtctatgggc ccgccgggcctggagagtga tcctgagccc gctgctttgg gctccagttc 1680 tgcacattgcacaaacaatg gggtgaaagt cggggactgt gatctgcggg

acagagcaga 1740 gggtgccttg ctggcggagt cccctcttgg ctctagtgatgcatagggaa acaggggaca 1800 tgggcactcc tgtgaacagt ttttcacttttgatgaaacg gggaaccaag aggaacttac 1860 ttgtgtaact gacaatttctgcagaaatcc cccttcctct aaattccctt tactccactg 1920 aggagctaaatcagaactgc acactccttc cctgatgata gaggaagtgg aagtgccttt 1980aggatggtga tactggggga ccgggtagtg ctggggagag atattttctt atgtttattc2040 ggagaatttg gagaagtgat tgaacttttc aagacattgg aaacaaatagaacacaatat 2100 aatttacatt aaaaaataat ttctaccaaa atggaaaggaaatgttctat gttgttcagg 2160 ctaggagtat attggttcga aatcccagggaaaaaaataa aaataaaaaa ttaaaggatt 2220 ttgat 2226 96 490 PRT Homosapiens 96 Met Arg Pro Ala Phe Ala Leu Cys Leu Leu Trp Gln Ala LeuTrp Pro 1 5 10 15 Gly Pro Gly Gly Gly Glu His Pro Thr Ala Asp ArgAla Gly Cys Ser 20 25 30 Ala Ser Gly Ala Cys Tyr Ser Leu His HisAla Thr Met Lys Arg Gln 35 40 45 Ala Ala Glu Glu Ala Cys Ile LeuArg Gly Gly Ala Leu Ser Thr Val 50 55 60 Arg Ala Gly Ala Glu LeuArg Ala Val Leu Ala Leu Leu Arg Ala Gly 65 70 75 80 Pro Gly Pro GlyGly Gly Ser Lys Asp Leu Leu Phe Trp Val Ala Leu 85 90 95 Glu ArgArg Arg Ser His Cys Thr Leu Glu Asn Glu Pro Leu Arg Gly 100 105 110Phe Ser Trp Leu Ser Ser Asp Pro Gly Gly Leu Glu Ser Asp Thr Leu 115120 125 Gln Trp Val Glu Glu Pro Gln Arg Ser Cys Thr Ala Arg Arg CysAla 130 135 140 Val Leu Gln Ala Thr Gly Gly Val Glu Pro Ala Gly TrpLys Glu Met 145 150 155 160 Arg Cys His Leu Arg Ala Asn Gly Tyr LeuCys Lys Tyr Gln Phe Glu 165 170 175 Val Leu Cys Pro Ala Pro Arg ProGly Ala Ala Ser Asn Leu Ser Tyr 180 185 190 Arg Ala Pro Phe Gln LeuHis Ser Ala Ala Leu Asp Phe Ser Pro Pro 195 200 205 Gly Thr Glu ValSer Ala Leu Cys Arg Gly Gln Leu Pro Ile Ser Val 210 215 220 Thr CysIle Ala Asp Glu Ile Gly Ala Arg Trp Asp Lys Leu Ser Gly 225 230 235240 Asp Val Leu Cys Pro Cys Pro Gly Arg Tyr Leu Arg Ala Gly Lys Cys245 250 255 Ala Glu Leu Pro Asn Cys Leu Asp Asp Leu Gly Gly Phe AlaCys Glu 260 265 270 Cys Ala Thr Gly Phe Glu Leu Gly Lys Asp Gly ArgSer Cys Val Thr 275 280 285 Ser Gly Glu Gly Gln Pro Thr Leu Gly GlyThr Gly Val Pro Thr Arg 290 295 300 Arg Pro Pro Ala Thr Ala Thr SerPro Val Pro Gln Arg Thr Trp Pro 305 310 315 320 Ile Arg Val Asp GluLys Leu Gly Glu Thr Pro Leu Val Pro Glu Gln 325 330 335 Asp Asn SerVal Thr Ser Ile Pro Glu Ile Pro Arg Trp Gly Ser Gln 340 345 350 SerThr Met Ser Thr Leu Gln Met Ser Leu Gln Ala Glu Ser Lys Ala 355 360365 Thr Ile Thr Pro Ser Gly Ser Val Ile Ser Lys Phe Asn Ser Thr Thr370 375 380 Ser Ser Ala Thr Pro Gln Ala Phe Asp Ser Ser Ser Ala ValVal Phe 385 390 395 400 Ile Phe Val Ser Thr Ala Val Val Val Leu ValIle Leu Thr Met Thr 405 410 415 Val Leu Gly Leu Val Lys Leu Cys PheHis Glu Ser Pro Ser Ser Gln 420 425 430 Pro Arg Lys Glu Ser Met GlyPro Pro Gly Leu Glu Ser Asp Pro Glu 435 440 445 Pro Ala Ala Leu GlySer Ser Ser Ala His Cys Thr Asn Asn Gly Val 450 455 460 Lys Val GlyAsp Cys Asp Leu Arg Asp Arg Ala Glu Gly Ala Leu Leu 465 470 475 480Ala Glu Ser Pro Leu Gly Ser Ser Asp Ala 485 490 97 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 97 tggaaggaga tgcgatgcca cctg 24 98 20 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 98 tgaccagtgg ggaaggacag 20 99 20 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 99 acagagcaga gggtgccttg 20 100 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 100 tcagggacaa gtggtgtctc tccc 24 101 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 101 tcagggaagg agtgtgcagt tctg 24 102 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 102 acagctcccg atctcagtta cttgcatcgcggacgaaatc ggcgctcgct 50 103 2026 DNA Homo sapiens 103 cggacgcgtgggattcagca gtggcctgtg gctgccagag cagctcctca ggggaaacta 60agcgtcgagt cagacggcac cataatcgcc tttaaaagtg cctccgccct gccggccgcg120 tatcccccgg ctacctgggc cgccccgcgg cggtgcgcgc gtgagagggagcgcgcgggc 180 agccgagcgc cggtgtgagc cagcgctgct gccagtgtgagcggcggtgt gagcgcggtg 240 ggtgcggagg ggcgtgtgtg ccggcgcgcgcgccgtgggg tgcaaacccc gagcgtctac 300 gctgccatga ggggcgcgaacgcctgggcg ccactctgcc tgctgctggc tgccgccacc 360 cagctctcgcggcagcagtc cccagagaga cctgttttca catgtggtgg cattcttact 420ggagagtctg gatttattgg cagtgaaggt tttcctggag tgtaccctcc aaatagcaaa480 tgtacttgga aaatcacagt tcccgaagga aaagtagtcg ttctcaatttccgattcata 540 gacctcgaga gtgacaacct gtgccgctat gactttgtggatgtgtacaa tggccatgcc 600 aatggccagc gcattggccg cttctgtggcactttccggc ctggagccct tgtgtccagt 660 ggcaacaaga tgatggtgcagatgatttct gatgccaaca cagctggcaa tggcttcatg 720 gccatgttctccgctgctga accaaacgaa agaggggatc agtattgtgg aggactcctt 780gacagacctt ccggctcttt taaaaccccc aactggccag accgggatta ccctgcagga840 gtcacttgtg tgtggcacat tgtagcccca aagaatcagc ttatagaattaaagtttgag 900 aagtttgatg tggagcgaga taactactgc cgatatgattatgtggctgt gtttaatggc 960 ggggaagtca acgatgctag aagaattggaaagtattgtg gtgatagtcc acctgcgcca 1020 attgtgtctg agagaaatgaacttcttatt cagtttttat cagacttaag tttaactgca 1080 gatgggtttattggtcacta catattcagg ccaaaaaaac tgcctacaac tacagaacag 1140cctgtcacca ccacattccc tgtaaccacg ggtttaaaac ccaccgtggc cttgtgtcaa1200 caaaagtgta gacggacggg gactctggag ggcaattatt gttcaagtgactttgtatta 1260 gccggcactg ttatcacaac catcactcgc gatgggagtttgcacgccac agtctcgatc 1320 atcaacatct acaaagaggg aaatttggcgattcagcagg cgggcaagaa catgagtgcc 1380 aggctgactg tcgtctgcaagcagtgccct ctcctcagaa gaggtctaaa ttacattatt 1440 atgggccaagtaggtgaaga tgggcgaggc aaaatcatgc caaacagctt tatcatgatg 1500ttcaagacca agaatcagaa gctcctggat gccttaaaaa ataagcaatg ttaacagtga1560 actgtgtcca tttaagctgt attctgccat tgcctttgaa agatctatgttctctcagta 1620 gaaaaaaaaa tacttataaa attacatatt ctgaaagaggattccgaaag atgggactgg 1680 ttgactcttc acatgatgga ggtatgaggcctccgagata gctgagggaa gttctttgcc 1740 tgctgtcaga ggagcagctatctgattgga aacctgccga cttagtgcgg tgataggaag 1800 ctaaaagtgtcaagcgttga cagcttggaa gcgtttattt atacatctct gtaaaaggat 1860attttagaat tgagttgtgt gaagatgtca aaaaaagatt ttagaagtgc aatatttata1920 gtgttatttg tttcaccttc aagcctttgc cctgaggtgt tacaatcttgtcttgcgttt 1980 tctaaatcaa tgcttaataa aatattttta aaggaaaaaa aaaaaa2026 104 415 PRT Homo sapiens 104 Met Arg Gly Ala Asn Ala Trp AlaPro Leu Cys Leu Leu Leu Ala Ala 1 5 10 15 Ala Thr Gln Leu Ser ArgGln Gln Ser Pro Glu Arg Pro Val Phe Thr 20 25 30 Cys Gly Gly IleLeu Thr Gly Glu Ser Gly Phe Ile Gly Ser Glu Gly 35 40 45 Phe ProGly Val Tyr Pro Pro Asn Ser Lys Cys Thr Trp Lys Ile Thr 50 55 60Val Pro Glu Gly Lys Val Val Val Leu Asn Phe Arg Phe Ile Asp Leu 6570 75 80 Glu Ser Asp Asn Leu Cys Arg Tyr Asp Phe Val Asp Val TyrAsn Gly 85 90 95 His Ala Asn Gly Gln Arg Ile Gly Arg Phe Cys GlyThr Phe Arg Pro 100 105 110 Gly Ala Leu Val Ser Ser Gly Asn Lys MetMet Val Gln Met Ile Ser 115 120 125 Asp Ala Asn Thr Ala Gly Asn GlyPhe Met Ala Met Phe Ser Ala Ala 130 135 140 Glu Pro Asn Glu Arg GlyAsp Gln Tyr Cys Gly Gly Leu Leu Asp Arg 145 150 155 160 Pro Ser GlySer Phe Lys Thr Pro Asn Trp Pro Asp Arg Asp Tyr Pro 165 170 175 AlaGly Val Thr Cys Val Trp His Ile Val Ala Pro Lys Asn Gln Leu 180 185190 Ile Glu Leu Lys Phe Glu Lys Phe Asp Val Glu Arg Asp Asn Tyr Cys195 200 205 Arg Tyr Asp Tyr Val Ala Val Phe Asn Gly Gly Glu Val AsnAsp Ala 210 215 220 Arg Arg Ile Gly Lys Tyr Cys Gly Asp Ser Pro ProAla Pro Ile Val 225 230 235 240 Ser Glu Arg Asn Glu Leu Leu Ile GlnPhe Leu Ser Asp Leu Ser Leu 245 250 255 Thr Ala Asp Gly Phe Ile GlyHis Tyr Ile Phe Arg Pro Lys Lys Leu 260 265 270 Pro Thr Thr Thr GluGln Pro Val Thr Thr Thr Phe Pro Val Thr Thr 275 280 285 Gly Leu LysPro Thr Val Ala Leu Cys Gln Gln Lys Cys Arg Arg Thr 290 295 300 GlyThr Leu Glu Gly Asn Tyr Cys Ser Ser Asp Phe Val Leu Ala Gly 305 310315 320 Thr Val Ile Thr Thr Ile Thr Arg Asp Gly Ser Leu His Ala ThrVal 325 330 335 Ser Ile Ile Asn Ile Tyr Lys Glu Gly Asn Leu Ala IleGln Gln Ala 340 345 350 Gly Lys Asn Met Ser Ala Arg Leu Thr Val ValCys Lys Gln Cys Pro 355 360 365 Leu Leu Arg Arg Gly Leu Asn Tyr IleIle Met Gly Gln Val Gly Glu 370 375 380 Asp Gly Arg Gly Lys Ile MetPro Asn Ser Phe Ile Met Met Phe Lys 385 390 395 400 Thr Lys Asn GlnLys Leu Leu Asp Ala Leu Lys Asn Lys Gln Cys 405 410 415 105 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 105 ccgattcata gacctcgaga gt 22 106 22 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 106 gtcaaggagt cctccacaat ac 22 107 45 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 107 gtgtacaatg gccatgccaa tggccagcgcattggccgct tctgt 45 108 1838 DNA Homo sapiens 108 cggacgcgtgggcggacgcg tgggcggccc acggcgcccg cgggctgggg cggtcgcttc 60ttccttctcc gtggcctacg agggtcccca gcctgggtaa agatggcccc atggcccccg120 aagggcctag tcccagctgt gctctggggc ctcagcctct tcctcaacctcccaggacct 180 atctggctcc agccctctcc acctccccag tcttctcccccgcctcagcc ccatccgtgt 240 catacctgcc ggggactggt tgacagctttaacaagggcc tggagagaac catccgggac 300 aactttggag gtggaaacactgcctgggag gaagagaatt tgtccaaata caaagacagt 360 gagacccgcctggtagaggt gctggagggt gtgtgcagca agtcagactt cgagtgccac 420cgcctgctgg agctgagtga ggagctggtg gagagctggt ggtttcacaa gcagcaggag480 gccccggacc tcttccagtg gctgtgctca gattccctga agctctgctgccccgcaggc 540 accttcgggc cctcctgcct tccctgtcct gggggaacagagaggccctg cggtggctac 600 gggcagtgtg aaggagaagg gacacgagggggcagcgggc actgtgactg ccaagccggc 660 tacgggggtg aggcctgtggccagtgtggc cttggctact ttgaggcaga acgcaacgcc 720 agccatctggtatgttcggc ttgttttggc ccctgtgccc gatgctcagg acctgaggaa 780tcaaactgtt tgcaatgcaa gaagggctgg gccctgcatc acctcaagtg tgtagacatt840 gatgagtgtg gcacagaggg agccaactgt ggagctgacc aattctgcgtgaacactgag 900 ggctcctatg agtgccgaga ctgtgccaag gcctgcctaggctgcatggg ggcagggcca 960 ggtcgctgta agaagtgtag ccctggctatcagcaggtgg gctccaagtg tctcgatgtg 1020 gatgagtgtg agacagaggtgtgtccggga gagaacaagc agtgtgaaaa caccgagggc 1080 ggttatcgctgcatctgtgc cgagggctac aagcagatgg aaggcatctg tgtgaaggag 1140cagatcccag agtcagcagg cttcttctca gagatgacag aagacgagtt ggtggtgctg1200 cagcagatgt tctttggcat catcatctgt gcactggcca cgctggctgctaagggcgac 1260 ttggtgttca ccgccatctt cattggggct gtggcggccatgactggcta ctggttgtca 1320 gagcgcagtg accgtgtgct ggagggcttcatcaagggca gataatcgcg gccaccacct 1380 gtaggacctc ctcccacccacgctgccccc agagcttggg ctgccctcct gctggacact 1440 caggacagcttggtttattt ttgagagtgg ggtaagcacc cctacctgcc ttacagagca 1500gcccaggtac ccaggcccgg gcagacaagg cccctggggt aaaaagtagc cctgaaggtg1560 gataccatga gctcttcacc tggcggggac tggcaggctt cacaatgtgtgaatttcaaa 1620 agtttttcct taatggtggc tgctagagct ttggcccctgcttaggatta ggtggtcctc 1680 acaggggtgg ggccatcaca gctccctcctgccagctgca tgctgccagt tcctgttctg 1740 tgttcaccac atccccacaccccattgcca cttatttatt catctcagga aataaagaaa 1800 ggtcttggaaagttaaaaaa aaaaaaaaaa aaaaaaaa 1838 109 420 PRT Homo sapiens 109Met Ala Pro Trp Pro Pro Lys Gly Leu Val Pro Ala Val Leu Trp Gly 1 510 15 Leu Ser Leu Phe Leu Asn Leu Pro Gly Pro Ile Trp Leu Gln ProSer 20 25 30 Pro Pro Pro Gln Ser Ser Pro Pro Pro Gln Pro His ProCys His Thr 35 40 45 Cys Arg Gly Leu Val Asp Ser Phe Asn Lys GlyLeu Glu Arg Thr Ile 50 55 60 Arg Asp Asn Phe Gly Gly Gly Asn ThrAla Trp Glu Glu Glu Asn Leu 65 70 75 80 Ser Lys Tyr Lys Asp Ser GluThr Arg Leu Val Glu Val Leu Glu Gly 85 90 95 Val Cys Ser Lys SerAsp Phe Glu Cys His Arg Leu Leu Glu Leu Ser 100 105 110 Glu Glu LeuVal Glu Ser Trp Trp Phe His Lys Gln Gln Glu Ala Pro 115 120 125 AspLeu Phe Gln Trp Leu Cys Ser Asp Ser Leu Lys Leu Cys Cys Pro 130 135140 Ala Gly Thr Phe Gly Pro Ser Cys Leu Pro Cys Pro Gly Gly Thr Glu145 150 155 160 Arg Pro Cys Gly Gly Tyr Gly Gln Cys Glu Gly Glu GlyThr Arg Gly 165 170 175 Gly Ser Gly His Cys Asp Cys Gln Ala Gly TyrGly Gly Glu Ala Cys 180 185 190 Gly Gln Cys Gly Leu Gly Tyr Phe GluAla Glu Arg Asn Ala Ser His 195 200 205 Leu Val Cys Ser Ala Cys PheGly Pro Cys Ala Arg Cys Ser Gly Pro 210 215 220 Glu Glu Ser Asn CysLeu Gln Cys Lys Lys Gly Trp Ala Leu His His 225 230 235 240 Leu LysCys Val Asp Ile Asp Glu Cys Gly Thr Glu Gly Ala Asn Cys 245 250 255Gly Ala Asp Gln Phe Cys Val Asn Thr Glu Gly Ser Tyr Glu Cys Arg 260265 270 Asp Cys Ala Lys Ala Cys Leu Gly Cys Met Gly Ala Gly Pro GlyArg 275 280 285 Cys Lys Lys Cys Ser Pro Gly Tyr Gln Gln Val Gly SerLys Cys Leu 290 295 300 Asp Val Asp Glu Cys Glu Thr Glu Val Cys ProGly Glu Asn Lys Gln 305 310 315 320 Cys Glu Asn Thr Glu Gly Gly TyrArg Cys Ile Cys Ala Glu Gly Tyr 325 330 335 Lys Gln Met Glu Gly IleCys Val Lys Glu Gln Ile Pro Glu Ser Ala 340 345 350 Gly Phe Phe SerGlu Met Thr Glu Asp Glu Leu Val Val Leu Gln Gln 355 360 365 Met PhePhe Gly Ile Ile Ile Cys Ala Leu Ala Thr Leu Ala Ala Lys 370 375 380Gly Asp Leu Val Phe Thr Ala Ile Phe Ile Gly Ala Val Ala Ala Met 385390 395 400 Thr Gly Tyr Trp Leu Ser Glu Arg Ser Asp Arg Val Leu GluGly Phe 405 410 415 Ile Lys Gly Arg 420 110 50 DNA ArtificialSequence Description of Artificial Sequence Syntheticoligonucleotide probe 110 cctggctatc agcaggtggg ctccaagtgtctcgatgtgg atgagtgtga 50 111 22 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 111attctgcgtg aacactgagg gc 22 112 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe112 atctgcttgt agccctcggc ac 22 113 1616 DNA Homo sapiensmodified_base (1461)..(1461) a, t, c or g 113 tgagaccctc ctgcagccttctcaagggac agccccactc tgcctcttgc tcctccaggg 60 cagcaccatgcagcccctgt ggctctgctg ggcactctgg gtgttgcccc tggccagccc 120cggggccgcc ctgaccgggg agcagctcct gggcagcctg ctgcggcagc tgcagctcaa180 agaggtgccc accctggaca gggccgacat ggaggagctg gtcatccccacccacgtgag 240 ggcccagtac gtggccctgc tgcagcgcag ccacggggaccgctcccgcg gaaagaggtt 300 cagccagagc ttccgagagg tggccggcaggttcctggcg ttggaggcca gcacacacct 360 gctggtgttc ggcatggagcagcggctgcc gcccaacagc gagctggtgc aggccgtgct 420 gcggctcttc

caggagccgg tccccaaggc cgcgctgcac aggcacgggc ggctgtcccc 480gcgcagcgcc cgggcccggg tgaccgtcga gtggctgcgc gtccgcgacg acggctccaa540 ccgcacctcc ctcatcgact ccaggctggt gtccgtccac gagagcggctggaaggcctt 600 cgacgtgacc gaggccgtga acttctggca gcagctgagccggccccggc agccgctgct 660 gctacaggtg tcggtgcaga gggagcatctgggcccgctg gcgtccggcg cccacaagct 720 ggtccgcttt gcctcgcagggggcgccagc cgggcttggg gagccccagc tggagctgca 780 caccctggaccttggggact atggagctca gggcgactgt gaccctgaag caccaatgac 840cgagggcacc cgctgctgcc gccaggagat gtacattgac ctgcagggga tgaagtgggc900 cgagaactgg gtgctggagc ccccgggctt cctggcttat gagtgtgtgggcacctgccg 960 gcagcccccg gaggccctgg ccttcaagtg gccgtttctggggcctcgac agtgcatcgc 1020 ctcggagact gactcgctgc ccatgatcgtcagcatcaag gagggaggca ggaccaggcc 1080 ccaggtggtc agcctgcccaacatgagggt gcagaagtgc agctgtgcct cggatggtgc 1140 gctcgtgccaaggaggctcc agccataggc gcctagtgta gccatcgagg gacttgactt 1200gtgtgtgttt ctgaagtgtt cgagggtacc aggagagctg gcgatgactg aactgctgat1260 ggacaaatgc tctgtgctct ctagtgagcc ctgaatttgc ttcctctgacaagttacctc 1320 acctaatttt tgcttctcag gaatgagaat ctttggccactggagagccc ttgctcagtt 1380 ttctctattc ttattattca ctgcactatattctaagcac ttacatgtgg agatactgta 1440 acctgagggc agaaagcccantgtgtcatt gtttacttgt cctgtcactg gatctgggct 1500 aaagtcctccaccaccactc tggacctaag acctggggtt aagtgtgggt tgtgcatccc 1560caatccagat aataaagact ttgtaaaaca tgaataaaac acattttatt ctaaaa 1616114 366 PRT Homo sapiens 114 Met Gln Pro Leu Trp Leu Cys Trp AlaLeu Trp Val Leu Pro Leu Ala 1 5 10 15 Ser Pro Gly Ala Ala Leu ThrGly Glu Gln Leu Leu Gly Ser Leu Leu 20 25 30 Arg Gln Leu Gln LeuLys Glu Val Pro Thr Leu Asp Arg Ala Asp Met 35 40 45 Glu Glu LeuVal Ile Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu 50 55 60 LeuGln Arg Ser His Gly Asp Arg Ser Arg Gly Lys Arg Phe Ser Gln 65 7075 80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Leu Glu Ala SerThr 85 90 95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro ProAsn Ser Glu 100 105 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln GluPro Val Pro Lys Ala 115 120 125 Ala Leu His Arg His Gly Arg Leu SerPro Arg Ser Ala Arg Ala Arg 130 135 140 Val Thr Val Glu Trp Leu ArgVal Arg Asp Asp Gly Ser Asn Arg Thr 145 150 155 160 Ser Leu Ile AspSer Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165 170 175 Ala PheAsp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180 185 190Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195200 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala SerGln 210 215 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu LeuHis Thr Leu 225 230 235 240 Asp Leu Gly Asp Tyr Gly Ala Gln Gly AspCys Asp Pro Glu Ala Pro 245 250 255 Met Thr Glu Gly Thr Arg Cys CysArg Gln Glu Met Tyr Ile Asp Leu 260 265 270 Gln Gly Met Lys Trp AlaGlu Asn Trp Val Leu Glu Pro Pro Gly Phe 275 280 285 Leu Ala Tyr GluCys Val Gly Thr Cys Arg Gln Pro Pro Glu Ala Leu 290 295 300 Ala PheLys Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305 310 315320 Thr Asp Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr325 330 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln LysCys Ser 340 345 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg LeuGln Pro 355 360 365 115 21 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 115 aggactgccataacttgcct g 21 116 22 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 116 ataggagttgaagcagcgct gc 22 117 45 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 117 tgtgtggacatagacgagtg ccgctaccgc tactgccagc accgc 45 118 1857 DNA Homo sapiens118 gtctgttccc aggagtcctt cggcggctgt tgtgtcagtg gcctgatcgcgatggggaca 60 aaggcgcaag tcgagaggaa actgttgtgc ctcttcatattggcgatcct gttgtgctcc 120 ctggcattgg gcagtgttac agtgcactcttctgaacctg aagtcagaat tcctgagaat 180 aatcctgtga agttgtcctgtgcctactcg ggcttttctt ctccccgtgt ggagtggaag 240 tttgaccaaggagacaccac cagactcgtt tgctataata acaagatcac agcttcctat 300gaggaccggg tgaccttctt gccaactggt atcaccttca agtccgtgac acgggaagac360 actgggacat acacttgtat ggtctctgag gaaggcggca acagctatggggaggtcaag 420 gtcaagctca tcgtgcttgt gcctccatcc aagcctacagttaacatccc ctcctctgcc 480 accattggga accgggcagt gctgacatgctcagaacaag atggttcccc accttctgaa 540 tacacctggt tcaaagatgggatagtgatg cctacgaatc ccaaaagcac ccgtgccttc 600 agcaactcttcctatgtcct gaatcccaca acaggagagc tggtctttga tcccctgtca 660gcctctgata ctggagaata cagctgtgag gcacggaatg ggtatgggac acccatgact720 tcaaatgctg tgcgcatgga agctgtggag cggaatgtgg gggtcatcgtggcagccgtc 780 cttgtaaccc tgattctcct gggaatcttg gtttttggcatctggtttgc ctatagccga 840 ggccactttg acagaacaaa gaaagggacttcgagtaaga aggtgattta cagccagcct 900 agtgcccgaa gtgaaggagaattcaaacag acctcgtcat tcctggtgtg agcctggtcg 960 gctcaccgcctatcatctgc atttgcctta ctcaggtgct accggactct ggcccctgat 1020gtctgtagtt tcacaggatg ccttatttgt cttctacacc ccacagggcc ccctacttct1080 tcggatgtgt ttttaataat gtcagctatg tgccccatcc tccttcatgccctccctccc 1140 tttcctacca ctgctgagtg gcctggaact tgtttaaagtgtttattccc catttctttg 1200 agggatcagg aaggaatcct gggtatgccattgacttccc ttctaagtag acagcaaaaa 1260 tggcgggggt cgcaggaatctgcactcaac tgcccacctg gctggcaggg atctttgaat 1320 aggtatcttgagcttggttc tgggctcttt ccttgtgtac tgacgaccag ggccagctgt 1380tctagagcgg gaattagagg ctagagcggc tgaaatggtt gtttggtgat gacactgggg1440 tccttccatc tctggggccc actctcttct gtcttcccat gggaagtgccactgggatcc 1500 ctctgccctg tcctcctgaa tacaagctga ctgacattgactgtgtctgt ggaaaatggg 1560 agctcttgtt gtggagagca tagtaaattttcagagaact tgaagccaaa aggatttaaa 1620 accgctgctc taaagaaaagaaaactggag gctgggcgca gtggctcacg cctgtaatcc 1680 cagaggctgaggcaggcgga tcacctgagg tcgggagttc gggatcagcc tgaccaacat 1740ggagaaaccc tactggaaat acaaagttag ccaggcatgg tggtgcatgc ctgtagtccc1800 agctgctcag gagcctggca acaagagcaa aactccagct caaaaaaaaa aaaaaaa1857 119 299 PRT Homo sapiens 119 Met Gly Thr Lys Ala Gln Val GluArg Lys Leu Leu Cys Leu Phe Ile 1 5 10 15 Leu Ala Ile Leu Leu CysSer Leu Ala Leu Gly Ser Val Thr Val His 20 25 30 Ser Ser Glu ProGlu Val Arg Ile Pro Glu Asn Asn Pro Val Lys Leu 35 40 45 Ser CysAla Tyr Ser Gly Phe Ser Ser Pro Arg Val Glu Trp Lys Phe 50 55 60Asp Gln Gly Asp Thr Thr Arg Leu Val Cys Tyr Asn Asn Lys Ile Thr 6570 75 80 Ala Ser Tyr Glu Asp Arg Val Thr Phe Leu Pro Thr Gly IleThr Phe 85 90 95 Lys Ser Val Thr Arg Glu Asp Thr Gly Thr Tyr ThrCys Met Val Ser 100 105 110 Glu Glu Gly Gly Asn Ser Tyr Gly Glu ValLys Val Lys Leu Ile Val 115 120 125 Leu Val Pro Pro Ser Lys Pro ThrVal Asn Ile Pro Ser Ser Ala Thr 130 135 140 Ile Gly Asn Arg Ala ValLeu Thr Cys Ser Glu Gln Asp Gly Ser Pro 145 150 155 160 Pro Ser GluTyr Thr Trp Phe Lys Asp Gly Ile Val Met Pro Thr Asn 165 170 175 ProLys Ser Thr Arg Ala Phe Ser Asn Ser Ser Tyr Val Leu Asn Pro 180 185190 Thr Thr Gly Glu Leu Val Phe Asp Pro Leu Ser Ala Ser Asp Thr Gly195 200 205 Glu Tyr Ser Cys Glu Ala Arg Asn Gly Tyr Gly Thr Pro MetThr Ser 210 215 220 Asn Ala Val Arg Met Glu Ala Val Glu Arg Asn ValGly Val Ile Val 225 230 235 240 Ala Ala Val Leu Val Thr Leu Ile LeuLeu Gly Ile Leu Val Phe Gly 245 250 255 Ile Trp Phe Ala Tyr Ser ArgGly His Phe Asp Arg Thr Lys Lys Gly 260 265 270 Thr Ser Ser Lys LysVal Ile Tyr Ser Gln Pro Ser Ala Arg Ser Glu 275 280 285 Gly Glu PheLys Gln Thr Ser Ser Phe Leu Val 290 295 120 24 DNA ArtificialSequence Description of Artificial Sequence Syntheticoligonucleotide probe 120 tcgcggagct gtgttctgtt tccc 24 121 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 121 tgatcgcgat ggggacaaag gcgcaagctcgagaggaaac tgttgtgcct 50 122 20 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 122acacctggtt caaagatggg 20 123 24 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 123taggaagagt tgctgaaggc acgg 24 124 20 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe124 ttgccttact caggtgctac 20 125 20 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe125 actcagcagt ggtaggaaag 20 126 1210 DNA Homo sapiens 126cagcgcgtgg ccggcgccgc tgtggggaca gcatgagcgg cggttggatg gcgcaggttg60 gagcgtggcg aacaggggct ctgggcctgg cgctgctgct gctgctcggcctcggactag 120 gcctggaggc cgccgcgagc ccgctttcca ccccgacctctgcccaggcc gcaggcccca 180 gctcaggctc gtgcccaccc accaagttccagtgccgcac cagtggctta tgcgtgcccc 240 tcacctggcg ctgcgacagggacttggact gcagcgatgg cagcgatgag gaggagtgca 300 ggattgagccatgtacccag aaagggcaat gcccaccgcc ccctggcctc ccctgcccct 360gcaccggcgt cagtgactgc tctgggggaa ctgacaagaa actgcgcaac tgcagccgcc420 tggcctgcct agcaggcgag ctccgttgca cgctgagcga tgactgcattccactcacgt 480 ggcgctgcga cggccaccca gactgtcccg actccagcgacgagctcggc tgtggaacca 540 atgagatcct cccggaaggg gatgccacaaccatggggcc ccctgtgacc ctggagagtg 600 tcacctctct caggaatgccacaaccatgg ggccccctgt gaccctggag agtgtcccct 660 ctgtcgggaatgccacatcc tcctctgccg gagaccagtc tggaagccca actgcctatg 720gggttattgc agctgctgcg gtgctcagtg caagcctggt caccgccacc ctcctccttt780 tgtcctggct ccgagcccag gagcgcctcc gcccactggg gttactggtggccatgaagg 840 agtccctgct gctgtcagaa cagaagacct cgctgccctgaggacaagca cttgccacca 900 ccgtcactca gccctgggcg tagccggacaggaggagagc agtgatgcgg atgggtaccc 960 gggcacacca gccctcagagacctgagttc ttctggccac gtggaacctc gaacccgagc 1020 tcctgcagaagtggccctgg agattgaggg tccctggaca ctccctatgg agatccgggg 1080agctaggatg gggaacctgc cacagccaga actgaggggc tggccccagg cagctcccag1140 ggggtagaac ggccctgtgc ttaagacact ccctgctgcc ccgtctgagggtggcgatta 1200 aagttgcttc 1210 127 282 PRT Homo sapiens 127 MetSer Gly Gly Trp Met Ala Gln Val Gly Ala Trp Arg Thr Gly Ala 1 5 1015 Leu Gly Leu Ala Leu Leu Leu Leu Leu Gly Leu Gly Leu Gly Leu Glu20 25 30 Ala Ala Ala Ser Pro Leu Ser Thr Pro Thr Ser Ala Gln AlaAla Gly 35 40 45 Pro Ser Ser Gly Ser Cys Pro Pro Thr Lys Phe GlnCys Arg Thr Ser 50 55 60 Gly Leu Cys Val Pro Leu Thr Trp Arg CysAsp Arg Asp Leu Asp Cys 65 70 75 80 Ser Asp Gly Ser Asp Glu Glu GluCys Arg Ile Glu Pro Cys Thr Gln 85 90 95 Lys Gly Gln Cys Pro ProPro Pro Gly Leu Pro Cys Pro Cys Thr Gly 100 105 110 Val Ser Asp CysSer Gly Gly Thr Asp Lys Lys Leu Arg Asn Cys Ser 115 120 125 Arg LeuAla Cys Leu Ala Gly Glu Leu Arg Cys Thr Leu Ser Asp Asp 130 135 140Cys Ile Pro Leu Thr Trp Arg Cys Asp Gly His Pro Asp Cys Pro Asp 145150 155 160 Ser Ser Asp Glu Leu Gly Cys Gly Thr Asn Glu Ile Leu ProGlu Gly 165 170 175 Asp Ala Thr Thr Met Gly Pro Pro Val Thr Leu GluSer Val Thr Ser 180 185 190 Leu Arg Asn Ala Thr Thr Met Gly Pro ProVal Thr Leu Glu Ser Val 195 200 205 Pro Ser Val Gly Asn Ala Thr SerSer Ser Ala Gly Asp Gln Ser Gly 210 215 220 Ser Pro Thr Ala Tyr GlyVal Ile Ala Ala Ala Ala Val Leu Ser Ala 225 230 235 240 Ser Leu ValThr Ala Thr Leu Leu Leu Leu Ser Trp Leu Arg Ala Gln 245 250 255 GluArg Leu Arg Pro Leu Gly Leu Leu Val Ala Met Lys Glu Ser Leu 260 265270 Leu Leu Ser Glu Gln Lys Thr Ser Leu Pro 275 280 128 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 128 aagttccagt gccgcaccag tggc 24 129 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 129 ttggttccac agccgagctc gtcg 24 130 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 130 gaggaggagt gcaggattga gccatgtacccagaaagggc aatgcccacc 50 131 1843 DNA Homo sapiens modified_base(1837)..(1837) a, t, c or g 131 cccacgcgtc cggtctcgct cgctcgcgcagcggcggcag cagaggtcgc gcacagatgc 60 gggttagact ggcggggggaggaggcggag gagggaagga agctgcatgc atgagaccca 120 cagactcttgcaagctggat gccctctgtg gatgaaagat gtatcatgga atgaacccga 180gcaatggaga tggatttcta gagcagcagc agcagcagca gcaacctcag tccccccaga240 gactcttggc cgtgatcctg tggtttcagc tggcgctgtg cttcggccctgcacagctca 300 cgggcgggtt cgatgacctt caagtgtgtg ctgaccccggcattcccgag aatggcttca 360 ggacccccag cggaggggtt ttctttgaaggctctgtagc ccgatttcac tgccaagacg 420 gattcaagct gaagggcgctacaaagagac tgtgtttgaa gcattttaat ggaaccctag 480 gctggatcccaagtgataat tccatctgtg tgcaagaaga ttgccgtatc cctcaaatcg 540aagatgctga gattcataac aagacatata gacatggaga gaagctaatc atcacttgtc600 atgaaggatt caagatccgg taccccgacc tacacaatat ggtttcattatgtcgcgatg 660 atggaacgtg gaataatctg cccatctgtc aaggctgcctgagacctcta gcctcttcta 720 atggctatgt aaacatctct gagctccagacctccttccc ggtggggact gtgatctcct 780 atcgctgctt tcccggatttaaacttgatg ggtctgcgta tcttgagtgc ttacaaaacc 840 ttatctggtcgtccagccca ccccggtgcc ttgctctgga agcccaagtc tgtccactac 900ctccaatggt gagtcacgga gatttcgtct gccacccgcg gccttgtgag cgctacaacc960 acggaactgt ggtggagttt tactgcgatc ctggctacag cctcaccagcgactacaagt 1020 acatcacctg ccagtatgga gagtggtttc cttcttatcaagtctactgc atcaaatcag 1080 agcaaacgtg gcccagcacc catgagaccctcctgaccac gtggaagatt gtggcgttca 1140 cggcaaccag tgtgctgctggtgctgctgc tcgtcatcct ggccaggatg ttccagacca 1200 agttcaaggcccactttccc cccagggggc ctccccggag ttccagcagt gaccctgact 1260ttgtggtggt agacggcgtg cccgtcatgc tcccgtccta tgacgaagct gtgagtggcg1320 gcttgagtgc cttaggcccc gggtacatgg cctctgtggg ccagggctgccccttacccg 1380 tggacgacca gagcccccca gcataccccg gctcaggggacacggacaca ggcccagggg 1440 agtcagaaac ctgtgacagc gtctcaggctcttctgagct gctccaaagt ctgtattcac 1500 ctcccaggtg ccaagagagcacccaccctg cttcggacaa ccctgacata attgccagca 1560 cggcagaggaggtggcatcc accagcccag gcatccatca tgcccactgg gtgttgttcc 1620taagaaactg attgattaaa aaatttccca aagtgtcctg aagtgtctct tcaaatacat1680 gttgatctgt ggagttgatt cctttccttc tcttggtttt agacaaatgtaaacaaagct 1740 ctgatcctta aaattgctat gctgatagag tggtgagggctggaagcttg atcaagtcct 1800 gtttcttctt gacacagact gattaaaaattaaaagnaaa aaa 1843 132 490 PRT Homo sapiens 132 Met Tyr His GlyMet Asn Pro Ser Asn Gly Asp Gly Phe Leu Glu Gln 1 5 10 15 Gln GlnGln Gln Gln Gln Pro Gln Ser Pro Gln Arg Leu Leu Ala Val 20 25 30Ile Leu Trp Phe Gln Leu Ala Leu Cys Phe Gly Pro Ala Gln Leu Thr 3540 45 Gly Gly Phe Asp Asp Leu Gln Val Cys Ala Asp Pro Gly Ile ProGlu 50 55 60 Asn Gly Phe Arg Thr Pro Ser Gly Gly Val Phe Phe GluGly Ser Val 65 70 75 80 Ala Arg Phe His Cys Gln Asp Gly Phe Lys LeuLys Gly Ala Thr Lys 85 90 95 Arg Leu Cys Leu Lys His Phe Asn GlyThr Leu Gly Trp Ile Pro Ser 100 105 110 Asp Asn Ser Ile Cys Val GlnGlu Asp Cys Arg Ile Pro Gln Ile Glu 115 120 125 Asp Ala Glu Ile HisAsn Lys Thr Tyr Arg His Gly Glu Lys Leu Ile 130 135 140 Ile Thr CysHis Glu Gly Phe Lys Ile Arg Tyr Pro Asp Leu His Asn 145 150 155 160Met Val Ser Leu Cys Arg Asp Asp Gly Thr Trp Asn Asn Leu

Pro Ile 165 170 175 Cys Gln Gly Cys Leu Arg Pro Leu Ala Ser Ser AsnGly Tyr Val Asn 180 185 190 Ile Ser Glu Leu Gln Thr Ser Phe Pro ValGly Thr Val Ile Ser Tyr 195 200 205 Arg Cys Phe Pro Gly Phe Lys LeuAsp Gly Ser Ala Tyr Leu Glu Cys 210 215 220 Leu Gln Asn Leu Ile TrpSer Ser Ser Pro Pro Arg Cys Leu Ala Leu 225 230 235 240 Glu Ala GlnVal Cys Pro Leu Pro Pro Met Val Ser His Gly Asp Phe 245 250 255 ValCys His Pro Arg Pro Cys Glu Arg Tyr Asn His Gly Thr Val Val 260 265270 Glu Phe Tyr Cys Asp Pro Gly Tyr Ser Leu Thr Ser Asp Tyr Lys Tyr275 280 285 Ile Thr Cys Gln Tyr Gly Glu Trp Phe Pro Ser Tyr Gln ValTyr Cys 290 295 300 Ile Lys Ser Glu Gln Thr Trp Pro Ser Thr His GluThr Leu Leu Thr 305 310 315 320 Thr Trp Lys Ile Val Ala Phe Thr AlaThr Ser Val Leu Leu Val Leu 325 330 335 Leu Leu Val Ile Leu Ala ArgMet Phe Gln Thr Lys Phe Lys Ala His 340 345 350 Phe Pro Pro Arg GlyPro Pro Arg Ser Ser Ser Ser Asp Pro Asp Phe 355 360 365 Val Val ValAsp Gly Val Pro Val Met Leu Pro Ser Tyr Asp Glu Ala 370 375 380 ValSer Gly Gly Leu Ser Ala Leu Gly Pro Gly Tyr Met Ala Ser Val 385 390395 400 Gly Gln Gly Cys Pro Leu Pro Val Asp Asp Gln Ser Pro Pro AlaTyr 405 410 415 Pro Gly Ser Gly Asp Thr Asp Thr Gly Pro Gly Glu SerGlu Thr Cys 420 425 430 Asp Ser Val Ser Gly Ser Ser Glu Leu Leu GlnSer Leu Tyr Ser Pro 435 440 445 Pro Arg Cys Gln Glu Ser Thr His ProAla Ser Asp Asn Pro Asp Ile 450 455 460 Ile Ala Ser Thr Ala Glu GluVal Ala Ser Thr Ser Pro Gly Ile His 465 470 475 480 His Ala His TrpVal Leu Phe Leu Arg Asn 485 490 133 23 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe133 atctcctatc gctgctttcc cgg 23 134 23 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe134 agccaggatc gcagtaaaac tcc 23 135 50 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe135 atttaaactt gatgggtctg cgtatcttga gtgcttacaa aaccttatct 50 1361815 DNA Homo sapiens 136 cccacgcgtc cgctccgcgc cctcccccccgcctcccgtg cggtccgtcg gtggcctaga 60 gatgctgctg ccgcggttgcagttgtcgcg cacgcctctg cccgccagcc cgctccaccg 120 ccgtagcgcccgagtgtcgg ggggcgcacc cgagtcgggc catgaggccg ggaaccgcgc 180tacaggccgt gctgctggcc gtgctgctgg tggggctgcg ggccgcgacg ggtcgcctgc240 tgagtgcctc ggatttggac ctcagaggag ggcagccagt ctgccggggagggacacaga 300 ggccttgtta taaagtcatt tacttccatg atacttctcgaagactgaac tttgaggaag 360 ccaaagaagc ctgcaggagg gatggaggccagctagtcag catcgagtct gaagatgaac 420 agaaactgat agaaaagttcattgaaaacc tcttgccatc tgatggtgac ttctggattg 480 ggctcaggaggcgtgaggag aaacaaagca atagcacagc ctgccaggac ctttatgctt 540ggactgatgg cagcatatca caatttagga actggtatgt ggatgagccg tcctgcggca600 gcgaggtctg cgtggtcatg taccatcagc catcggcacc cgctggcatcggaggcccct 660 acatgttcca gtggaatgat gaccggtgca acatgaagaacaatttcatt tgcaaatatt 720 ctgatgagaa accagcagtt ccttctagagaagctgaagg tgaggaaaca gagctgacaa 780 cacctgtact tccagaagaaacacaggaag aagatgccaa aaaaacattt aaagaaagta 840 gagaagctgccttgaatctg gcctacatcc taatccccag cattcccctt ctcctcctcc 900ttgtggtcac cacagttgta tgttgggttt ggatctgtag aaaaagaaaa cgggagcagc960 cagaccctag cacaaagaag caacacacca tctggccctc tcctcaccagggaaacagcc 1020 cggacctaga ggtctacaat gtcataagaa aacaaagcgaagctgactta gctgagaccc 1080 ggccagacct gaagaatatt tcattccgagtgtgttcggg agaagccact cccgatgaca 1140 tgtcttgtga ctatgacaacatggctgtga acccatcaga aagtgggttt gtgactctgg 1200 tgagcgtggagagtggattt gtgaccaatg acatttatga gttctcccca gaccaaatgg 1260ggaggagtaa ggagtctgga tgggtggaaa atgaaatata tggttattag gacatataaa1320 aaactgaaac tgacaacaat ggaaaagaaa tgataagcaa aatcctcttattttctataa 1380 ggaaaataca cagaaggtct atgaacaagc ttagatcaggtcctgtggat gagcatgtgg 1440 tccccacgac ctcctgttgg acccccacgttttggctgta tcctttatcc cagccagtca 1500 tccagctcga ccttatgagaaggtaccttg cccaggtctg gcacatagta gagtctcaat 1560 aaatgtcacttggttggttg tatctaactt ttaagggaca gagctttacc tggcagtgat 1620aaagatgggc tgtggagctt ggaaaaccac ctctgttttc cttgctctat acagcagcac1680 atattatcat acagacagaa aatccagaat cttttcaaag cccacatatggtagcacagg 1740 ttggcctgtg catcggcaat tctcatatct gtttttttcaaagaataaaa tcaaataaag 1800 agcaggaaaa aaaaa 1815 137 382 PRT Homosapiens 137 Met Arg Pro Gly Thr Ala Leu Gln Ala Val Leu Leu Ala ValLeu Leu 1 5 10 15 Val Gly Leu Arg Ala Ala Thr Gly Arg Leu Leu SerAla Ser Asp Leu 20 25 30 Asp Leu Arg Gly Gly Gln Pro Val Cys ArgGly Gly Thr Gln Arg Pro 35 40 45 Cys Tyr Lys Val Ile Tyr Phe HisAsp Thr Ser Arg Arg Leu Asn Phe 50 55 60 Glu Glu Ala Lys Glu AlaCys Arg Arg Asp Gly Gly Gln Leu Val Ser 65 70 75 80 Ile Glu Ser GluAsp Glu Gln Lys Leu Ile Glu Lys Phe Ile Glu Asn 85 90 95 Leu LeuPro Ser Asp Gly Asp Phe Trp Ile Gly Leu Arg Arg Arg Glu 100 105 110Glu Lys Gln Ser Asn Ser Thr Ala Cys Gln Asp Leu Tyr Ala Trp Thr 115120 125 Asp Gly Ser Ile Ser Gln Phe Arg Asn Trp Tyr Val Asp Glu ProSer 130 135 140 Cys Gly Ser Glu Val Cys Val Val Met Tyr His Gln ProSer Ala Pro 145 150 155 160 Ala Gly Ile Gly Gly Pro Tyr Met Phe GlnTrp Asn Asp Asp Arg Cys 165 170 175 Asn Met Lys Asn Asn Phe Ile CysLys Tyr Ser Asp Glu Lys Pro Ala 180 185 190 Val Pro Ser Arg Glu AlaGlu Gly Glu Glu Thr Glu Leu Thr Thr Pro 195 200 205 Val Leu Pro GluGlu Thr Gln Glu Glu Asp Ala Lys Lys Thr Phe Lys 210 215 220 Glu SerArg Glu Ala Ala Leu Asn Leu Ala Tyr Ile Leu Ile Pro Ser 225 230 235240 Ile Pro Leu Leu Leu Leu Leu Val Val Thr Thr Val Val Cys Trp Val245 250 255 Trp Ile Cys Arg Lys Arg Lys Arg Glu Gln Pro Asp Pro SerThr Lys 260 265 270 Lys Gln His Thr Ile Trp Pro Ser Pro His Gln GlyAsn Ser Pro Asp 275 280 285 Leu Glu Val Tyr Asn Val Ile Arg Lys GlnSer Glu Ala Asp Leu Ala 290 295 300 Glu Thr Arg Pro Asp Leu Lys AsnIle Ser Phe Arg Val Cys Ser Gly 305 310 315 320 Glu Ala Thr Pro AspAsp Met Ser Cys Asp Tyr Asp Asn Met Ala Val 325 330 335 Asn Pro SerGlu Ser Gly Phe Val Thr Leu Val Ser Val Glu Ser Gly 340 345 350 PheVal Thr Asn Asp Ile Tyr Glu Phe Ser Pro Asp Gln Met Gly Arg 355 360365 Ser Lys Glu Ser Gly Trp Val Glu Asn Glu Ile Tyr Gly Tyr 370 375380 138 50 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 138 gttcattgaa aacctcttgccatctgatgg tgacttctgg attgggctca 50 139 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe139 aagccaaaga agcctgcagg aggg 24 140 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe140 cagtccaagc ataaaggtcc tggc 24 141 1514 DNA Homo sapiens 141ggggtctccc tcagggccgg gaggcacagc ggtccctgct tgctgaaggg ctggatgtac60 gcatccgcag gttcccgcgg acttgggggc gcccgctgag ccccggcgcccgcagaagac 120 ttgtgtttgc ctcctgcagc ctcaacccgg agggcagcgagggcctacca ccatgatcac 180 tggtgtgttc agcatgcgct tgtggaccccagtgggcgtc ctgacctcgc tggcgtactg 240 cctgcaccag cggcgggtggccctggccga gctgcaggag gccgatggcc agtgtccggt 300 cgaccgcagcctgctgaagt tgaaaatggt gcaggtcgtg tttcgacacg gggctcggag 360tcctctcaag ccgctcccgc tggaggagca ggtagagtgg aacccccagc tattagaggt420 cccaccccaa actcagtttg attacacagt caccaatcta gctggtggtccgaaaccata 480 ttctccttac gactctcaat accatgagac caccctgaaggggggcatgt ttgctgggca 540 gctgaccaag gtgggcatgc agcaaatgtttgccttggga gagagactga ggaagaacta 600 tgtggaagac attccctttctttcaccaac cttcaaccca caggaggtct ttattcgttc 660 cactaacatttttcggaatc tggagtccac ccgttgtttg ctggctgggc ttttccagtg 720tcagaaagaa ggacccatca tcatccacac tgatgaagca gattcagaag tcttgtatcc780 caactaccaa agctgctgga gcctgaggca gagaaccaga ggccggaggcagactgcctc 840 tttacagcca ggaatctcag aggatttgaa aaaggtgaaggacaggatgg gcattgacag 900 tagtgataaa gtggacttct tcatcctcctggacaacgtg gctgccgagc aggcacacaa 960 cctcccaagc tgccccatgctgaagagatt tgcacggatg atcgaacaga gagctgtgga 1020 cacatccttgtacatactgc ccaaggaaga cagggaaagt cttcagatgg cagtaggccc 1080attcctccac atcctagaga gcaacctgct gaaagccatg gactctgcca ctgcccccga1140 caagatcaga aagctgtatc tctatgcggc tcatgatgtg accttcataccgctcttaat 1200 gaccctgggg atttttgacc acaaatggcc accgtttgctgttgacctga ccatggaact 1260 ttaccagcac ctggaatcta aggagtggtttgtgcagctc tattaccacg ggaaggagca 1320 ggtgccgaga ggttgccctgatgggctctg cccgctggac atgttcttga atgccatgtc 1380 agtttataccttaagcccag aaaaatacca tgcactctgc tctcaaactc aggtgatgga 1440agttggaaat gaagagtaac tgatttataa aagcaggatg tgttgatttt aaaataaagt1500 gcctttatac aatg 1514 142 428 PRT Homo sapiens 142 Met Ile ThrGly Val Phe Ser Met Arg Leu Trp Thr Pro Val Gly Val 1 5 10 15 LeuThr Ser Leu Ala Tyr Cys Leu His Gln Arg Arg Val Ala Leu Ala 20 2530 Glu Leu Gln Glu Ala Asp Gly Gln Cys Pro Val Asp Arg Ser Leu Leu35 40 45 Lys Leu Lys Met Val Gln Val Val Phe Arg His Gly Ala ArgSer Pro 50 55 60 Leu Lys Pro Leu Pro Leu Glu Glu Gln Val Glu TrpAsn Pro Gln Leu 65 70 75 80 Leu Glu Val Pro Pro Gln Thr Gln Phe AspTyr Thr Val Thr Asn Leu 85 90 95 Ala Gly Gly Pro Lys Pro Tyr SerPro Tyr Asp Ser Gln Tyr His Glu 100 105 110 Thr Thr Leu Lys Gly GlyMet Phe Ala Gly Gln Leu Thr Lys Val Gly 115 120 125 Met Gln Gln MetPhe Ala Leu Gly Glu Arg Leu Arg Lys Asn Tyr Val 130 135 140 Glu AspIle Pro Phe Leu Ser Pro Thr Phe Asn Pro Gln Glu Val Phe 145 150 155160 Ile Arg Ser Thr Asn Ile Phe Arg Asn Leu Glu Ser Thr Arg Cys Leu165 170 175 Leu Ala Gly Leu Phe Gln Cys Gln Lys Glu Gly Pro Ile IleIle His 180 185 190 Thr Asp Glu Ala Asp Ser Glu Val Leu Tyr Pro AsnTyr Gln Ser Cys 195 200 205 Trp Ser Leu Arg Gln Arg Thr Arg Gly ArgArg Gln Thr Ala Ser Leu 210 215 220 Gln Pro Gly Ile Ser Glu Asp LeuLys Lys Val Lys Asp Arg Met Gly 225 230 235 240 Ile Asp Ser Ser AspLys Val Asp Phe Phe Ile Leu Leu Asp Asn Val 245 250 255 Ala Ala GluGln Ala His Asn Leu Pro Ser Cys Pro Met Leu Lys Arg 260 265 270 PheAla Arg Met Ile Glu Gln Arg Ala Val Asp Thr Ser Leu Tyr Ile 275 280285 Leu Pro Lys Glu Asp Arg Glu Ser Leu Gln Met Ala Val Gly Pro Phe290 295 300 Leu His Ile Leu Glu Ser Asn Leu Leu Lys Ala Met Asp SerAla Thr 305 310 315 320 Ala Pro Asp Lys Ile Arg Lys Leu Tyr Leu TyrAla Ala His Asp Val 325 330 335 Thr Phe Ile Pro Leu Leu Met Thr LeuGly Ile Phe Asp His Lys Trp 340 345 350 Pro Pro Phe Ala Val Asp LeuThr Met Glu Leu Tyr Gln His Leu Glu 355 360 365 Ser Lys Glu Trp PheVal Gln Leu Tyr Tyr His Gly Lys Glu Gln Val 370 375 380 Pro Arg GlyCys Pro Asp Gly Leu Cys Pro Leu Asp Met Phe Leu Asn 385 390 395 400Ala Met Ser Val Tyr Thr Leu Ser Pro Glu Lys Tyr His Ala Leu Cys 405410 415 Ser Gln Thr Gln Val Met Glu Val Gly Asn Glu Glu 420 425 14324 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 143 ccaactacca aagctgctgg agcc 24144 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 144 gcagctctat taccacggga agga 24145 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 145 tccttcccgt ggtaatagag ctgc 24146 45 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 146 ggcagagaac cagaggccggaggagactgc ctctttacag ccagg 45 147 1686 DNA Homo sapiens 147ctcctcttaa catacttgca gctaaaacta aatattgctg cttggggacc tccttctagc60 cttaaatttc agctcatcac cttcacctgc cttggtcatg gctctgctattctccttgat 120 ccttgccatt tgcaccagac ctggattcct agcgtctccatctggagtgc ggctggtggg 180 gggcctccac cgctgtgaag ggcgggtggaggtggaacag aaaggccagt ggggcaccgt 240 gtgtgatgac ggctgggacattaaggacgt ggctgtgttg tgccgggagc tgggctgtgg 300 agctgccagcggaaccccta gtggtatttt gtatgagcca ccagcagaaa aagagcaaaa 360ggtcctcatc caatcagtca gttgcacagg aacagaagat acattggctc agtgtgagca420 agaagaagtt tatgattgtt cacatgatga agatgctggg gcatcgtgtgagaacccaga 480 gagctctttc tccccagtcc cagagggtgt caggctggctgacggccctg ggcattgcaa 540 gggacgcgtg gaagtgaagc accagaaccagtggtatacc gtgtgccaga caggctggag 600 cctccgggcc gcaaaggtggtgtgccggca gctgggatgt gggagggctg tactgactca 660 aaaacgctgcaacaagcatg cctatggccg aaaacccatc tggctgagcc agatgtcatg 720ctcaggacga gaagcaaccc ttcaggattg cccttctggg ccttggggga agaacacctg780 caaccatgat gaagacacgt gggtcgaatg tgaagatccc tttgacttgagactagtagg 840 aggagacaac ctctgctctg ggcgactgga ggtgctgcacaagggcgtat ggggctctgt 900 ctgtgatgac aactggggag aaaaggaggaccaggtggta tgcaagcaac tgggctgtgg 960 gaagtccctc tctccctccttcagagaccg gaaatgctat ggccctgggg ttggccgcat 1020 ctggctggataatgttcgtt gctcagggga ggagcagtcc ctggagcagt gccagcacag 1080attttggggg tttcacgact gcacccacca ggaagatgtg gctgtcatct gctcagtgta1140 ggtgggcatc atctaatctg ttgagtgcct gaatagaaga aaaacacagaagaagggagc 1200 atttactgtc tacatgactg catgggatga acactgatcttcttctgccc ttggactggg 1260 acttatactt ggtgcccctg attctcaggccttcagagtt ggatcagaac ttacaacatc 1320 aggtctagtt ctcaggccatcagacatagt ttggaactac atcaccacct ttcctatgtc 1380 tccacattgcacacagcaga ttcccagcct ccataattgt gtgtatcaac tacttaaata 1440cattctcaca cacacacaca cacacacaca cacacacaca cacacataca ccatttgtcc1500 tgtttctctg aagaactctg acaaaataca gattttggta ctgaaagagattctagagga 1560 acggaatttt aaggataaat tttctgaatt ggttatggggtttctgaaat tggctctata 1620 atctaattag atataaaatt ctggtaactttatttacaat aataaagata gcactatgtg 1680 ttcaaa 1686 148 347 PRT Homosapiens 148 Met Ala Leu Leu Phe Ser Leu Ile Leu Ala Ile Cys Thr ArgPro Gly 1 5 10 15 Phe Leu Ala Ser Pro Ser Gly Val Arg Leu Val GlyGly Leu His Arg 20 25 30 Cys Glu Gly Arg Val Glu Val Glu Gln LysGly Gln Trp Gly Thr Val 35 40 45 Cys Asp Asp Gly Trp Asp Ile LysAsp Val Ala Val Leu Cys Arg Glu 50 55 60 Leu Gly Cys Gly Ala AlaSer Gly Thr Pro Ser Gly Ile Leu Tyr Glu 65 70 75 80 Pro Pro Ala GluLys Glu Gln Lys Val Leu Ile Gln Ser Val Ser Cys 85 90 95 Thr GlyThr Glu Asp Thr Leu Ala Gln Cys Glu Gln Glu Glu Val Tyr 100 105 110Asp Cys Ser His Asp Glu Asp Ala Gly Ala Ser Cys Glu Asn Pro Glu 115120 125 Ser Ser Phe Ser Pro Val Pro Glu Gly Val Arg Leu Ala Asp GlyPro 130 135 140 Gly His Cys Lys Gly Arg Val Glu Val Lys His Gln AsnGln Trp Tyr 145 150 155 160 Thr Val Cys Gln Thr Gly Trp Ser Leu ArgAla Ala Lys Val Val Cys 165 170 175 Arg Gln Leu Gly Cys Gly Arg AlaVal Leu Thr Gln Lys Arg Cys Asn 180 185 190 Lys His Ala Tyr Gly ArgLys Pro Ile Trp Leu Ser Gln Met Ser Cys 195 200

205 Ser Gly Arg Glu Ala Thr Leu Gln Asp Cys Pro Ser Gly Pro Trp Gly210 215 220 Lys Asn Thr Cys Asn His Asp Glu Asp Thr Trp Val Glu CysGlu Asp 225 230 235 240 Pro Phe Asp Leu Arg Leu Val Gly Gly Asp AsnLeu Cys Ser Gly Arg 245 250 255 Leu Glu Val Leu His Lys Gly Val TrpGly Ser Val Cys Asp Asp Asn 260 265 270 Trp Gly Glu Lys Glu Asp GlnVal Val Cys Lys Gln Leu Gly Cys Gly 275 280 285 Lys Ser Leu Ser ProSer Phe Arg Asp Arg Lys Cys Tyr Gly Pro Gly 290 295 300 Val Gly ArgIle Trp Leu Asp Asn Val Arg Cys Ser Gly Glu Glu Gln 305 310 315 320Ser Leu Glu Gln Cys Gln His Arg Phe Trp Gly Phe His Asp Cys Thr 325330 335 His Gln Glu Asp Val Ala Val Ile Cys Ser Val 340 345 149 24DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 149 ttcagctcat caccttcacc tgcc 24150 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 150 ggctcataca aaataccact aggg 24151 50 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 151 gggcctccac cgctgtgaagggcgggtgga ggtggaacag aaaggccagt 50 152 1427 DNA Homo sapiens 152actgcactcg gttctatcga ttgaattccc cggggatcct ctagagatcc ctcgacctcg60 acccacgcgt ccgcggacgc gtgggcggac gcgtgggccg gctaccaggaagagtctgcc 120 gaaggtgaag gccatggact tcatcacctc cacagccatcctgcccctgc tgttcggctg 180 cctgggcgtc ttcggcctct tccggctgctgcagtgggtg cgcgggaagg cctacctgcg 240 gaatgctgtg gtggtgatcacaggcgccac ctcagggctg ggcaaagaat gtgcaaaagt 300 cttctatgctgcgggtgcta aactggtgct ctgtggccgg aatggtgggg ccctagaaga 360gctcatcaga gaacttaccg cttctcatgc caccaaggtg cagacacaca agccttactt420 ggtgaccttc gacctcacag actctggggc catagttgca gcagcagctgagatcctgca 480 gtgctttggc tatgtcgaca tacttgtcaa caatgctgggatcagctacc gtggtaccat 540 catggacacc acagtggatg tggacaagagggtcatggag acaaactact ttggcccagt 600 tgctctaacg aaagcactcctgccctccat gatcaagagg aggcaaggcc acattgtcgc 660 catcagcagcatccagggca agatgagcat tccttttcga tcagcatatg cagcctccaa 720gcacgcaacc caggctttct ttgactgtct gcgtgccgag atggaacagt atgaaattga780 ggtgaccgtc atcagccccg gctacatcca caccaacctc tctgtaaatgccatcaccgc 840 ggatggatct aggtatggag ttatggacac caccacagcccagggccgaa gccctgtgga 900 ggtggcccag gatgttcttg ctgctgtggggaagaagaag aaagatgtga tcctggctga 960 cttactgcct tccttggctgtttatcttcg aactctggct cctgggctct tcttcagcct 1020 catggcctccagggccagaa aagagcggaa atccaagaac tcctagtact ctgaccagcc 1080agggccaggg cagagaagca gcactcttag gcttgcttac tctacaaggg acagttgcat1140 ttgttgagac tttaatggag atttgtctca caagtgggaa agactgaagaaacacatctc 1200 gtgcagatct gctggcagag gacaatcaaa aacgacaacaagcttcttcc cagggtgagg 1260 ggaaacactt aaggaataaa tatggagctggggtttaaca ctaaaaacta gaaataaaca 1320 tctcaaacag taaaaaaaaaaaaaaagggc ggccgcgact ctagagtcga cctgcagaag 1380 cttggccgccatggcccaac ttgtttattg cagcttataa tggttac 1427 153 310 PRT Homosapiens 153 Met Asp Phe Ile Thr Ser Thr Ala Ile Leu Pro Leu Leu PheGly Cys 1 5 10 15 Leu Gly Val Phe Gly Leu Phe Arg Leu Leu Gln TrpVal Arg Gly Lys 20 25 30 Ala Tyr Leu Arg Asn Ala Val Val Val IleThr Gly Ala Thr Ser Gly 35 40 45 Leu Gly Lys Glu Cys Ala Lys ValPhe Tyr Ala Ala Gly Ala Lys Leu 50 55 60 Val Leu Cys Gly Arg AsnGly Gly Ala Leu Glu Glu Leu Ile Arg Glu 65 70 75 80 Leu Thr Ala SerHis Ala Thr Lys Val Gln Thr His Lys Pro Tyr Leu 85 90 95 Val ThrPhe Asp Leu Thr Asp Ser Gly Ala Ile Val Ala Ala Ala Ala 100 105 110Glu Ile Leu Gln Cys Phe Gly Tyr Val Asp Ile Leu Val Asn Asn Ala 115120 125 Gly Ile Ser Tyr Arg Gly Thr Ile Met Asp Thr Thr Val Asp ValAsp 130 135 140 Lys Arg Val Met Glu Thr Asn Tyr Phe Gly Pro Val AlaLeu Thr Lys 145 150 155 160 Ala Leu Leu Pro Ser Met Ile Lys Arg ArgGln Gly His Ile Val Ala 165 170 175 Ile Ser Ser Ile Gln Gly Lys MetSer Ile Pro Phe Arg Ser Ala Tyr 180 185 190 Ala Ala Ser Lys His AlaThr Gln Ala Phe Phe Asp Cys Leu Arg Ala 195 200 205 Glu Met Glu GlnTyr Glu Ile Glu Val Thr Val Ile Ser Pro Gly Tyr 210 215 220 Ile HisThr Asn Leu Ser Val Asn Ala Ile Thr Ala Asp Gly Ser Arg 225 230 235240 Tyr Gly Val Met Asp Thr Thr Thr Ala Gln Gly Arg Ser Pro Val Glu245 250 255 Val Ala Gln Asp Val Leu Ala Ala Val Gly Lys Lys Lys LysAsp Val 260 265 270 Ile Leu Ala Asp Leu Leu Pro Ser Leu Ala Val TyrLeu Arg Thr Leu 275 280 285 Ala Pro Gly Leu Phe Phe Ser Leu Met AlaSer Arg Ala Arg Lys Glu 290 295 300 Arg Lys Ser Lys Asn Ser 305 310154 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 154 ggtgctaaac tggtgctctg tggc 24155 20 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 155 cagggcaaga tgagcattcc 20 156 24DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 156 tcatactgtt ccatctcggc acgc 24157 50 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 157 aatggtgggg ccctagaagagctcatcaga gaactcaccg cttctcatgc 50 158 1771 DNA Homo sapiens 158cccacgcgtc cgctggtgtt agatcgagca accctctaaa agcagtttag agtggtaaaa60 aaaaaaaaaa acacaccaaa cgctcgcagc cacaaaaggg atgaaatttcttctggacat 120 cctcctgctt ctcccgttac tgatcgtctg ctccctagagtccttcgtga agctttttat 180 tcctaagagg agaaaatcag tcaccggcgaaatcgtgctg attacaggag ctgggcatgg 240 aattgggaga ctgactgcctatgaatttgc taaacttaaa agcaagctgg ttctctggga 300 tataaataagcatggactgg aggaaacagc tgccaaatgc aagggactgg gtgccaaggt 360tcataccttt gtggtagact gcagcaaccg agaagatatt tacagctctg caaagaaggt420 gaaggcagaa attggagatg ttagtatttt agtaaataat gctggtgtagtctatacatc 480 agatttgttt gctacacaag atcctcagat tgaaaagacttttgaagtta atgtacttgc 540 acatttctgg actacaaagg catttcttcctgcaatgacg aagaataacc atggccatat 600 tgtcactgtg gcttcggcagctggacatgt ctcggtcccc ttcttactgg cttactgttc 660 aagcaagtttgctgctgttg gatttcataa aactttgaca gatgaactgg ctgccttaca 720aataactgga gtcaaaacaa catgtctgtg tcctaatttc gtaaacactg gcttcatcaa780 aaatccaagt acaagtttgg gacccactct ggaacctgag gaagtggtaaacaggctgat 840 gcatgggatt ctgactgagc agaagatgat ttttattccatcttctatag cttttttaac 900 aacattggaa aggatccttc ctgagcgtttcctggcagtt ttaaaacgaa aaatcagtgt 960 taagtttgat gcagttattggatataaaat gaaagcgcaa taagcaccta gttttctgaa 1020 aactgatttaccaggtttag gttgatgtca tctaatagtg ccagaatttt aatgtttgaa 1080cttctgtttt ttctaattat ccccatttct tcaatatcat ttttgaggct ttggcagtct1140 tcatttacta ccacttgttc tttagccaaa agctgattac atatgatataaacagagaaa 1200 tacctttaga ggtgacttta aggaaaatga agaaaaagaaccaaaatgac tttattaaaa 1260 taatttccaa gattatttgt ggctcacctgaaggctttgc aaaatttgta ccataaccgt 1320 ttatttaaca tatatttttatttttgattg cacttaaatt ttgtataatt tgtgtttctt 1380 tttctgttctacataaaatc agaaacttca agctctctaa ataaaatgaa ggactatatc 1440tagtggtatt tcacaatgaa tatcatgaac tctcaatggg taggtttcat cctacccatt1500 gccactctgt ttcctgagag atacctcaca ttccaatgcc aaacatttctgcacagggaa 1560 gctagaggtg gatacacgtg ttgcaagtat aaaagcatcactgggattta aggagaattg 1620 agagaatgta cccacaaatg gcagcaataataaatggatc acacttaaaa aaaaaaaaaa 1680 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1740 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa a 1771 159 300 PRT Homo sapiens 159 Met LysPhe Leu Leu Asp Ile Leu Leu Leu Leu Pro Leu Leu Ile Val 1 5 10 15Cys Ser Leu Glu Ser Phe Val Lys Leu Phe Ile Pro Lys Arg Arg Lys 2025 30 Ser Val Thr Gly Glu Ile Val Leu Ile Thr Gly Ala Gly His GlyIle 35 40 45 Gly Arg Leu Thr Ala Tyr Glu Phe Ala Lys Leu Lys SerLys Leu Val 50 55 60 Leu Trp Asp Ile Asn Lys His Gly Leu Glu GluThr Ala Ala Lys Cys 65 70 75 80 Lys Gly Leu Gly Ala Lys Val His ThrPhe Val Val Asp Cys Ser Asn 85 90 95 Arg Glu Asp Ile Tyr Ser SerAla Lys Lys Val Lys Ala Glu Ile Gly 100 105 110 Asp Val Ser Ile LeuVal Asn Asn Ala Gly Val Val Tyr Thr Ser Asp 115 120 125 Leu Phe AlaThr Gln Asp Pro Gln Ile Glu Lys Thr Phe Glu Val Asn 130 135 140 ValLeu Ala His Phe Trp Thr Thr Lys Ala Phe Leu Pro Ala Met Thr 145 150155 160 Lys Asn Asn His Gly His Ile Val Thr Val Ala Ser Ala Ala GlyHis 165 170 175 Val Ser Val Pro Phe Leu Leu Ala Tyr Cys Ser Ser LysPhe Ala Ala 180 185 190 Val Gly Phe His Lys Thr Leu Thr Asp Glu LeuAla Ala Leu Gln Ile 195 200 205 Thr Gly Val Lys Thr Thr Cys Leu CysPro Asn Phe Val Asn Thr Gly 210 215 220 Phe Ile Lys Asn Pro Ser ThrSer Leu Gly Pro Thr Leu Glu Pro Glu 225 230 235 240 Glu Val Val AsnArg Leu Met His Gly Ile Leu Thr Glu Gln Lys Met 245 250 255 Ile PheIle Pro Ser Ser Ile Ala Phe Leu Thr Thr Leu Glu Arg Ile 260 265 270Leu Pro Glu Arg Phe Leu Ala Val Leu Lys Arg Lys Ile Ser Val Lys 275280 285 Phe Asp Ala Val Ile Gly Tyr Lys Met Lys Ala Gln 290 295 300160 23 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 160 ggtgaaggca gaaattggag atg 23161 24 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 161 atcccatgca tcagcctgtt tacc 24162 48 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 162 gctggtgtag tctatacatcagatttgttt gctacacaag atcctcag 48 163 2076 DNA Homo sapiens 163cccacgcgtc cgcggacgcg tgggtcgact agttctagat cgcgagcggc cgcccgcggc60 tcagggagga gcaccgactg cgccgcaccc tgagagatgg ttggtgccatgtggaaggtg 120 attgtttcgc tggtcctgtt gatgcctggc ccctgtgatgggctgtttcg ctccctatac 180 agaagtgttt ccatgccacc taagggagactcaggacagc cattatttct caccccttac 240 attgaagctg ggaagatccaaaaaggaaga gaattgagtt tggtcggccc tttcccagga 300 ctgaacatgaagagttatgc cggcttcctc accgtgaata agacttacaa cagcaacctc 360ttcttctggt tcttcccagc tcagatacag ccagaagatg ccccagtagt tctctggcta420 cagggtgggc cgggaggttc atccatgttt ggactctttg tggaacatgggccttatgtt 480 gtcacaagta acatgacctt gcgtgacaga gacttcccctggaccacaac gctctccatg 540 ctttacattg acaatccagt gggcacaggcttcagtttta ctgatgatac ccacggatat 600 gcagtcaatg aggacgatgtagcacgggat ttatacagtg cactaattca gtttttccag 660 atatttcctgaatataaaaa taatgacttt tatgtcactg gggagtctta tgcagggaaa 720tatgtgccag ccattgcaca cctcatccat tccctcaacc ctgtgagaga ggtgaagatc780 aacctgaacg gaattgctat tggagatgga tattctgatc ccgaatcaattatagggggc 840 tatgcagaat tcctgtacca aattggcttg ttggatgagaagcaaaaaaa gtacttccag 900 aagcagtgcc atgaatgcat agaacacatcaggaagcaga actggtttga ggcctttgaa 960 atactggata aactactagatggcgactta acaagtgatc cttcttactt ccagaatgtt 1020 acaggatgtagtaattacta taactttttg cggtgcacgg aacctgagga tcagctttac 1080tatgtgaaat ttttgtcact cccagaggtg agacaagcca tccacgtggg gaatcagact1140 tttaatgatg gaactatagt tgaaaagtac ttgcgagaag atacagtacagtcagttaag 1200 ccatggttaa ctgaaatcat gaataattat aaggttctgatctacaatgg ccaactggac 1260 atcatcgtgg cagctgccct gacagagcgctccttgatgg gcatggactg gaaaggatcc 1320 caggaataca agaaggcagaaaaaaaagtt tggaagatct ttaaatctga cagtgaagtg 1380 gctggttacatccggcaagc gggtgacttc catcaggtaa ttattcgagg tggaggacat 1440attttaccct atgaccagcc tctgagagct tttgacatga ttaatcgatt catttatgga1500 aaaggatggg atccttatgt tggataaact accttcccaa aagagaacatcagaggtttt 1560 cattgctgaa aagaaaatcg taaaaacaga aaatgtcataggaataaaaa aattatcttt 1620 tcatatctgc aagatttttt tcatcaataaaaattatcct tgaaacaagt gagcttttgt 1680 ttttgggggg agatgtttactacaaaatta acatgagtac atgagtaaga attacattat 1740 ttaacttaaaggatgaaagg tatggatgat gtgacactga gacaagatgt ataaatgaaa 1800ttttagggtc ttgaatagga agttttaatt tcttctaaga gtaagtgaaa agtgcagttg1860 taacaaacaa agctgtaaca tctttttctg ccaataacag aagtttggcatgccgtgaag 1920 gtgtttggaa atattattgg ataagaatag ctcaattatcccaaataaat ggatgaagct 1980 ataatagttt tggggaaaag attctcaaatgtataaagtc ttagaacaaa agaattcttt 2040 gaaataaaaa tattatatataaaagtaaaa aaaaaa 2076 164 476 PRT Homo sapiens 164 Met Val Gly AlaMet Trp Lys Val Ile Val Ser Leu Val Leu Leu Met 1 5 10 15 Pro GlyPro Cys Asp Gly Leu Phe Arg Ser Leu Tyr Arg Ser Val Ser 20 25 30Met Pro Pro Lys Gly Asp Ser Gly Gln Pro Leu Phe Leu Thr Pro Tyr 3540 45 Ile Glu Ala Gly Lys Ile Gln Lys Gly Arg Glu Leu Ser Leu ValGly 50 55 60 Pro Phe Pro Gly Leu Asn Met Lys Ser Tyr Ala Gly PheLeu Thr Val 65 70 75 80 Asn Lys Thr Tyr Asn Ser Asn Leu Phe Phe TrpPhe Phe Pro Ala Gln 85 90 95 Ile Gln Pro Glu Asp Ala Pro Val ValLeu Trp Leu Gln Gly Gly Pro 100 105 110 Gly Gly Ser Ser Met Phe GlyLeu Phe Val Glu His Gly Pro Tyr Val 115 120 125 Val Thr Ser Asn MetThr Leu Arg Asp Arg Asp Phe Pro Trp Thr Thr 130 135 140 Thr Leu SerMet Leu Tyr Ile Asp Asn Pro Val Gly Thr Gly Phe Ser 145 150 155 160Phe Thr Asp Asp Thr His Gly Tyr Ala Val Asn Glu Asp Asp Val Ala 165170 175 Arg Asp Leu Tyr Ser Ala Leu Ile Gln Phe Phe Gln Ile Phe ProGlu 180 185 190 Tyr Lys Asn Asn Asp Phe Tyr Val Thr Gly Glu Ser TyrAla Gly Lys 195 200 205 Tyr Val Pro Ala Ile Ala His Leu Ile His SerLeu Asn Pro Val Arg 210 215 220 Glu Val Lys Ile Asn Leu Asn Gly IleAla Ile Gly Asp Gly Tyr Ser 225 230 235 240 Asp Pro Glu Ser Ile IleGly Gly Tyr Ala Glu Phe Leu Tyr Gln Ile 245 250 255 Gly Leu Leu AspGlu Lys Gln Lys Lys Tyr Phe Gln Lys Gln Cys His 260 265 270 Glu CysIle Glu His Ile Arg Lys Gln Asn Trp Phe Glu Ala Phe Glu 275 280 285Ile Leu Asp Lys Leu Leu Asp Gly Asp Leu Thr Ser Asp Pro Ser Tyr 290295 300 Phe Gln Asn Val Thr Gly Cys Ser Asn Tyr Tyr Asn Phe Leu ArgCys 305 310 315 320 Thr Glu Pro Glu Asp Gln Leu Tyr Tyr Val Lys PheLeu Ser Leu Pro 325 330 335 Glu Val Arg Gln Ala Ile His Val Gly AsnGln Thr Phe Asn Asp Gly 340 345 350 Thr Ile Val Glu Lys Tyr Leu ArgGlu Asp Thr Val Gln Ser Val Lys 355 360 365 Pro Trp Leu Thr Glu IleMet Asn Asn Tyr Lys Val Leu Ile Tyr Asn 370 375 380 Gly Gln Leu AspIle Ile Val Ala Ala Ala Leu Thr Glu Arg Ser Leu 385 390 395 400 MetGly Met Asp Trp Lys Gly Ser Gln Glu Tyr Lys Lys Ala Glu Lys 405 410415 Lys Val Trp Lys Ile Phe Lys Ser Asp Ser Glu Val Ala Gly Tyr Ile420 425 430 Arg Gln Ala Gly Asp Phe His Gln Val Ile Ile Arg Gly GlyGly His 435 440 445 Ile Leu Pro Tyr Asp Gln Pro Leu Arg Ala Phe AspMet Ile Asn Arg 450 455 460 Phe Ile Tyr Gly Lys Gly Trp Asp Pro TyrVal Gly 465 470 475 165 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 165 ttccatgccacctaagggag actc 24 166 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 166 tggatgaggtgtgcaatggc tggc 24 167 24 DNA Artificial Sequence Description ofArtificial Sequence Synthetic oligonucleotide probe 167 agctctcagaggctggtcat aggg 24 168 50 DNA Artificial Sequence Descriptionof

Artificial Sequence Synthetic oligonucleotide probe 168 gtcggccctttcccaggact gaacatgaag agttatgccg gcttcctcac 50 169 2477 DNA Homosapiens 169 cgagggcttt tccggctccg gaatggcaca tgtgggaatc ccagtcttgttggctacaac 60 atttttccct ttcctaacaa gttctaacag ctgttctaacagctagtgat caggggttct 120 tcttgctgga gaagaaaggg ctgagggcagagcagggcac tctcactcag ggtgaccagc 180 tccttgcctc tctgtggataacagagcatg agaaagtgaa gagatgcagc ggagtgaggt 240 gatggaagtctaaaatagga aggaattttg tgtgcaatat cagactctgg gagcagttga 300cctggagagc ctgggggagg gcctgcctaa caagctttca aaaaacagga gcgacttcca360 ctgggctggg ataagacgtg ccggtaggat agggaagact gggtttagtcctaatatcaa 420 attgactggc tgggtgaact tcaacagcct tttaacctctctgggagatg aaaacgatgg 480 cttaaggggc cagaaataga gatgctttgtaaaataaaat tttaaaaaaa gcaagtattt 540 tatagcataa aggctagagaccaaaataga taacaggatt ccctgaacat tcctaagagg 600 gagaaagtatgttaaaaata gaaaaaccaa aatgcagaag gaggagactc acagagctaa 660accaggatgg ggaccctggg tcaggccagc ctctttgctc ctcccggaaa ttatttttgg720 tctgaccact ctgccttgtg ttttgcagaa tcatgtgagg gccaaccggggaaggtggag 780 cagatgagca cacacaggag ccgtctcctc accgccgcccctctcagcat ggaacagagg 840 cagccctggc cccgggccct ggaggtggacagccgctctg tggtcctgct ctcagtggtc 900 tgggtgctgc tggcccccccagcagccggc atgcctcagt tcagcacctt ccactctgag 960 aatcgtgactggaccttcaa ccacttgacc gtccaccaag ggacgggggc cgtctatgtg 1020ggggccatca accgggtcta taagctgaca ggcaacctga ccatccaggt ggctcataag1080 acagggccag aagaggacaa caagtctcgt tacccgcccc tcatcgtgcagccctgcagc 1140 gaagtgctca ccctcaccaa caatgtcaac aagctgctcatcattgacta ctctgagaac 1200 cgcctgctgg cctgtgggag cctctaccagggggtctgca agctgctgcg gctggatgac 1260 ctcttcatcc tggtggagccatcccacaag aaggagcact acctgtccag tgtcaacaag 1320 acgggcaccatgtacggggt gattgtgcgc tctgagggtg aggatggcaa gctcttcatc 1380ggcacggctg tggatgggaa gcaggattac ttcccgaccc tgtccagccg gaagctgccc1440 cgagaccctg agtcctcagc catgctcgac tatgagctac acagcgattttgtctcctct 1500 ctcatcaaga tcccttcaga caccctggcc ctggtctcccactttgacat cttctacatc 1560 tacggctttg ctagtggggg ctttgtctactttctcactg tccagcccga gacccctgag 1620 ggtgtggcca tcaactccgctggagacctc ttctacacct cacgcatcgt gcggctctgc 1680 aaggatgaccccaagttcca ctcatacgtg tccctgccct tcggctgcac ccgggccggg 1740gtggaatacc gcctcctgca ggctgcttac ctggccaagc ctggggactc actggcccag1800 gccttcaata tcaccagcca ggacgatgta ctctttgcca tcttctccaaagggcagaag 1860 cagtatcacc acccgcccga tgactctgcc ctgtgtgccttccctatccg ggccatcaac 1920 ttgcagatca aggagcgcct gcagtcctgctaccagggcg agggcaacct ggagctcaac 1980 tggctgctgg ggaaggacgtccagtgcacg aaggcgcctg tccccatcga tgataacttc 2040 tgtggactggacatcaacca gcccctggga ggctcaactc cagtggaggg cctgaccctg 2100tacaccacca gcagggaccg catgacctct gtggcctcct acgtttacaa cggctacagc2160 gtggtttttg tggggactaa gagtggcaag ctgaaaaagg taagagtctatgagttcaga 2220 tgctccaatg ccattcacct cctcagcaaa gagtccctcttggaaggtag ctattggtgg 2280 agatttaact ataggcaact ttattttcttggggaacaaa ggtgaaatgg ggaggtaaga 2340 aggggttaat tttgtgacttagcttctagc tacttcctcc agccatcagt cattgggtat 2400 gtaaggaatgcaagcgtatt tcaatatttc ccaaacttta agaaaaaact ttaagaaggt 2460acatctgcaa aagcaaa 2477 170 552 PRT Homo sapiens 170 Met Gly ThrLeu Gly Gln Ala Ser Leu Phe Ala Pro Pro Gly Asn Tyr 1 5 10 15 PheTrp Ser Asp His Ser Ala Leu Cys Phe Ala Glu Ser Cys Glu Gly 20 2530 Gln Pro Gly Lys Val Glu Gln Met Ser Thr His Arg Ser Arg Leu Leu35 40 45 Thr Ala Ala Pro Leu Ser Met Glu Gln Arg Gln Pro Trp ProArg Ala 50 55 60 Leu Glu Val Asp Ser Arg Ser Val Val Leu Leu SerVal Val Trp Val 65 70 75 80 Leu Leu Ala Pro Pro Ala Ala Gly Met ProGln Phe Ser Thr Phe His 85 90 95 Ser Glu Asn Arg Asp Trp Thr PheAsn His Leu Thr Val His Gln Gly 100 105 110 Thr Gly Ala Val Tyr ValGly Ala Ile Asn Arg Val Tyr Lys Leu Thr 115 120 125 Gly Asn Leu ThrIle Gln Val Ala His Lys Thr Gly Pro Glu Glu Asp 130 135 140 Asn LysSer Arg Tyr Pro Pro Leu Ile Val Gln Pro Cys Ser Glu Val 145 150 155160 Leu Thr Leu Thr Asn Asn Val Asn Lys Leu Leu Ile Ile Asp Tyr Ser165 170 175 Glu Asn Arg Leu Leu Ala Cys Gly Ser Leu Tyr Gln Gly ValCys Lys 180 185 190 Leu Leu Arg Leu Asp Asp Leu Phe Ile Leu Val GluPro Ser His Lys 195 200 205 Lys Glu His Tyr Leu Ser Ser Val Asn LysThr Gly Thr Met Tyr Gly 210 215 220 Val Ile Val Arg Ser Glu Gly GluAsp Gly Lys Leu Phe Ile Gly Thr 225 230 235 240 Ala Val Asp Gly LysGln Asp Tyr Phe Pro Thr Leu Ser Ser Arg Lys 245 250 255 Leu Pro ArgAsp Pro Glu Ser Ser Ala Met Leu Asp Tyr Glu Leu His 260 265 270 SerAsp Phe Val Ser Ser Leu Ile Lys Ile Pro Ser Asp Thr Leu Ala 275 280285 Leu Val Ser His Phe Asp Ile Phe Tyr Ile Tyr Gly Phe Ala Ser Gly290 295 300 Gly Phe Val Tyr Phe Leu Thr Val Gln Pro Glu Thr Pro GluGly Val 305 310 315 320 Ala Ile Asn Ser Ala Gly Asp Leu Phe Tyr ThrSer Arg Ile Val Arg 325 330 335 Leu Cys Lys Asp Asp Pro Lys Phe HisSer Tyr Val Ser Leu Pro Phe 340 345 350 Gly Cys Thr Arg Ala Gly ValGlu Tyr Arg Leu Leu Gln Ala Ala Tyr 355 360 365 Leu Ala Lys Pro GlyAsp Ser Leu Ala Gln Ala Phe Asn Ile Thr Ser 370 375 380 Gln Asp AspVal Leu Phe Ala Ile Phe Ser Lys Gly Gln Lys Gln Tyr 385 390 395 400His His Pro Pro Asp Asp Ser Ala Leu Cys Ala Phe Pro Ile Arg Ala 405410 415 Ile Asn Leu Gln Ile Lys Glu Arg Leu Gln Ser Cys Tyr Gln GlyGlu 420 425 430 Gly Asn Leu Glu Leu Asn Trp Leu Leu Gly Lys Asp ValGln Cys Thr 435 440 445 Lys Ala Pro Val Pro Ile Asp Asp Asn Phe CysGly Leu Asp Ile Asn 450 455 460 Gln Pro Leu Gly Gly Ser Thr Pro ValGlu Gly Leu Thr Leu Tyr Thr 465 470 475 480 Thr Ser Arg Asp Arg MetThr Ser Val Ala Ser Tyr Val Tyr Asn Gly 485 490 495 Tyr Ser Val ValPhe Val Gly Thr Lys Ser Gly Lys Leu Lys Lys Val 500 505 510 Arg ValTyr Glu Phe Arg Cys Ser Asn Ala Ile His Leu Leu Ser Lys 515 520 525Glu Ser Leu Leu Glu Gly Ser Tyr Trp Trp Arg Phe Asn Tyr Arg Gln 530535 540 Leu Tyr Phe Leu Gly Glu Gln Arg 545 550 171 20 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 171 tggaataccg cctcctgcag 20 172 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 172 cttctgccct ttggagaaga tggc 24 173 43 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 173 ggactcactg gcccaggcct tcaatatcaccagccaggac gat 43 174 3106 DNA Homo sapiens modified_base(1683)..(1683) a, t, c or g 174 aggctcccgc gcgcggctga gtgcggactggagtgggaac ccgggtcccc gcgcttagag 60 aacacgcgat gaccacgtggagcctccggc ggaggccggc ccgcacgctg ggactcctgc 120 tgctggtcgtcttgggcttc ctggtgctcc gcaggctgga ctggagcacc ctggtccctc 180tgcggctccg ccatcgacag ctggggctgc aggccaaggg ctggaacttc atgctggagg240 attccacctt ctggatcttc gggggctcca tccactattt ccgtgtgcccagggagtact 300 ggagggaccg cctgctgaag atgaaggcct gtggcttgaacaccctcacc acctatgttc 360 cgtggaacct gcatgagcca gaaagaggcaaatttgactt ctctgggaac ctggacctgg 420 aggccttcgt cctgatggccgcagagatcg ggctgtgggt gattctgcgt ccaggcccct 480 acatctgcagtgagatggac ctcgggggct tgcccagctg gctactccaa gaccctggca 540tgaggctgag gacaacttac aagggcttca ccgaagcagt ggacctttat tttgaccacc600 tgatgtccag ggtggtgcca ctccagtaca agcgtggggg acctatcattgccgtgcagg 660 tggagaatga atatggttcc tataataaag accccgcatacatgccctac gtcaagaagg 720 cactggagga ccgtggcatt gtggaactgctcctgacttc agacaacaag gatgggctga 780 gcaaggggat tgtccagggagtcttggcca ccatcaactt gcagtcaaca cacgagctgc 840 agctactgaccacctttctc ttcaacgtcc aggggactca gcccaagatg gtgatggagt 900actggacggg gtggtttgac tcgtggggag gccctcacaa tatcttggat tcttctgagg960 ttttgaaaac cgtgtctgcc attgtggacg ccggctcctc catcaacctctacatgttcc 1020 acggaggcac caactttggc ttcatgaatg gagccatgcacttccatgac tacaagtcag 1080 atgtcaccag ctatgactat gatgctgtgctgacagaagc cggcgattac acggccaagt 1140 acatgaagct tcgagacttcttcggctcca tctcaggcat ccctctccct cccccacctg 1200 accttcttcccaagatgccg tatgagccct taacgccagt cttgtacctg tctctgtggg 1260acgccctcaa gtacctgggg gagccaatca agtctgaaaa gcccatcaac atggagaacc1320 tgccagtcaa tgggggaaat ggacagtcct tcgggtacat tctctatgagaccagcatca 1380 cctcgtctgg catcctcagt ggccacgtgc atgatcgggggcaggtgttt gtgaacacag 1440 tatccatagg attcttggac tacaagacaacgaagattgc tgtccccctg atccagggtt 1500 acaccgtgct gaggatcttggtggagaatc gtgggcgagt caactatggg gagaatattg 1560 atgaccagcgcaaaggctta attggaaatc tctatctgaa tgattcaccc ctgaaaaact 1620tcagaatcta tagcctggat atgaagaaga gcttctttca gaggttcggc ctggacaaat1680 ggngttccct cccagaaaca cccacattac ctgctttctt cttgggtagcttgtccatca 1740 gctccacgcc ttgtgacacc tttctgaagc tggagggctgggagaagggg gttgtattca 1800 tcaatggcca gaaccttgga cgttactggaacattggacc ccagaagacg ctttacctcc 1860 caggtccctg gttgagcagcggaatcaacc aggtcatcgt ttttgaggag acgatggcgg 1920 gccctgcattacagttcacg gaaacccccc acctgggcag gaaccagtac attaagtgag 1980cggtggcacc ccctcctgct ggtgccagtg ggagactgcc gcctcctctt gacctgaagc2040 ctggtggctg ctgccccacc cctcactgca aaagcatctc cttaagtagcaacctcaggg 2100 actgggggct acagtctgcc cctgtctcag ctcaaaaccctaagcctgca gggaaaggtg 2160 ggatggctct gggcctggct ttgttgatgatggctttcct acagccctgc tcttgtgccg 2220 aggctgtcgg gctgtctctagggtgggagc agctaatcag atcgcccagc ctttggccct 2280 cagaaaaagtgctgaaacgt gcccttgcac cggacgtcac agccctgcga gcatctgctg 2340gactcaggcg tgctctttgc tggttcctgg gaggcttggc cacatccctc atggccccat2400 tttatccccg aaatcctggg tgtgtcacca gtgtagaggg tggggaaggggtgtctcacc 2460 tgagctgact ttgttcttcc ttcacaacct tctgagccttctttgggatt ctggaaggaa 2520 ctcggcgtga gaaacatgtg acttcccctttcccttccca ctcgctgctt cccacagggt 2580 gacaggctgg gctggagaaacagaaatcct caccctgcgt cttcccaagt tagcaggtgt 2640 ctctggtgttcagtgaggag gacatgtgag tcctggcaga agccatggcc catgtctgca 2700catccaggga ggaggacaga aggcccagct cacatgtgag tcctggcaga agccatggcc2760 catgtctgca catccaggga ggaggacaga aggcccagct cacatgtgagtcctggcaga 2820 agccatggcc catgtctgca catccaggga ggaggacagaaggcccagct cacatgtgag 2880 tcctggcaga agccatggcc catgtctgcacatccaggga ggaggacaga aggcccagct 2940 cagtggcccc cgctccccaccccccacgcc cgaacagcag gggcagagca gccctccttc 3000 gaagtgtgtccaagtccgca tttgagcctt gttctggggc ccagcccaac acctggcttg 3060ggctcactgt cctgagttgc agtaaagcta taaccttgaa tcacaa 3106 175 636 PRTHomo sapiens MOD_RES (539) Any amino acid 175 Met Thr Thr Trp SerLeu Arg Arg Arg Pro Ala Arg Thr Leu Gly Leu 1 5 10 15 Leu Leu LeuVal Val Leu Gly Phe Leu Val Leu Arg Arg Leu Asp Trp 20 25 30 SerThr Leu Val Pro Leu Arg Leu Arg His Arg Gln Leu Gly Leu Gln 35 4045 Ala Lys Gly Trp Asn Phe Met Leu Glu Asp Ser Thr Phe Trp Ile Phe50 55 60 Gly Gly Ser Ile His Tyr Phe Arg Val Pro Arg Glu Tyr TrpArg Asp 65 70 75 80 Arg Leu Leu Lys Met Lys Ala Cys Gly Leu Asn ThrLeu Thr Thr Tyr 85 90 95 Val Pro Trp Asn Leu His Glu Pro Glu ArgGly Lys Phe Asp Phe Ser 100 105 110 Gly Asn Leu Asp Leu Glu Ala PheVal Leu Met Ala Ala Glu Ile Gly 115 120 125 Leu Trp Val Ile Leu ArgPro Gly Pro Tyr Ile Cys Ser Glu Met Asp 130 135 140 Leu Gly Gly LeuPro Ser Trp Leu Leu Gln Asp Pro Gly Met Arg Leu 145 150 155 160 ArgThr Thr Tyr Lys Gly Phe Thr Glu Ala Val Asp Leu Tyr Phe Asp 165 170175 His Leu Met Ser Arg Val Val Pro Leu Gln Tyr Lys Arg Gly Gly Pro180 185 190 Ile Ile Ala Val Gln Val Glu Asn Glu Tyr Gly Ser Tyr AsnLys Asp 195 200 205 Pro Ala Tyr Met Pro Tyr Val Lys Lys Ala Leu GluAsp Arg Gly Ile 210 215 220 Val Glu Leu Leu Leu Thr Ser Asp Asn LysAsp Gly Leu Ser Lys Gly 225 230 235 240 Ile Val Gln Gly Val Leu AlaThr Ile Asn Leu Gln Ser Thr His Glu 245 250 255 Leu Gln Leu Leu ThrThr Phe Leu Phe Asn Val Gln Gly Thr Gln Pro 260 265 270 Lys Met ValMet Glu Tyr Trp Thr Gly Trp Phe Asp Ser Trp Gly Gly 275 280 285 ProHis Asn Ile Leu Asp Ser Ser Glu Val Leu Lys Thr Val Ser Ala 290 295300 Ile Val Asp Ala Gly Ser Ser Ile Asn Leu Tyr Met Phe His Gly Gly305 310 315 320 Thr Asn Phe Gly Phe Met Asn Gly Ala Met His Phe HisAsp Tyr Lys 325 330 335 Ser Asp Val Thr Ser Tyr Asp Tyr Asp Ala ValLeu Thr Glu Ala Gly 340 345 350 Asp Tyr Thr Ala Lys Tyr Met Lys LeuArg Asp Phe Phe Gly Ser Ile 355 360 365 Ser Gly Ile Pro Leu Pro ProPro Pro Asp Leu Leu Pro Lys Met Pro 370 375 380 Tyr Glu Pro Leu ThrPro Val Leu Tyr Leu Ser Leu Trp Asp Ala Leu 385 390 395 400 Lys TyrLeu Gly Glu Pro Ile Lys Ser Glu Lys Pro Ile Asn Met Glu 405 410 415Asn Leu Pro Val Asn Gly Gly Asn Gly Gln Ser Phe Gly Tyr Ile Leu 420425 430 Tyr Glu Thr Ser Ile Thr Ser Ser Gly Ile Leu Ser Gly His ValHis 435 440 445 Asp Arg Gly Gln Val Phe Val Asn Thr Val Ser Ile GlyPhe Leu Asp 450 455 460 Tyr Lys Thr Thr Lys Ile Ala Val Pro Leu IleGln Gly Tyr Thr Val 465 470 475 480 Leu Arg Ile Leu Val Glu Asn ArgGly Arg Val Asn Tyr Gly Glu Asn 485 490 495 Ile Asp Asp Gln Arg LysGly Leu Ile Gly Asn Leu Tyr Leu Asn Asp 500 505 510 Ser Pro Leu LysAsn Phe Arg Ile Tyr Ser Leu Asp Met Lys Lys Ser 515 520 525 Phe PheGln Arg Phe Gly Leu Asp Lys Trp Xaa Ser Leu Pro Glu Thr 530 535 540Pro Thr Leu Pro Ala Phe Phe Leu Gly Ser Leu Ser Ile Ser Ser Thr 545550 555 560 Pro Cys Asp Thr Phe Leu Lys Leu Glu Gly Trp Glu Lys GlyVal Val 565 570 575 Phe Ile Asn Gly Gln Asn Leu Gly Arg Tyr Trp AsnIle Gly Pro Gln 580 585 590 Lys Thr Leu Tyr Leu Pro Gly Pro Trp LeuSer Ser Gly Ile Asn Gln 595 600 605 Val Ile Val Phe Glu Glu Thr MetAla Gly Pro Ala Leu Gln Phe Thr 610 615 620 Glu Thr Pro His Leu GlyArg Asn Gln Tyr Ile Lys 625 630 635 176 2505 DNA Homo sapiens 176ggggacgcgg agctgagagg ctccgggcta gctaggtgta ggggtggacg ggtcccagga60 ccctggtgag ggttctctac ttggccttcg gtgggggtca agacgcaggcacctacgcca 120 aaggggagca aagccgggct cggcccgagg cccccaggacctccatctcc caatgttgga 180 ggaatccgac acgtgacggt ctgtccgccgtctcagacta gaggagcgct gtaaacgcca 240 tggctcccaa gaagctgtcctgccttcgtt ccctgctgct gccgctcagc ctgacgctac 300 tgctgccccaggcagacact cggtcgttcg tagtggatag gggtcatgac cggtttctcc 360tagacggggc cccgttccgc tatgtgtctg gcagcctgca ctactttcgg gtaccgcggg420 tgctttgggc cgaccggctt ttgaagatgc gatggagcgg cctcaacgccatacagtttt 480 atgtgccctg gaactaccac gagccacagc ctggggtctataactttaat ggcagccggg 540 acctcattgc ctttctgaat gaggcagctctagcgaacct gttggtcata ctgagaccag 600 gaccttacat ctgtgcagagtgggagatgg ggggtctccc atcctggttg cttcgaaaac 660 ctgaaattcatctaagaacc tcagatccag acttccttgc cgcagtggac tcctggttca 720aggtcttgct gcccaagata tatccatggc tttatcacaa tgggggcaac atcattagca780 ttcaggtgga gaatgaatat ggtagctaca gagcctgtga cttcagctacatgaggcact 840 tggctgggct cttccgtgca ctgctaggag aaaagatcttgctcttcacc acagatgggc 900 ctgaaggact caagtgtggc tccctccggggactctatac cactgtagat tttggcccag 960 ctgacaacat gaccaaaatctttaccctgc ttcggaagta tgaaccccat gggccattgg 1020 taaactctgagtactacaca ggctggctgg attactgggg ccagaatcac tccacacggt 1080ctgtgtcagc tgtaaccaaa ggactagaga acatgctcaa gttgggagcc agtgtgaaca1140 tgtacatgtt ccatggaggt accaactttg gatattggaa tggtgccgataagaagggac 1200 gcttccttcc gattactacc agctatgact atgatgcacctatatctgaa gcaggggacc 1260 ccacacctaa gctttttgct cttcgagatgtcatcagcaa gttccaggaa gttcctttgg 1320 gacctttacc tcccccgagccccaagatga tgcttggacc tgtgactctg

cacctggttg 1380 ggcatttact ggctttccta gacttgcttt gcccccgtgggcccattcat tcaatcttgc 1440 caatgacctt tgaggctgtc aagcaggaccatggcttcat gttgtaccga acctatatga 1500 cccataccat ttttgagccaacaccattct gggtgccaaa taatggagtc catgaccgtg 1560 cctatgtgatggtggatggg gtgttccagg gtgttgtgga gcgaaatatg agagacaaac 1620tatttttgac ggggaaactg gggtccaaac tggatatctt ggtggagaac atggggaggc1680 tcagctttgg gtctaacagc agtgacttca agggcctgtt gaagccaccaattctggggc 1740 aaacaatcct tacccagtgg atgatgttcc ctctgaaaattgataacctt gtgaagtggt 1800 ggtttcccct ccagttgcca aaatggccatatcctcaagc tccttctggc cccacattct 1860 actccaaaac atttccaattttaggctcag ttggggacac atttctatat ctacctggat 1920 ggaccaagggccaagtctgg atcaatgggt ttaacttggg ccggtactgg acaaagcagg 1980ggccacaaca gaccctctac gtgccaagat tcctgctgtt tcctagggga gccctcaaca2040 aaattacatt gctggaacta gaagatgtac ctctccagcc ccaagtccaatttttggata 2100 agcctatcct caatagcact agtactttgc acaggacacatatcaattcc ctttcagctg 2160 atacactgag tgcctctgaa ccaatggagttaagtgggca ctgaaaggta ggccgggcat 2220 ggtggctcat gcctgtaatcccagcacttt gggaggctga gacgggtgga ttacctgagg 2280 tcaggacttcaagaccagcc tggccaacat ggtgaaaccc cgtctccact aaaaatacaa 2340aaattagccg ggcgtgatgg tgggcacctc taatcccagc tacttgggag gctgagggca2400 ggagaattgc ttgaatccag gaggcagagg ttgcagtgag tggaggttgtaccactgcac 2460 tccagcctgg ctgacagtga gacactccat ctcaaaaaaa aaaaa2505 177 654 PRT Homo sapiens 177 Met Ala Pro Lys Lys Leu Ser CysLeu Arg Ser Leu Leu Leu Pro Leu 1 5 10 15 Ser Leu Thr Leu Leu LeuPro Gln Ala Asp Thr Arg Ser Phe Val Val 20 25 30 Asp Arg Gly HisAsp Arg Phe Leu Leu Asp Gly Ala Pro Phe Arg Tyr 35 40 45 Val SerGly Ser Leu His Tyr Phe Arg Val Pro Arg Val Leu Trp Ala 50 55 60Asp Arg Leu Leu Lys Met Arg Trp Ser Gly Leu Asn Ala Ile Gln Phe 6570 75 80 Tyr Val Pro Trp Asn Tyr His Glu Pro Gln Pro Gly Val TyrAsn Phe 85 90 95 Asn Gly Ser Arg Asp Leu Ile Ala Phe Leu Asn GluAla Ala Leu Ala 100 105 110 Asn Leu Leu Val Ile Leu Arg Pro Gly ProTyr Ile Cys Ala Glu Trp 115 120 125 Glu Met Gly Gly Leu Pro Ser TrpLeu Leu Arg Lys Pro Glu Ile His 130 135 140 Leu Arg Thr Ser Asp ProAsp Phe Leu Ala Ala Val Asp Ser Trp Phe 145 150 155 160 Lys Val LeuLeu Pro Lys Ile Tyr Pro Trp Leu Tyr His Asn Gly Gly 165 170 175 AsnIle Ile Ser Ile Gln Val Glu Asn Glu Tyr Gly Ser Tyr Arg Ala 180 185190 Cys Asp Phe Ser Tyr Met Arg His Leu Ala Gly Leu Phe Arg Ala Leu195 200 205 Leu Gly Glu Lys Ile Leu Leu Phe Thr Thr Asp Gly Pro GluGly Leu 210 215 220 Lys Cys Gly Ser Leu Arg Gly Leu Tyr Thr Thr ValAsp Phe Gly Pro 225 230 235 240 Ala Asp Asn Met Thr Lys Ile Phe ThrLeu Leu Arg Lys Tyr Glu Pro 245 250 255 His Gly Pro Leu Val Asn SerGlu Tyr Tyr Thr Gly Trp Leu Asp Tyr 260 265 270 Trp Gly Gln Asn HisSer Thr Arg Ser Val Ser Ala Val Thr Lys Gly 275 280 285 Leu Glu AsnMet Leu Lys Leu Gly Ala Ser Val Asn Met Tyr Met Phe 290 295 300 HisGly Gly Thr Asn Phe Gly Tyr Trp Asn Gly Ala Asp Lys Lys Gly 305 310315 320 Arg Phe Leu Pro Ile Thr Thr Ser Tyr Asp Tyr Asp Ala Pro IleSer 325 330 335 Glu Ala Gly Asp Pro Thr Pro Lys Leu Phe Ala Leu ArgAsp Val Ile 340 345 350 Ser Lys Phe Gln Glu Val Pro Leu Gly Pro LeuPro Pro Pro Ser Pro 355 360 365 Lys Met Met Leu Gly Pro Val Thr LeuHis Leu Val Gly His Leu Leu 370 375 380 Ala Phe Leu Asp Leu Leu CysPro Arg Gly Pro Ile His Ser Ile Leu 385 390 395 400 Pro Met Thr PheGlu Ala Val Lys Gln Asp His Gly Phe Met Leu Tyr 405 410 415 Arg ThrTyr Met Thr His Thr Ile Phe Glu Pro Thr Pro Phe Trp Val 420 425 430Pro Asn Asn Gly Val His Asp Arg Ala Tyr Val Met Val Asp Gly Val 435440 445 Phe Gln Gly Val Val Glu Arg Asn Met Arg Asp Lys Leu Phe LeuThr 450 455 460 Gly Lys Leu Gly Ser Lys Leu Asp Ile Leu Val Glu AsnMet Gly Arg 465 470 475 480 Leu Ser Phe Gly Ser Asn Ser Ser Asp PheLys Gly Leu Leu Lys Pro 485 490 495 Pro Ile Leu Gly Gln Thr Ile LeuThr Gln Trp Met Met Phe Pro Leu 500 505 510 Lys Ile Asp Asn Leu ValLys Trp Trp Phe Pro Leu Gln Leu Pro Lys 515 520 525 Trp Pro Tyr ProGln Ala Pro Ser Gly Pro Thr Phe Tyr Ser Lys Thr 530 535 540 Phe ProIle Leu Gly Ser Val Gly Asp Thr Phe Leu Tyr Leu Pro Gly 545 550 555560 Trp Thr Lys Gly Gln Val Trp Ile Asn Gly Phe Asn Leu Gly Arg Tyr565 570 575 Trp Thr Lys Gln Gly Pro Gln Gln Thr Leu Tyr Val Pro ArgPhe Leu 580 585 590 Leu Phe Pro Arg Gly Ala Leu Asn Lys Ile Thr LeuLeu Glu Leu Glu 595 600 605 Asp Val Pro Leu Gln Pro Gln Val Gln PheLeu Asp Lys Pro Ile Leu 610 615 620 Asn Ser Thr Ser Thr Leu His ArgThr His Ile Asn Ser Leu Ser Ala 625 630 635 640 Asp Thr Leu Ser AlaSer Glu Pro Met Glu Leu Ser Gly His 645 650 178 24 DNA ArtificialSequence Description of Artificial Sequence Syntheticoligonucleotide probe 178 tggctactcc aagaccctgg catg 24 179 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 179 tggacaaatc cccttgctca gccc 24 180 50 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 180 gggcttcacc gaagcagtgg acctttattttgaccacctg atgtccaggg 50 181 22 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 181ccagctatga ctatgatgca cc 22 182 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe182 tggcacccag aatggtgttg gctc 24 183 50 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe183 cgagatgtca tcagcaagtt ccaggaagtt cctttgggac ctttacctcc 50 1841947 DNA Homo sapiens 184 gctttgaaca cgtctgcaag cccaaagttgagcatctgat tggttatgag gtatttgagt 60 gcacccacaa tatggcttacatgttgaaaa agcttctcat cagttacata tccattattt 120 gtgtttatggctttatctgc ctctacactc tcttctggtt attcaggata cctttgaagg 180aatattcttt cgaaaaagtc agagaagaga gcagttttag tgacattcca gatgtcaaaa240 acgattttgc gttccttctt cacatggtag accagtatga ccagctatattccaagcgtt 300 ttggtgtgtt cttgtcagaa gttagtgaaa ataaacttagggaaattagt ttgaaccatg 360 agtggacatt tgaaaaactc aggcagcacatttcacgcaa cgcccaggac aagcaggagt 420 tgcatctgtt catgctgtcgggggtgcccg atgctgtctt tgacctcaca gacctggatg 480 tgctaaagcttgaactaatt ccagaagcta aaattcctgc taagatttct caaatgacta 540acctccaaga gctccacctc tgccactgcc ctgcaaaagt tgaacagact gcttttagct600 ttcttcgcga tcacttgaga tgccttcacg tgaagttcac tgatgtggctgaaattcctg 660 cctgggtgta tttgctcaaa aaccttcgag agttgtacttaataggcaat ttgaactctg 720 aaaacaataa gatgatagga cttgaatctctccgagagtt gcggcacctt aagattctcc 780 acgtgaagag caatttgaccaaagttccct ccaacattac agatgtggct ccacatctta 840 caaagttagtcattcataat gacggcacta aactcttggt actgaacagc cttaagaaaa 900tgatgaatgt cgctgagctg gaactccaga actgtgagct agagagaatc ccacatgcta960 ttttcagcct ctctaattta caggaactgg atttaaagtc caataacattcgcacaattg 1020 aggaaatcat cagtttccag catttaaaac gactgacttgtttaaaatta tggcataaca 1080 aaattgttac tattcctccc tctattacccatgtcaaaaa cttggagtca ctttatttct 1140 ctaacaacaa gctcgaatccttaccagtgg cagtatttag tttacagaaa ctcagatgct 1200 tagatgtgagctacaacaac atttcaatga ttccaataga aataggattg cttcagaacc 1260tgcagcattt gcatatcact gggaacaaag tggacattct gccaaaacaa ttgtttaaat1320 gcataaagtt gaggactttg aatctgggac agaactgcat cacctcactcccagagaaag 1380 ttggtcagct ctcccagctc actcagctgg agctgaaggggaactgcttg gaccgcctgc 1440 cagcccagct gggccagtgt cggatgctcaagaaaagcgg gcttgttgtg gaagatcacc 1500 tttttgatac cctgccactcgaagtcaaag aggcattgaa tcaagacata aatattccct 1560 ttgcaaatgggatttaaact aagataatat atgcacagtg atgtgcagga acaacttcct 1620agattgcaag tgctcacgta caagttatta caagataatg cattttagga gtagatacat1680 cttttaaaat aaaacagaga ggatgcatag aaggctgata gaagacataactgaatgttc 1740 aatgtttgta gggttttaag tcattcattt ccaaatcatttttttttttc ttttggggaa 1800 agggaaggaa aaattataat cactaatcttggttcttttt aaattgtttg taacttggat 1860 gctgccgcta ctgaatgtttacaaattgct tgcctgctaa agtaaatgat taaattgaca 1920 ttttcttactaaaaaaaaaa aaaaaaa 1947 185 501 PRT Homo sapiens 185 Met Ala TyrMet Leu Lys Lys Leu Leu Ile Ser Tyr Ile Ser Ile Ile 1 5 10 15 CysVal Tyr Gly Phe Ile Cys Leu Tyr Thr Leu Phe Trp Leu Phe Arg 20 2530 Ile Pro Leu Lys Glu Tyr Ser Phe Glu Lys Val Arg Glu Glu Ser Ser35 40 45 Phe Ser Asp Ile Pro Asp Val Lys Asn Asp Phe Ala Phe LeuLeu His 50 55 60 Met Val Asp Gln Tyr Asp Gln Leu Tyr Ser Lys ArgPhe Gly Val Phe 65 70 75 80 Leu Ser Glu Val Ser Glu Asn Lys Leu ArgGlu Ile Ser Leu Asn His 85 90 95 Glu Trp Thr Phe Glu Lys Leu ArgGln His Ile Ser Arg Asn Ala Gln 100 105 110 Asp Lys Gln Glu Leu HisLeu Phe Met Leu Ser Gly Val Pro Asp Ala 115 120 125 Val Phe Asp LeuThr Asp Leu Asp Val Leu Lys Leu Glu Leu Ile Pro 130 135 140 Glu AlaLys Ile Pro Ala Lys Ile Ser Gln Met Thr Asn Leu Gln Glu 145 150 155160 Leu His Leu Cys His Cys Pro Ala Lys Val Glu Gln Thr Ala Phe Ser165 170 175 Phe Leu Arg Asp His Leu Arg Cys Leu His Val Lys Phe ThrAsp Val 180 185 190 Ala Glu Ile Pro Ala Trp Val Tyr Leu Leu Lys AsnLeu Arg Glu Leu 195 200 205 Tyr Leu Ile Gly Asn Leu Asn Ser Glu AsnAsn Lys Met Ile Gly Leu 210 215 220 Glu Ser Leu Arg Glu Leu Arg HisLeu Lys Ile Leu His Val Lys Ser 225 230 235 240 Asn Leu Thr Lys ValPro Ser Asn Ile Thr Asp Val Ala Pro His Leu 245 250 255 Thr Lys LeuVal Ile His Asn Asp Gly Thr Lys Leu Leu Val Leu Asn 260 265 270 SerLeu Lys Lys Met Met Asn Val Ala Glu Leu Glu Leu Gln Asn Cys 275 280285 Glu Leu Glu Arg Ile Pro His Ala Ile Phe Ser Leu Ser Asn Leu Gln290 295 300 Glu Leu Asp Leu Lys Ser Asn Asn Ile Arg Thr Ile Glu GluIle Ile 305 310 315 320 Ser Phe Gln His Leu Lys Arg Leu Thr Cys LeuLys Leu Trp His Asn 325 330 335 Lys Ile Val Thr Ile Pro Pro Ser IleThr His Val Lys Asn Leu Glu 340 345 350 Ser Leu Tyr Phe Ser Asn AsnLys Leu Glu Ser Leu Pro Val Ala Val 355 360 365 Phe Ser Leu Gln LysLeu Arg Cys Leu Asp Val Ser Tyr Asn Asn Ile 370 375 380 Ser Met IlePro Ile Glu Ile Gly Leu Leu Gln Asn Leu Gln His Leu 385 390 395 400His Ile Thr Gly Asn Lys Val Asp Ile Leu Pro Lys Gln Leu Phe Lys 405410 415 Cys Ile Lys Leu Arg Thr Leu Asn Leu Gly Gln Asn Cys Ile ThrSer 420 425 430 Leu Pro Glu Lys Val Gly Gln Leu Ser Gln Leu Thr GlnLeu Glu Leu 435 440 445 Lys Gly Asn Cys Leu Asp Arg Leu Pro Ala GlnLeu Gly Gln Cys Arg 450 455 460 Met Leu Lys Lys Ser Gly Leu Val ValGlu Asp His Leu Phe Asp Thr 465 470 475 480 Leu Pro Leu Glu Val LysGlu Ala Leu Asn Gln Asp Ile Asn Ile Pro 485 490 495 Phe Ala Asn GlyIle 500 186 21 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 186 cctccctcta ttacccatgtc 21 187 24 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 187 gaccaacttt ctctgggagtgagg 24 188 47 DNA Artificial Sequence Description of ArtificialSequence Synthetic oligonucleotide probe 188 gtcactttat ttctctaacaacaagctcga atccttacca gtggcag 47 189 2917 DNA Homo sapiens 189cccacgcgtc cggccttctc tctggacttt gcatttccat tccttttcat tgacaaactg60 acttttttta tttctttttt tccatctctg ggccagcttg ggatcctaggccgccctggg 120 aagacatttg tgttttacac acataaggat ctgtgtttggggtttcttct tcctcccctg 180 acattggcat tgcttagtgg ttgtgtggggagggagacca cgtgggctca gtgcttgctt 240 gcacttatct gcctaggtacatcgaagtct tttgacctcc atacagtgat tatgcctgtc 300 atcgctggtggtatcctggc ggccttgctc ctgctgatag ttgtcgtgct ctgtctttac 360ttcaaaatac acaacgcgct aaaagctgca aaggaacctg aagctgtggc tgtaaaaaat420 cacaacccag acaaggtgtg gtgggccaag aacagccagg ccaaaaccattgccacggag 480 tcttgtcctg ccctgcagtg ctgtgaagga tatagaatgtgtgccagttt tgattccctg 540 ccaccttgct gttgcgacat aaatgagggcctctgagtta ggaaaggctc ccttctcaaa 600 gcagagccct gaagacttcaatgatgtcaa tgaggccacc tgtttgtgat gtgcaggcac 660 agaagaaaggcacagctccc catcagtttc atggaaaata actcagtgcc tgctgggaac 720cagctgctgg agatccctac agagagcttc cactgggggc aacccttcca ggaaggagtt780 ggggagagag aaccctcact gtggggaatg ctgataaacc agtcacacagctgctctatt 840 ctcacacaaa tctacccctt gcgtggctgg aactgacgtttccctggagg tgtccagaaa 900 gctgatgtaa cacagagcct ataaaagctgtcggtcctta aggctgccca gcgccttgcc 960 aaaatggagc ttgtaagaaggctcatgcca ttgaccctct taattctctc ctgtttggcg 1020 gagctgacaatggcggaggc tgaaggcaat gcaagctgca cagtcagtct agggggtgcc 1080aatatggcag agacccacaa agccatgatc ctgcaactca atcccagtga gaactgcacc1140 tggacaatag aaagaccaga aaacaaaagc atcagaatta tcttttcctatgtccagctt 1200 gatccagatg gaagctgtga aagtgaaaac attaaagtctttgacggaac ctccagcaat 1260 gggcctctgc tagggcaagt ctgcagtaaaaacgactatg ttcctgtatt tgaatcatca 1320 tccagtacat tgacgtttcaaatagttact gactcagcaa gaattcaaag aactgtcttt 1380 gtcttctactacttcttctc tcctaacatc tctattccaa actgtggcgg ttacctggat 1440accttggaag gatccttcac cagccccaat tacccaaagc cgcatcctga gctggcttat1500 tgtgtgtggc acatacaagt ggagaaagat tacaagataa aactaaacttcaaagagatt 1560 ttcctagaaa tagacaaaca gtgcaaattt gattttcttgccatctatga tggcccctcc 1620 accaactctg gcctgattgg acaagtctgtggccgtgtga ctcccacctt cgaatcgtca 1680 tcaaactctc tgactgtcgtgttgtctaca gattatgcca attcttaccg gggattttct 1740 gcttcctacacctcaattta tgcagaaaac atcaacacta catctttaac ttgctcttct 1800gacaggatga gagttattat aagcaaatcc tacctagagg cttttaactc taatgggaat1860 aacttgcaac taaaagaccc aacttgcaga ccaaaattat caaatgttgtggaattttct 1920 gtccctctta atggatgtgg tacaatcaga aaggtagaagatcagtcaat tacttacacc 1980 aatataatca ccttttctgc atcctcaacttctgaagtga tcacccgtca gaaacaactc 2040 cagattattg tgaagtgtgaaatgggacat aattctacag tggagataat atacataaca 2100 gaagatgatgtaatacaaag tcaaaatgca ctgggcaaat ataacaccag catggctctt 2160tttgaatcca attcatttga aaagactata cttgaatcac catattatgt ggatttgaac2220 caaactcttt ttgttcaagt tagtctgcac acctcagatc caaatttggtggtgtttctt 2280 gatacctgta gagcctctcc cacctctgac tttgcatctccaacctacga cctaatcaag 2340 agtggatgta gtcgagatga aacttgtaaggtgtatccct tatttggaca ctatgggaga 2400 ttccagttta atgcctttaaattcttgaga agtatgagct ctgtgtatct gcagtgtaaa 2460 gttttgatatgtgatagcag tgaccaccag tctcgctgca atcaaggttg tgtctccaga 2520agcaaacgag acatttcttc atataaatgg aaaacagatt ccatcatagg acccattcgt2580 ctgaaaaggg atcgaagtgc aagtggcaat tcaggatttc agcatgaaacacatgcggaa 2640 gaaactccaa accagccttt caacagtgtg catctgttttccttcatggt tctagctctg 2700 aatgtggtga ctgtagcgac aatcacagtgaggcattttg taaatcaacg ggcagactac 2760 aaataccaga agctgcagaactattaacta acaggtccaa ccctaagtga gacatgtttc 2820 tccaggatgccaaaggaaat gctacctcgt ggctacacat attatgaata aatgaggaag 2880ggcctgaaag tgacacacag gcctgcatgt aaaaaaa 2917 190 607 PRT Homosapiens 190 Met Glu Leu Val Arg Arg Leu Met Pro Leu Thr Leu Leu IleLeu Ser 1 5 10 15 Cys Leu Ala Glu Leu Thr Met Ala Glu Ala Glu GlyAsn Ala Ser Cys 20 25 30 Thr Val Ser Leu Gly Gly Ala Asn Met AlaGlu Thr His Lys Ala Met 35 40 45 Ile Leu Gln Leu Asn Pro Ser GluAsn Cys Thr Trp Thr Ile Glu Arg 50 55

60 Pro Glu Asn Lys Ser Ile Arg Ile Ile Phe Ser Tyr Val Gln Leu Asp65 70 75 80 Pro Asp Gly Ser Cys Glu Ser Glu Asn Ile Lys Val Phe AspGly Thr 85 90 95 Ser Ser Asn Gly Pro Leu Leu Gly Gln Val Cys SerLys Asn Asp Tyr 100 105 110 Val Pro Val Phe Glu Ser Ser Ser Ser ThrLeu Thr Phe Gln Ile Val 115 120 125 Thr Asp Ser Ala Arg Ile Gln ArgThr Val Phe Val Phe Tyr Tyr Phe 130 135 140 Phe Ser Pro Asn Ile SerIle Pro Asn Cys Gly Gly Tyr Leu Asp Thr 145 150 155 160 Leu Glu GlySer Phe Thr Ser Pro Asn Tyr Pro Lys Pro His Pro Glu 165 170 175 LeuAla Tyr Cys Val Trp His Ile Gln Val Glu Lys Asp Tyr Lys Ile 180 185190 Lys Leu Asn Phe Lys Glu Ile Phe Leu Glu Ile Asp Lys Gln Cys Lys195 200 205 Phe Asp Phe Leu Ala Ile Tyr Asp Gly Pro Ser Thr Asn SerGly Leu 210 215 220 Ile Gly Gln Val Cys Gly Arg Val Thr Pro Thr PheGlu Ser Ser Ser 225 230 235 240 Asn Ser Leu Thr Val Val Leu Ser ThrAsp Tyr Ala Asn Ser Tyr Arg 245 250 255 Gly Phe Ser Ala Ser Tyr ThrSer Ile Tyr Ala Glu Asn Ile Asn Thr 260 265 270 Thr Ser Leu Thr CysSer Ser Asp Arg Met Arg Val Ile Ile Ser Lys 275 280 285 Ser Tyr LeuGlu Ala Phe Asn Ser Asn Gly Asn Asn Leu Gln Leu Lys 290 295 300 AspPro Thr Cys Arg Pro Lys Leu Ser Asn Val Val Glu Phe Ser Val 305 310315 320 Pro Leu Asn Gly Cys Gly Thr Ile Arg Lys Val Glu Asp Gln SerIle 325 330 335 Thr Tyr Thr Asn Ile Ile Thr Phe Ser Ala Ser Ser ThrSer Glu Val 340 345 350 Ile Thr Arg Gln Lys Gln Leu Gln Ile Ile ValLys Cys Glu Met Gly 355 360 365 His Asn Ser Thr Val Glu Ile Ile TyrIle Thr Glu Asp Asp Val Ile 370 375 380 Gln Ser Gln Asn Ala Leu GlyLys Tyr Asn Thr Ser Met Ala Leu Phe 385 390 395 400 Glu Ser Asn SerPhe Glu Lys Thr Ile Leu Glu Ser Pro Tyr Tyr Val 405 410 415 Asp LeuAsn Gln Thr Leu Phe Val Gln Val Ser Leu His Thr Ser Asp 420 425 430Pro Asn Leu Val Val Phe Leu Asp Thr Cys Arg Ala Ser Pro Thr Ser 435440 445 Asp Phe Ala Ser Pro Thr Tyr Asp Leu Ile Lys Ser Gly Cys SerArg 450 455 460 Asp Glu Thr Cys Lys Val Tyr Pro Leu Phe Gly His TyrGly Arg Phe 465 470 475 480 Gln Phe Asn Ala Phe Lys Phe Leu Arg SerMet Ser Ser Val Tyr Leu 485 490 495 Gln Cys Lys Val Leu Ile Cys AspSer Ser Asp His Gln Ser Arg Cys 500 505 510 Asn Gln Gly Cys Val SerArg Ser Lys Arg Asp Ile Ser Ser Tyr Lys 515 520 525 Trp Lys Thr AspSer Ile Ile Gly Pro Ile Arg Leu Lys Arg Asp Arg 530 535 540 Ser AlaSer Gly Asn Ser Gly Phe Gln His Glu Thr His Ala Glu Glu 545 550 555560 Thr Pro Asn Gln Pro Phe Asn Ser Val His Leu Phe Ser Phe Met Val565 570 575 Leu Ala Leu Asn Val Val Thr Val Ala Thr Ile Thr Val ArgHis Phe 580 585 590 Val Asn Gln Arg Ala Asp Tyr Lys Tyr Gln Lys LeuGln Asn Tyr 595 600 605 191 21 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 191tctctattcc aaactgtggc g 21 192 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe192 tttgatgacg attcgaaggt gg 22 193 47 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe193 ggaaggatcc ttcaccagcc ccaattaccc aaagccgcat cctgagc 47 194 2362DNA Homo sapiens 194 gacggaagaa cagcgctccc gaggccgcgg gagcctgcagagaggacagc cggcctgcgc 60 cgggacatgc ggccccagga gctccccaggctcgcgttcc cgttgctgct gttgctgttg 120 ctgctgctgc cgccgccgccgtgccctgcc cacagcgcca cgcgcttcga ccccacctgg 180 gagtccctggacgcccgcca gctgcccgcg tggtttgacc aggccaagtt cggcatcttc 240atccactggg gagtgttttc cgtgcccagc ttcggtagcg agtggttctg gtggtattgg300 caaaaggaaa agataccgaa gtatgtggaa tttatgaaag ataattaccctcctagtttc 360 aaatatgaag attttggacc actatttaca gcaaaattttttaatgccaa ccagtgggca 420 gatatttttc aggcctctgg tgccaaatacattgtcttaa cttccaaaca tcatgaaggc 480 tttaccttgt gggggtcagaatattcgtgg aactggaatg ccatagatga ggggcccaag 540 agggacattgtcaaggaact tgaggtagcc attaggaaca gaactgacct gcgttttgga 600ctgtactatt ccctttttga atggtttcat ccgctcttcc ttgaggatga atccagttca660 ttccataagc ggcaatttcc agtttctaag acattgccag agctctatgagttagtgaac 720 aactatcagc ctgaggttct gtggtcggat ggtgacggaggagcaccgga tcaatactgg 780 aacagcacag gcttcttggc ctggttatataatgaaagcc cagttcgggg cacagtagtc 840 accaatgatc gttggggagctggtagcatc tgtaagcatg gtggcttcta tacctgcagt 900 gatcgttataacccaggaca tcttttgcca cataaatggg aaaactgcat gacaatagac 960aaactgtcct ggggctatag gagggaagct ggaatctctg actatcttac aattgaagaa1020 ttggtgaagc aacttgtaga gacagtttca tgtggaggaa atcttttgatgaatattggg 1080 cccacactag atggcaccat ttctgtagtt tttgaggagcgactgaggca agtggggtcc 1140 tggctaaaag tcaatggaga agctatttatgaaacctata cctggcgatc ccagaatgac 1200 actgtcaccc cagatgtgtggtacacatcc aagcctaaag aaaaattagt ctatgccatt 1260 tttcttaaatggcccacatc aggacagctg ttccttggcc atcccaaagc tattctgggg 1320gcaacagagg tgaaactact gggccatgga cagccactta actggatttc tttggagcaa1380 aatggcatta tggtagaact gccacagcta accattcatc agatgccgtgtaaatggggc 1440 tgggctctag ccctaactaa tgtgatctaa agtgcagcagagtggctgat gctgcaagtt 1500 atgtctaagg ctaggaacta tcaggtgtctataattgtag cacatggaga aagcaatgta 1560 aactggataa gaaaattatttggcagttca gccctttccc tttttcccac taaatttttc 1620 ttaaattacccatgtaacca ttttaactct ccagtgcact ttgccattaa agtctcttca 1680cattgatttg tttccatgtg tgactcagag gtgagaattt tttcacatta tagtagcaag1740 gaattggtgg tattatggac cgaactgaaa attttatgtt gaagccatatcccccatgat 1800 tatatagtta tgcatcactt aatatgggga tattttctgggaaatgcatt gctagtcaat 1860 ttttttttgt gccaacatca tagagtgtatttacaaaatc ctagatggca tagcctacta 1920 cacacctaat gtgtatggtatagactgttg ctcctaggct acagacatat acagcatgtt 1980 actgaatactgtaggcaata gtaacagtgg tatttgtata tcgaaacata tggaaacata 2040gagaaggtac agtaaaaata ctgtaaaata aatggtgcac ctgtataggg cacttaccac2100 gaatggagct tacaggactg gaagttgctc tgggtgagtc agtgagtgaatgtgaaggcc 2160 taggacatta ttgaacactg ccagacgtta taaatactgtatgcttaggc tacactacat 2220 ttataaaaaa aagtttttct ttcttcaattataaattaac ataagtgtac tgtaacttta 2280 caaacgtttt aatttttaaaacctttttgg ctcttttgta ataacactta gcttaaaaca 2340 taaactcattgtgcaaatgt aa 2362 195 467 PRT Homo sapiens 195 Met Arg Pro Gln GluLeu Pro Arg Leu Ala Phe Pro Leu Leu Leu Leu 1 5 10 15 Leu Leu LeuLeu Leu Pro Pro Pro Pro Cys Pro Ala His Ser Ala Thr 20 25 30 ArgPhe Asp Pro Thr Trp Glu Ser Leu Asp Ala Arg Gln Leu Pro Ala 35 4045 Trp Phe Asp Gln Ala Lys Phe Gly Ile Phe Ile His Trp Gly Val Phe50 55 60 Ser Val Pro Ser Phe Gly Ser Glu Trp Phe Trp Trp Tyr TrpGln Lys 65 70 75 80 Glu Lys Ile Pro Lys Tyr Val Glu Phe Met Lys AspAsn Tyr Pro Pro 85 90 95 Ser Phe Lys Tyr Glu Asp Phe Gly Pro LeuPhe Thr Ala Lys Phe Phe 100 105 110 Asn Ala Asn Gln Trp Ala Asp IlePhe Gln Ala Ser Gly Ala Lys Tyr 115 120 125 Ile Val Leu Thr Ser LysHis His Glu Gly Phe Thr Leu Trp Gly Ser 130 135 140 Glu Tyr Ser TrpAsn Trp Asn Ala Ile Asp Glu Gly Pro Lys Arg Asp 145 150 155 160 IleVal Lys Glu Leu Glu Val Ala Ile Arg Asn Arg Thr Asp Leu Arg 165 170175 Phe Gly Leu Tyr Tyr Ser Leu Phe Glu Trp Phe His Pro Leu Phe Leu180 185 190 Glu Asp Glu Ser Ser Ser Phe His Lys Arg Gln Phe Pro ValSer Lys 195 200 205 Thr Leu Pro Glu Leu Tyr Glu Leu Val Asn Asn TyrGln Pro Glu Val 210 215 220 Leu Trp Ser Asp Gly Asp Gly Gly Ala ProAsp Gln Tyr Trp Asn Ser 225 230 235 240 Thr Gly Phe Leu Ala Trp LeuTyr Asn Glu Ser Pro Val Arg Gly Thr 245 250 255 Val Val Thr Asn AspArg Trp Gly Ala Gly Ser Ile Cys Lys His Gly 260 265 270 Gly Phe TyrThr Cys Ser Asp Arg Tyr Asn Pro Gly His Leu Leu Pro 275 280 285 HisLys Trp Glu Asn Cys Met Thr Ile Asp Lys Leu Ser Trp Gly Tyr 290 295300 Arg Arg Glu Ala Gly Ile Ser Asp Tyr Leu Thr Ile Glu Glu Leu Val305 310 315 320 Lys Gln Leu Val Glu Thr Val Ser Cys Gly Gly Asn LeuLeu Met Asn 325 330 335 Ile Gly Pro Thr Leu Asp Gly Thr Ile Ser ValVal Phe Glu Glu Arg 340 345 350 Leu Arg Gln Val Gly Ser Trp Leu LysVal Asn Gly Glu Ala Ile Tyr 355 360 365 Glu Thr Tyr Thr Trp Arg SerGln Asn Asp Thr Val Thr Pro Asp Val 370 375 380 Trp Tyr Thr Ser LysPro Lys Glu Lys Leu Val Tyr Ala Ile Phe Leu 385 390 395 400 Lys TrpPro Thr Ser Gly Gln Leu Phe Leu Gly His Pro Lys Ala Ile 405 410 415Leu Gly Ala Thr Glu Val Lys Leu Leu Gly His Gly Gln Pro Leu Asn 420425 430 Trp Ile Ser Leu Glu Gln Asn Gly Ile Met Val Glu Leu Pro GlnLeu 435 440 445 Thr Ile His Gln Met Pro Cys Lys Trp Gly Trp Ala LeuAla Leu Thr 450 455 460 Asn Val Ile 465 196 23 DNA ArtificialSequence Description of Artificial Sequence Syntheticoligonucleotide probe 196 tggtttgacc aggccaagtt cgg 23 197 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 197 ggattcatcc tcaaggaaga gcgg 24 198 24 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 198 aacttgcagc atcagccact ctgc 24 199 45 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 199 ttccgtgccc agcttcggta gcgagtggttctggtggtat tggca 45 200 2372 DNA Homo sapiens 200 agcagggaaatccggatgtc tcggttatga agtggagcag tgagtgtgag cctcaacata 60gttccagaac tctccatccg gactagttat tgagcatctg cctctcatat caccagtggc120 catctgaggt gtttccctgg ctctgaaggg gtaggcacga tggccaggtgcttcagcctg 180 gtgttgcttc tcacttccat ctggaccacg aggctcctggtccaaggctc tttgcgtgca 240 gaagagcttt ccatccaggt gtcatgcagaattatgggga tcacccttgt gagcaaaaag 300 gcgaaccagc agctgaatttcacagaagct aaggaggcct gtaggctgct gggactaagt 360 ttggccggcaaggaccaagt tgaaacagcc ttgaaagcta gctttgaaac ttgcagctat 420ggctgggttg gagatggatt cgtggtcatc tctaggatta gcccaaaccc caagtgtggg480 aaaaatgggg tgggtgtcct gatttggaag gttccagtga gccgacagtttgcagcctat 540 tgttacaact catctgatac ttggactaac tcgtgcattccagaaattat caccaccaaa 600 gatcccatat tcaacactca aactgcaacacaaacaacag aatttattgt cagtgacagt 660 acctactcgg tggcatccccttactctaca atacctgccc ctactactac tcctcctgct 720 ccagcttccacttctattcc acggagaaaa aaattgattt gtgtcacaga agtttttatg 780gaaactagca ccatgtctac agaaactgaa ccatttgttg aaaataaagc agcattcaag840 aatgaagctg ctgggtttgg aggtgtcccc acggctctgc tagtgcttgctctcctcttc 900 tttggtgctg cagctggtct tggattttgc tatgtcaaaaggtatgtgaa ggccttccct 960 tttacaaaca agaatcagca gaaggaaatgatcgaaacca aagtagtaaa ggaggagaag 1020 gccaatgata gcaaccctaatgaggaatca aagaaaactg ataaaaaccc agaagagtcc 1080 aagagtccaagcaaaactac cgtgcgatgc ctggaagctg aagtttagat gagacagaaa 1140tgaggagaca cacctgaggc tggtttcttt catgctcctt accctgcccc agctggggaa1200 atcaaaaggg ccaaagaacc aaagaagaaa gtccaccctt ggttcctaactggaatcagc 1260 tcaggactgc cattggacta tggagtgcac caaagagaatgcccttctcc ttattgtaac 1320 cctgtctgga tcctatcctc ctacctccaaagcttcccac ggcctttcta gcctggctat 1380 gtcctaataa tatcccactgggagaaagga gttttgcaaa gtgcaaggac ctaaaacatc 1440 tcatcagtatccagtggtaa aaaggcctcc tggctgtctg aggctaggtg ggttgaaagc 1500caaggagtca ctgagaccaa ggctttctct actgattccg cagctcagac cctttcttca1560 gctctgaaag agaaacacgt atcccacctg acatgtcctt ctgagcccggtaagagcaaa 1620 agaatggcag aaaagtttag cccctgaaag ccatggagattctcataact tgagacctaa 1680 tctctgtaaa gctaaaataa agaaatagaacaaggctgag gatacgacag tacactgtca 1740 gcagggactg taaacacagacagggtcaaa gtgttttctc tgaacacatt gagttggaat 1800 cactgtttagaacacacaca cttacttttt ctggtctcta ccactgctga tattttctct 1860aggaaatata cttttacaag taacaaaaat aaaaactctt ataaatttct atttttatct1920 gagttacaga aatgattact aaggaagatt actcagtaat ttgtttaaaaagtaataaaa 1980 ttcaacaaac atttgctgaa tagctactat atgtcaagtgctgtgcaagg tattacactc 2040 tgtaattgaa tattattcct caaaaaattgcacatagtag aacgctatct gggaagctat 2100 ttttttcagt tttgatatttctagcttatc tacttccaaa ctaattttta tttttgctga 2160 gactaatcttattcattttc tctaatatgg caaccattat aaccttaatt tattattaac 2220atacctaaga agtacattgt tacctctata taccaaagca cattttaaaa gtgccattaa2280 caaatgtatc actagccctc ctttttccaa caagaaggga ctgagagatgcagaaatatt 2340 tgtgacaaaa aattaaagca tttagaaaac tt 2372 201 322PRT Artificial sequence Synthetic protein 201 Met Ala Arg Cys PheSer Leu Val Leu Leu Leu Thr Ser Ile Trp Thr 1 5 10 15 Thr Arg LeuLeu Val Gln Gly Ser Leu Arg Ala Glu Glu Leu Ser Ile 20 25 30 GlnVal Ser Cys Arg Ile Met Gly Ile Thr Leu Val Ser Lys Lys Ala 35 4045 Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys Glu Ala Cys Arg Leu Leu50 55 60 Gly Leu Ser Leu Ala Gly Lys Asp Gln Val Glu Thr Ala LeuLys Ala 65 70 75 80 Ser Phe Glu Thr Cys Ser Tyr Gly Trp Val Gly AspGly Phe Val Val 85 90 95 Ile Ser Arg Ile Ser Pro Asn Pro Lys CysGly Lys Asn Gly Val Gly 100 105 110 Val Leu Ile Trp Lys Val Pro ValSer Arg Gln Phe Ala Ala Tyr Cys 115 120 125 Tyr Asn Ser Ser Asp ThrTrp Thr Asn Ser Cys Ile Pro Glu Ile Ile 130 135 140 Thr Thr Lys AspPro Ile Phe Asn Thr Gln Thr Ala Thr Gln Thr Thr 145 150 155 160 GluPhe Ile Val Ser Asp Ser Thr Tyr Ser Val Ala Ser Pro Tyr Ser 165 170175 Thr Ile Pro Ala Pro Thr Thr Thr Pro Pro Ala Pro Ala Ser Thr Ser180 185 190 Ile Pro Arg Arg Lys Lys Leu Ile Cys Val Thr Glu Val PheMet Glu 195 200 205 Thr Ser Thr Met Ser Thr Glu Thr Glu Pro Phe ValGlu Asn Lys Ala 210 215 220 Ala Phe Lys Asn Glu Ala Ala Gly Phe GlyGly Val Pro Thr Ala Leu 225 230 235 240 Leu Val Leu Ala Leu Leu PhePhe Gly Ala Ala Ala Gly Leu Gly Phe 245 250 255 Cys Tyr Val Lys ArgTyr Val Lys Ala Phe Pro Phe Thr Asn Lys Asn 260 265 270 Gln Gln LysGlu Met Ile Glu Thr Lys Val Val Lys Glu Glu Lys Ala 275 280 285 AsnAsp Ser Asn Pro Asn Glu Glu Ser Lys Lys Thr Asp Lys Asn Pro 290 295300 Glu Glu Ser Lys Ser Pro Ser Lys Thr Thr Val Arg Cys Leu Glu Ala305 310 315 320 Glu Val 202 24 DNA Artificial Sequence Descriptionof Artificial Sequence Synthetic oligonucleotide probe 202gagctttcca tccaggtgtc atgc 24 203 22 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe203 gtcagtgaca gtacctactc gg 22 204 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe204 tggagcagga ggagtagtag tagg 24 205 50 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe205 aggaggcctg taggctgctg ggactaagtt tggccggcaa ggaccaagtt 50 2061620 DNA Homo sapiens modified_base (973)..(973) a, t, c or g 206agatggcggt cttggcacct ctaattgctc tcgtgtattc ggtgccgcga ctttcacgat60 ggctcgccca accttactac cttctgtcgg ccctgctctc tgctgccttcctactcgtga 120 ggaaactgcc gccgctctgc cacggtctgc ccacccaacgcgaagacggt aacccgtgtg 180 actttgactg gagagaagtg gagatcctgatgtttctcag

tgccattgtg atgatgaaga 240 accgcagatc catcactgtg gagcaacatataggcaacat tttcatgttt agtaaagtgg 300 ccaacacaat tcttttcttccgcttggata ttcgcatggg cctactttac atcacactct 360 gcatagtgttcctgatgacg tgcaaacccc ccctatatat gggccctgag tatatcaagt 420acttcaatga taaaaccatt gatgaggaac tagaacggga caagagggtc acttggattg480 tggagttctt tgccaattgg tctaatgact gccaatcatt tgcccctatctatgctgacc 540 tctcccttaa atacaactgt acagggctaa attttgggaaggtggatgtt ggacgctata 600 ctgatgttag tacgcggtac aaagtgagcacatcacccct caccaagcaa ctccctaccc 660 tgatcctgtt ccaaggtggcaaggaggcaa tgcggcggcc acagattgac aagaaaggac 720 gggctgtctcatggaccttc tctgaggaga atgtgatccg agaatttaac ttaaatgagc 780tataccagcg ggccaagaaa ctatcaaagg ctggagacaa tatccctgag gagcagcctg840 tggcttcaac ccccaccaca gtgtcagatg gggaaaacaa gaaggataaataagatcctc 900 actttggcag tgcttcctct cctgtcaatt ccaggctctttccataacca caagcctgag 960 gctgcagcct ttnattnatg ttttccctttggctgngact ggntggggca gcatgcagct 1020 tctgatttta aagaggcatctagggaattg tcaggcaccc tacaggaagg cctgccatgc 1080 tgtggccaactgtttcactg gagcaagaaa gagatctcat aggacggagg gggaaatggt 1140ttccctccaa gcttgggtca gtgtgttaac tgcttatcag ctattcagac atctccatgg1200 tttctccatg aaactctgtg gtttcatcat tccttcttag ttgacctgcacagcttggtt 1260 agacctagat ttaaccctaa ggtaagatgc tggggtatagaacgctaaga attttccccc 1320 aaggactctt gcttccttaa gcccttctggcttcgtttat ggtcttcatt aaaagtataa 1380 gcctaacttt gtcgctagtcctaaggagaa acctttaacc acaaagtttt tatcattgaa 1440 gacaatattgaacaaccccc tattttgtgg ggattgagaa ggggtgaata gaggcttgag 1500actttccttt gtgtggtagg acttggagga gaaatcccct ggactttcac taaccctctg1560 acatactccc cacacccagt tgatggcttt ccgtaataaa aagattgggatttccttttg 1620 207 296 PRT Homo sapiens 207 Met Ala Val Leu AlaPro Leu Ile Ala Leu Val Tyr Ser Val Pro Arg 1 5 10 15 Leu Ser ArgTrp Leu Ala Gln Pro Tyr Tyr Leu Leu Ser Ala Leu Leu 20 25 30 SerAla Ala Phe Leu Leu Val Arg Lys Leu Pro Pro Leu Cys His Gly 35 4045 Leu Pro Thr Gln Arg Glu Asp Gly Asn Pro Cys Asp Phe Asp Trp Arg50 55 60 Glu Val Glu Ile Leu Met Phe Leu Ser Ala Ile Val Met MetLys Asn 65 70 75 80 Arg Arg Ser Ile Thr Val Glu Gln His Ile Gly AsnIle Phe Met Phe 85 90 95 Ser Lys Val Ala Asn Thr Ile Leu Phe PheArg Leu Asp Ile Arg Met 100 105 110 Gly Leu Leu Tyr Ile Thr Leu CysIle Val Phe Leu Met Thr Cys Lys 115 120 125 Pro Pro Leu Tyr Met GlyPro Glu Tyr Ile Lys Tyr Phe Asn Asp Lys 130 135 140 Thr Ile Asp GluGlu Leu Glu Arg Asp Lys Arg Val Thr Trp Ile Val 145 150 155 160 GluPhe Phe Ala Asn Trp Ser Asn Asp Cys Gln Ser Phe Ala Pro Ile 165 170175 Tyr Ala Asp Leu Ser Leu Lys Tyr Asn Cys Thr Gly Leu Asn Phe Gly180 185 190 Lys Val Asp Val Gly Arg Tyr Thr Asp Val Ser Thr Arg TyrLys Val 195 200 205 Ser Thr Ser Pro Leu Thr Lys Gln Leu Pro Thr LeuIle Leu Phe Gln 210 215 220 Gly Gly Lys Glu Ala Met Arg Arg Pro GlnIle Asp Lys Lys Gly Arg 225 230 235 240 Ala Val Ser Trp Thr Phe SerGlu Glu Asn Val Ile Arg Glu Phe Asn 245 250 255 Leu Asn Glu Leu TyrGln Arg Ala Lys Lys Leu Ser Lys Ala Gly Asp 260 265 270 Asn Ile ProGlu Glu Gln Pro Val Ala Ser Thr Pro Thr Thr Val Ser 275 280 285 AspGly Glu Asn Lys Lys Asp Lys 290 295 208 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe208 gcttggatat tcgcatgggc ctac 24 209 20 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe209 tggagacaat atccctgagg 20 210 24 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe210 aacagttggc cacagcatgg cagg 24 211 50 DNA Artificial SequenceDescription of Artificial Sequence Synthetic oligonucleotide probe211 ccattgatga ggaactagaa cgggacaaga gggtcacttg gattgtggag 50 2121985 DNA Homo sapiens 212 ggacagctcg cggcccccga gagctctagccgtcgaggag ctgcctgggg acgtttgccc 60 tggggcccca gcctggcccgggtcaccctg gcatgaggag atgggcctgt tgctcctggt 120 cccattgctcctgctgcccg gctcctacgg actgcccttc tacaacggct tctactactc 180caacagcgcc aacgaccaga acctaggcaa cggtcatggc aaagacctcc ttaatggagt240 gaagctggtg gtggagacac ccgaggagac cctgttcacc taccaaggggccagtgtgat 300 cctgccctgc cgctaccgct acgagccggc cctggtctccccgcggcgtg tgcgtgtcaa 360 atggtggaag ctgtcggaga acggggccccagagaaggac gtgctggtgg ccatcgggct 420 gaggcaccgc tcctttggggactaccaagg ccgcgtgcac ctgcggcagg acaaagagca 480 tgacgtctcgctggagatcc aggatctgcg gctggaggac tatgggcgtt accgctgtga 540ggtcattgac gggctggagg atgaaagcgg tctggtggag ctggagctgc ggggtgtggt600 ctttccttac cagtccccca acgggcgcta ccagttcaac ttccacgagggccagcaggt 660 ctgtgcagag caggctgcgg tggtggcctc ctttgagcagctcttccggg cctgggagga 720 gggcctggac tggtgcaacg cgggctggctgcaggatgct acggtgcagt accccatcat 780 gttgccccgg cagccctgcggtggcccagg cctggcacct ggcgtgcgaa gctacggccc 840 ccgccaccgccgcctgcacc gctatgatgt attctgcttc gctactgccc tcaaggggcg 900ggtgtactac ctggagcacc ctgagaagct gacgctgaca gaggcaaggg aggcctgcca960 ggaagatgat gccacgatcg ccaaggtggg acagctcttt gccgcctggaagttccatgg 1020 cctggaccgc tgcgacgctg gctggctggc agatggcagcgtccgctacc ctgtggttca 1080 cccgcatcct aactgtgggc ccccagagcctggggtccga agctttggct tccccgaccc 1140 gcagagccgc ttgtacggtgtttactgcta ccgccagcac taggacctgg ggccctcccc 1200 tgccgcattccctcactggc tgtgtattta ttgagtggtt cgttttccct tgtgggttgg 1260agccatttta actgttttta tacttctcaa tttaaatttt ctttaaacat ttttttacta1320 ttttttgtaa agcaaacaga acccaatgcc tccctttgct cctggatgccccactccagg 1380 aatcatgctt gctcccctgg gccatttgcg gttttgtgggcttctggagg gttccccgcc 1440 atccaggctg gtctccctcc cttaaggaggttggtgccca gagtgggcgg tggcctgtct 1500 agaatgccgc cgggagtccgggcatggtgg gcacagttct ccctgcccct cagcctgggg 1560 gaagaagagggcctcggggg cctccggagc tgggctttgg gcctctcctg cccacctcta 1620cttctctgtg aagccgctga ccccagtctg cccactgagg ggctagggct ggaagccagt1680 tctaggcttc caggcgaaat ctgagggaag gaagaaactc ccctccccgttccccttccc 1740 ctctcggttc caaagaatct gttttgttgt catttgtttctcctgtttcc ctgtgtgggg 1800 aggggccctc aggtgtgtgt actttggacaataaatggtg ctatgactgc cttccgccaa 1860 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1920 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1980 aaaaa1985 213 360 PRT Homo sapiens 213 Met Gly Leu Leu Leu Leu Val ProLeu Leu Leu Leu Pro Gly Ser Tyr 1 5 10 15 Gly Leu Pro Phe Tyr AsnGly Phe Tyr Tyr Ser Asn Ser Ala Asn Asp 20 25 30 Gln Asn Leu GlyAsn Gly His Gly Lys Asp Leu Leu Asn Gly Val Lys 35 40 45 Leu ValVal Glu Thr Pro Glu Glu Thr Leu Phe Thr Tyr Gln Gly Ala 50 55 60Ser Val Ile Leu Pro Cys Arg Tyr Arg Tyr Glu Pro Ala Leu Val Ser 6570 75 80 Pro Arg Arg Val Arg Val Lys Trp Trp Lys Leu Ser Glu AsnGly Ala 85 90 95 Pro Glu Lys Asp Val Leu Val Ala Ile Gly Leu ArgHis Arg Ser Phe 100 105 110 Gly Asp Tyr Gln Gly Arg Val His Leu ArgGln Asp Lys Glu His Asp 115 120 125 Val Ser Leu Glu Ile Gln Asp LeuArg Leu Glu Asp Tyr Gly Arg Tyr 130 135 140 Arg Cys Glu Val Ile AspGly Leu Glu Asp Glu Ser Gly Leu Val Glu 145 150 155 160 Leu Glu LeuArg Gly Val Val Phe Pro Tyr Gln Ser Pro Asn Gly Arg 165 170 175 TyrGln Phe Asn Phe His Glu Gly Gln Gln Val Cys Ala Glu Gln Ala 180 185190 Ala Val Val Ala Ser Phe Glu Gln Leu Phe Arg Ala Trp Glu Glu Gly195 200 205 Leu Asp Trp Cys Asn Ala Gly Trp Leu Gln Asp Ala Thr ValGln Tyr 210 215 220 Pro Ile Met Leu Pro Arg Gln Pro Cys Gly Gly ProGly Leu Ala Pro 225 230 235 240 Gly Val Arg Ser Tyr Gly Pro Arg HisArg Arg Leu His Arg Tyr Asp 245 250 255 Val Phe Cys Phe Ala Thr AlaLeu Lys Gly Arg Val Tyr Tyr Leu Glu 260 265 270 His Pro Glu Lys LeuThr Leu Thr Glu Ala Arg Glu Ala Cys Gln Glu 275 280 285 Asp Asp AlaThr Ile Ala Lys Val Gly Gln Leu Phe Ala Ala Trp Lys 290 295 300 PheHis Gly Leu Asp Arg Cys Asp Ala Gly Trp Leu Ala Asp Gly Ser 305 310315 320 Val Arg Tyr Pro Val Val His Pro His Pro Asn Cys Gly Pro ProGlu 325 330 335 Pro Gly Val Arg Ser Phe Gly Phe Pro Asp Pro Gln SerArg Leu Tyr 340 345 350 Gly Val Tyr Cys Tyr Arg Gln His 355 360 21418 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 214 tgcttcgcta ctgccctc 18 215 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 215 ttcccttgtg ggttggag 18 216 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 216 agggctggaa gccagttc 18 217 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 217 agccagtgag gaaatgcg 18 218 24DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 218 tgtccaaagt acacacacct gagg 24219 45 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 219 gatgccacga tcgccaaggtgggacagctc tttgccgcct ggaag 45 220 1503 DNA Homo sapiens 220ggagagcgga gcgaagctgg ataacagggg accgatgatg tggcgaccat cagttctgct60 gcttctgttg ctactgaggc acggggccca ggggaagcca tccccagacgcaggccctca 120 tggccagggg agggtgcacc aggcggcccc cctgagcgacgctccccatg atgacgccca 180 cgggaacttc cagtacgacc atgaggctttcctgggacgg gaagtggcca aggaattcga 240 ccaactcacc ccagaggaaagccaggcccg tctggggcgg atcgtggacc gcatggaccg 300 cgcgggggacggcgacggct gggtgtcgct ggccgagctt cgcgcgtgga tcgcgcacac 360gcagcagcgg cacatacggg actcggtgag cgcggcctgg gacacgtacg acacggaccg420 cgacgggcgt gtgggttggg aggagctgcg caacgccacc tatggccactacgcgcccgg 480 tgaagaattt catgacgtgg aggatgcaga gacctacaaaaagatgctgg ctcgggacga 540 gcggcgtttc cgggtggccg accaggatggggactcgatg gccactcgag aggagctgac 600 agccttcctg caccccgaggagttccctca catgcgggac atcgtgattg ctgaaaccct 660 ggaggacctggacagaaaca aagatggcta tgtccaggtg gaggagtaca tcgcggatct 720gtactcagcc gagcctgggg aggaggagcc ggcgtgggtg cagacggaga ggcagcagtt780 ccgggacttc cgggatctga acaaggatgg gcacctggat gggagtgaggtgggccactg 840 ggtgctgccc cctgcccagg accagcccct ggtggaagccaaccacctgc tgcacgagag 900 cgacacggac aaggatgggc ggctgagcaaagcggaaatc ctgggtaatt ggaacatgtt 960 tgtgggcagt caggccaccaactatggcga ggacctgacc cggcaccacg atgagctgtg 1020 agcaccgcgcacctgccaca gcctcagagg cccgcacaat gaccggagga ggggccgctg 1080tggtctggcc ccctccctgt ccaggccccg caggaggcag atgcagtccc aggcatcctc1140 ctgcccctgg gctctcaggg accccctggg tcggcttctg tccctgtcacacccccaacc 1200 ccagggaggg gctgtcatag tcccagagga taagcaatacctatttctga ctgagtctcc 1260 cagcccagac ccagggaccc ttggccccaagctcagctct aagaaccgcc ccaacccctc 1320 cagctccaaa tctgagcctccaccacatag actgaaactc ccctggcccc agccctctcc 1380 tgcctggcctggcctgggac acctcctctc tgccaggagg caataaaagc cagcgccggg 1440accttgaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa1500 aaa 1503 221 328 PRT Homo sapiens 221 Met Met Trp Arg Pro SerVal Leu Leu Leu Leu Leu Leu Leu Arg His 1 5 10 15 Gly Ala Gln GlyLys Pro Ser Pro Asp Ala Gly Pro His Gly Gln Gly 20 25 30 Arg ValHis Gln Ala Ala Pro Leu Ser Asp Ala Pro His Asp Asp Ala 35 40 45His Gly Asn Phe Gln Tyr Asp His Glu Ala Phe Leu Gly Arg Glu Val 5055 60 Ala Lys Glu Phe Asp Gln Leu Thr Pro Glu Glu Ser Gln Ala ArgLeu 65 70 75 80 Gly Arg Ile Val Asp Arg Met Asp Arg Ala Gly Asp GlyAsp Gly Trp 85 90 95 Val Ser Leu Ala Glu Leu Arg Ala Trp Ile AlaHis Thr Gln Gln Arg 100 105 110 His Ile Arg Asp Ser Val Ser Ala AlaTrp Asp Thr Tyr Asp Thr Asp 115 120 125 Arg Asp Gly Arg Val Gly TrpGlu Glu Leu Arg Asn Ala Thr Tyr Gly 130 135 140 His Tyr Ala Pro GlyGlu Glu Phe His Asp Val Glu Asp Ala Glu Thr 145 150 155 160 Tyr LysLys Met Leu Ala Arg Asp Glu Arg Arg Phe Arg Val Ala Asp 165 170 175Gln Asp Gly Asp Ser Met Ala Thr Arg Glu Glu Leu Thr Ala Phe Leu 180185 190 His Pro Glu Glu Phe Pro His Met Arg Asp Ile Val Ile Ala GluThr 195 200 205 Leu Glu Asp Leu Asp Arg Asn Lys Asp Gly Tyr Val GlnVal Glu Glu 210 215 220 Tyr Ile Ala Asp Leu Tyr Ser Ala Glu Pro GlyGlu Glu Glu Pro Ala 225 230 235 240 Trp Val Gln Thr Glu Arg Gln GlnPhe Arg Asp Phe Arg Asp Leu Asn 245 250 255 Lys Asp Gly His Leu AspGly Ser Glu Val Gly His Trp Val Leu Pro 260 265 270 Pro Ala Gln AspGln Pro Leu Val Glu Ala Asn His Leu Leu His Glu 275 280 285 Ser AspThr Asp Lys Asp Gly Arg Leu Ser Lys Ala Glu Ile Leu Gly 290 295 300Asn Trp Asn Met Phe Val Gly Ser Gln Ala Thr Asn Tyr Gly Glu Asp 305310 315 320 Leu Thr Arg His His Asp Glu Leu 325 222 20 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 222 cgcaggccct catggccagg 20 223 18 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 223 gaaatcctgg gtaattgg 18 224 23 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 224 gtgcgcggtg ctcacagctc atc 23 225 44 DNAArtificial Sequence Description of Artificial Sequence Syntheticoligonucleotide probe 225 cccccctgag cgacgctccc ccatgatgacgcccacggga actt 44 226 2403 DNA Homo sapiens 226 ggggccttgccttccgcact cgggcgcagc cgggtggatc tcgagcaggt gcggagcccc 60gggcggcggg cgcgggtgcg agggatccct gacgcctctg tccctgtttc tttgtcgctc120 ccagcctgtc tgtcgtcgtt ttggcgcccc cgcctccccg cggtgcggggttgcacaccg 180 atcctgggct tcgctcgatt tgccgccgag gcgcctcccagacctagagg ggcgctggcc 240 tggagcagcg ggtcgtctgt gtcctctctcctctgcgccg cgcccgggga tccgaagggt 300 gcggggctct gaggaggtgacgcgcggggc ctcccgcacc ctggccttgc ccgcattctc 360 cctctctcccaggtgtgagc agcctatcag tcaccatgtc cgcagcctgg atcccggctc 420tcggcctcgg tgtgtgtctg ctgctgctgc cggggcccgc gggcagcgag ggagccgctc480 ccattgctat cacatgtttt accagaggct tggacatcag gaaagagaaagcagatgtcc 540 tctgcccagg gggctgccct cttgaggaat tctctgtgtatgggaacata gtatatgctt 600 ctgtatcgag catatgtggg gctgctgtccacaggggagt aatcagcaac tcagggggac 660 ctgtacgagt ctatagcctacctggtcgag aaaactattc ctcagtagat gccaatggca 720 tccagtctcaaatgctttct agatggtctg cttctttcac agtaactaaa ggcaaaagta 780gtacacagga ggccacagga caagcagtgt ccacagcaca tccaccaaca ggtaaacgac840 taaagaaaac acccgagaag aaaactggca ataaagattg taaagcagacattgcatttc 900 tgattgatgg aagctttaat attgggcagc gccgatttaatttacagaag aattttgttg 960 gaaaagtggc tctaatgttg ggaattggaacagaaggacc acatgtgggc cttgttcaag 1020 ccagtgaaca tcccaaaatagaattttact tgaaaaactt tacatcagcc aaagatgttt 1080 tgtttgccataaaggaagta ggtttcagag ggggtaattc caatacagga aaagccttga 1140agcatactgc tcagaaattc ttcacggtag atgctggagt aagaaaaggg atccccaaag1200 tggtggtggt atttattgat ggttggcctt ctgatgacat cgaggaagcaggcattgtgg 1260 ccagagagtt tggtgtcaat gtatttatag tttctgtggccaagcctatc cctgaagaac 1320 tggggatggt tcaggatgtc acatttgttgacaaggctgt ctgtcggaat aatggcttct 1380 tctcttacca catgcccaactggtttggca ccacaaaata cgtaaagcct ctggtacaga 1440 agctgtgcactcatgaacaa atgatgtgca gcaagacctg ttataactca gtgaacattg 1500cctttctaat tgatggctcc agcagtgttg gagatagcaa tttccgcctc atgcttgaat1560 ttgtttccaa catagccaag acttttgaaa tctcggacat tggtgccaagatagctgctg 1620 tacagtttac ttatgatcag cgcacggagt tcagtttcactgactatagc accaaagaga 1680 atgtcctagc tgtcatcaga aacatccgctatatgagtgg tggaacagct actggtgatg 1740 ccatttcctt

cactgttaga aatgtgtttg gccctataag ggagagcccc aacaagaact 1800tcctagtaat tgtcacagat gggcagtcct atgatgatgt ccaaggccct gcagctgctg1860 cacatgatgc aggaatcact atcttctctg ttggtgtggc ttgggcacctctggatgacc 1920 tgaaagatat ggcttctaaa ccgaaggagt ctcacgctttcttcacaaga gagttcacag 1980 gattagaacc aattgtttct gatgtcatcagaggcatttg tagagatttc ttagaatccc 2040 agcaataatg gtaacattttgacaactgaa agaaaaagta caaggggatc cagtgtgtaa 2100 attgtattctcataatactg aaatgcttta gcatactaga atcagataca aaactattaa 2160gtatgtcaac agccatttag gcaaataagc actcctttaa agccgctgcc ttctggttac2220 aatttacagt gtactttgtt aaaaacactg ctgaggcttc ataatcatggctcttagaaa 2280 ctcaggaaag aggagataat gtggattaaa accttaagagttctaaccat gcctactaaa 2340 tgtacagata tgcaaattcc atagctcaataaaagaatct gatacttaga ccaaaaaaaa 2400 aaa 2403 227 550 PRT Homosapiens 227 Met Ser Ala Ala Trp Ile Pro Ala Leu Gly Leu Gly Val CysLeu Leu 1 5 10 15 Leu Leu Pro Gly Pro Ala Gly Ser Glu Gly Ala AlaPro Ile Ala Ile 20 25 30 Thr Cys Phe Thr Arg Gly Leu Asp Ile ArgLys Glu Lys Ala Asp Val 35 40 45 Leu Cys Pro Gly Gly Cys Pro LeuGlu Glu Phe Ser Val Tyr Gly Asn 50 55 60 Ile Val Tyr Ala Ser ValSer Ser Ile Cys Gly Ala Ala Val His Arg 65 70 75 80 Gly Val Ile SerAsn Ser Gly Gly Pro Val Arg Val Tyr Ser Leu Pro 85 90 95 Gly ArgGlu Asn Tyr Ser Ser Val Asp Ala Asn Gly Ile Gln Ser Gln 100 105 110Met Leu Ser Arg Trp Ser Ala Ser Phe Thr Val Thr Lys Gly Lys Ser 115120 125 Ser Thr Gln Glu Ala Thr Gly Gln Ala Val Ser Thr Ala His ProPro 130 135 140 Thr Gly Lys Arg Leu Lys Lys Thr Pro Glu Lys Lys ThrGly Asn Lys 145 150 155 160 Asp Cys Lys Ala Asp Ile Ala Phe Leu IleAsp Gly Ser Phe Asn Ile 165 170 175 Gly Gln Arg Arg Phe Asn Leu GlnLys Asn Phe Val Gly Lys Val Ala 180 185 190 Leu Met Leu Gly Ile GlyThr Glu Gly Pro His Val Gly Leu Val Gln 195 200 205 Ala Ser Glu HisPro Lys Ile Glu Phe Tyr Leu Lys Asn Phe Thr Ser 210 215 220 Ala LysAsp Val Leu Phe Ala Ile Lys Glu Val Gly Phe Arg Gly Gly 225 230 235240 Asn Ser Asn Thr Gly Lys Ala Leu Lys His Thr Ala Gln Lys Phe Phe245 250 255 Thr Val Asp Ala Gly Val Arg Lys Gly Ile Pro Lys Val ValVal Val 260 265 270 Phe Ile Asp Gly Trp Pro Ser Asp Asp Ile Glu GluAla Gly Ile Val 275 280 285 Ala Arg Glu Phe Gly Val Asn Val Phe IleVal Ser Val Ala Lys Pro 290 295 300 Ile Pro Glu Glu Leu Gly Met ValGln Asp Val Thr Phe Val Asp Lys 305 310 315 320 Ala Val Cys Arg AsnAsn Gly Phe Phe Ser Tyr His Met Pro Asn Trp 325 330 335 Phe Gly ThrThr Lys Tyr Val Lys Pro Leu Val Gln Lys Leu Cys Thr 340 345 350 HisGlu Gln Met Met Cys Ser Lys Thr Cys Tyr Asn Ser Val Asn Ile 355 360365 Ala Phe Leu Ile Asp Gly Ser Ser Ser Val Gly Asp Ser Asn Phe Arg370 375 380 Leu Met Leu Glu Phe Val Ser Asn Ile Ala Lys Thr Phe GluIle Ser 385 390 395 400 Asp Ile Gly Ala Lys Ile Ala Ala Val Gln PheThr Tyr Asp Gln Arg 405 410 415 Thr Glu Phe Ser Phe Thr Asp Tyr SerThr Lys Glu Asn Val Leu Ala 420 425 430 Val Ile Arg Asn Ile Arg TyrMet Ser Gly Gly Thr Ala Thr Gly Asp 435 440 445 Ala Ile Ser Phe ThrVal Arg Asn Val Phe Gly Pro Ile Arg Glu Ser 450 455 460 Pro Asn LysAsn Phe Leu Val Ile Val Thr Asp Gly Gln Ser Tyr Asp 465 470 475 480Asp Val Gln Gly Pro Ala Ala Ala Ala His Asp Ala Gly Ile Thr Ile 485490 495 Phe Ser Val Gly Val Ala Trp Ala Pro Leu Asp Asp Leu Lys AspMet 500 505 510 Ala Ser Lys Pro Lys Glu Ser His Ala Phe Phe Thr ArgGlu Phe Thr 515 520 525 Gly Leu Glu Pro Ile Val Ser Asp Val Ile ArgGly Ile Cys Arg Asp 530 535 540 Phe Leu Glu Ser Gln Gln 545 550 22818 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 228 tggtctcgca caccgatc 18 229 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 229 ctgctgtcca caggggag 18 230 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 230 ccttgaagca tactgctc 18 231 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 231 gagatagcaa tttccgcc 18 232 18DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 232 ttcctcaaga gggcagcc 18 233 24DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 233 cttggcacca atgtccgaga tttc 24234 45 DNA Artificial Sequence Description of Artificial SequenceSynthetic oligonucleotide probe 234 gctctgagga aggtgacgcgcggggcctcc gaacccttgg ccttg 45 235 2586 DNA Homo sapiens 235cgccgcgctc ccgcacccgc ggcccgccca ccgcgccgct cccgcatctg cacccgcagc60 ccggcggcct cccggcggga gcgagcagat ccagtccggc ccgcagcgcaactcggtcca 120 gtcggggcgg cggctgcggg cgcagagcgg agatgcagcggcttggggcc accctgctgt 180 gcctgctgct ggcggcggcg gtccccacggcccccgcgcc cgctccgacg gcgacctcgg 240 ctccagtcaa gcccggcccggctctcagct acccgcagga ggaggccacc ctcaatgaga 300 tgttccgcgaggttgaggaa ctgatggagg acacgcagca caaattgcgc agcgcggtgg 360aagagatgga ggcagaagaa gctgctgcta aagcatcatc agaagtgaac ctggcaaact420 tacctcccag ctatcacaat gagaccaaca cagacacgaa ggttggaaataataccatcc 480 atgtgcaccg agaaattcac aagataacca acaaccagactggacaaatg gtcttttcag 540 agacagttat cacatctgtg ggagacgaagaaggcagaag gagccacgag tgcatcatcg 600 acgaggactg tgggcccagcatgtactgcc agtttgccag cttccagtac acctgccagc 660 catgccggggccagaggatg ctctgcaccc gggacagtga gtgctgtgga gaccagctgt 720gtgtctgggg tcactgcacc aaaatggcca ccaggggcag caatgggacc atctgtgaca780 accagaggga ctgccagccg gggctgtgct gtgccttcca gagaggcctgctgttccctg 840 tgtgcacacc cctgcccgtg gagggcgagc tttgccatgaccccgccagc cggcttctgg 900 acctcatcac ctgggagcta gagcctgatggagccttgga ccgatgccct tgtgccagtg 960 gcctcctctg ccagccccacagccacagcc tggtgtatgt gtgcaagccg accttcgtgg 1020 ggagccgtgaccaagatggg gagatcctgc tgcccagaga ggtccccgat gagtatgaag 1080ttggcagctt catggaggag gtgcgccagg agctggagga cctggagagg agcctgactg1140 aagagatggc gctgggggag cctgcggctg ccgccgctgc actgctgggaggggaagaga 1200 tttagatctg gaccaggctg tgggtagatg tgcaatagaaatagctaatt tatttcccca 1260 ggtgtgtgct ttaggcgtgg gctgaccaggcttcttccta catcttcttc ccagtaagtt 1320 tcccctctgg cttgacagcatgaggtgttg tgcatttgtt cagctccccc aggctgttct 1380 ccaggcttcacagtctggtg cttgggagag tcaggcaggg ttaaactgca ggagcagttt 1440gccacccctg tccagattat tggctgcttt gcctctacca gttggcagac agccgtttgt1500 tctacatggc tttgataatt gtttgagggg aggagatgga aacaatgtggagtctccctc 1560 tgattggttt tggggaaatg tggagaagag tgccctgctttgcaaacatc aacctggcaa 1620 aaatgcaaca aatgaatttt ccacgcagttctttccatgg gcataggtaa gctgtgcctt 1680 cagctgttgc agatgaaatgttctgttcac cctgcattac atgtgtttat tcatccagca 1740 gtgttgctcagctcctacct ctgtgccagg gcagcatttt catatccaag atcaattccc 1800tctctcagca cagcctgggg agggggtcat tgttctcctc gtccatcagg gatctcagag1860 gctcagagac tgcaagctgc ttgcccaagt cacacagcta gtgaagaccagagcagtttc 1920 atctggttgt gactctaagc tcagtgctct ctccactaccccacaccagc cttggtgcca 1980 ccaaaagtgc tccccaaaag gaaggagaatgggatttttc ttgaggcatg cacatctgga 2040 attaaggtca aactaattctcacatccctc taaaagtaaa ctactgttag gaacagcagt 2100 gttctcacagtgtggggcag ccgtccttct aatgaagaca atgatattga cactgtccct 2160ctttggcagt tgcattagta actttgaaag gtatatgact gagcgtagca tacaggttaa2220 cctgcagaaa cagtacttag gtaattgtag ggcgaggatt ataaatgaaatttgcaaaat 2280 cacttagcag caactgaaga caattatcaa ccacgtggagaaaatcaaac cgagcagggc 2340 tgtgtgaaac atggttgtaa tatgcgactgcgaacactga actctacgcc actccacaaa 2400 tgatgttttc aggtgtcatggactgttgcc accatgtatt catccagagt tcttaaagtt 2460 taaagttgcacatgattgta taagcatgct ttctttgagt tttaaattat gtataaacat 2520aagttgcatt tagaaatcaa gcataaatca cttcaactgc aaaaaaaaaa aaaaaaaaaa2580 aaaaaa 2586 236 350 PRT Homo sapiens 236 Met Gln Arg Leu GlyAla Thr Leu Leu Cys Leu Leu Leu Ala Ala Ala 1 5 10 15 Val Pro ThrAla Pro Ala Pro Ala Pro Thr Ala Thr Ser Ala Pro Val 20 25 30 LysPro Gly Pro Ala Leu Ser Tyr Pro Gln Glu Glu Ala Thr Leu Asn 35 4045 Glu Met Phe Arg Glu Val Glu Glu Leu Met Glu Asp Thr Gln His Lys50 55 60 Leu Arg Ser Ala Val Glu Glu Met Glu Ala Glu Glu Ala AlaAla Lys 65 70 75 80 Ala Ser Ser Glu Val Asn Leu Ala Asn Leu Pro ProSer Tyr His Asn 85 90 95 Glu Thr Asn Thr Asp Thr Lys Val Gly AsnAsn Thr Ile His Val His 100 105 110 Arg Glu Ile His Lys Ile Thr AsnAsn Gln Thr Gly Gln Met Val Phe 115 120 125 Ser Glu Thr Val Ile ThrSer Val Gly Asp Glu Glu Gly Arg Arg Ser 130 135 140 His Glu Cys IleIle Asp Glu Asp Cys Gly Pro Ser Met Tyr Cys Gln 145 150 155 160 PheAla Ser Phe Gln Tyr Thr Cys Gln Pro Cys Arg Gly Gln Arg Met 165 170175 Leu Cys Thr Arg Asp Ser Glu Cys Cys Gly Asp Gln Leu Cys Val Trp180 185 190 Gly His Cys Thr Lys Met Ala Thr Arg Gly Ser Asn Gly ThrIle Cys 195 200 205 Asp Asn Gln Arg Asp Cys Gln Pro Gly Leu Cys CysAla Phe Gln Arg 210 215 220 Gly Leu Leu Phe Pro Val Cys Thr Pro LeuPro Val Glu Gly Glu Leu 225 230 235 240 Cys His Asp Pro Ala Ser ArgLeu Leu Asp Leu Ile Thr Trp Glu Leu 245 250 255 Glu Pro Asp Gly AlaLeu Asp Arg Cys Pro Cys Ala Ser Gly Leu Leu 260 265 270 Cys Gln ProHis Ser His Ser Leu Val Tyr Val Cys Lys Pro Thr Phe 275 280 285 ValGly Ser Arg Asp Gln Asp Gly Glu Ile Leu Leu Pro Arg Glu Val 290 295300 Pro Asp Glu Tyr Glu Val Gly Ser Phe Met Glu Glu Val Arg Gln Glu305 310 315 320 Leu Glu Asp Leu Glu Arg Ser Leu Thr Glu Glu Met AlaLeu Gly Glu 325 330 335 Pro Ala Ala Ala Ala Ala Ala Leu Leu Gly GlyGlu Glu Ile 340 345 350 237 17 DNA Artificial Sequence Syntheticoligonucleotide probe 237 ggagctgcac cccttgc 17 238 49 DNAArtificial Sequence Synthetic Oligonucleotide Probe 238 ggaggactgtgccaccatga gagactcttc aaacccaagg caaaattgg 49 239 24 DNA ArtificialSequence Synthetic Oligonucleotide Probe 239 gcagagcgga gatgcagcggcttg 24 240 18 DNA Artificial Sequence Synthetic OligonucleotideProbe 240 ttggcagctt catggagg 18 241 18 DNA Artificial SequenceSynthetic Oligonucleotide Probe 241 cctgggcaaa aatgcaac 18 242 24DNA Artificial Sequence Synthetic Oligonucleotide Probe 242ctccagctcc tggcgcacct cctc 24 243 45 DNA Artificial SequenceSynthetic Oligonucleotide Probe 243 ggctctcagc taccgcgcaggagcgaggcc accctcaatg agatg 45 244 3679 DNA Homo Sapien 244aaggaggctg ggaggaaaga ggtaagaaag gttagagaac ctacctcaca 50tctctctggg ctcagaagga ctctgaagat aacaataatt tcagcccatc 100cactctcctt ccctcccaaa cacacatgtg catgtacaca cacacataca 150cacacataca ccttcctctc cttcactgaa gactcacagt cactcactct 200gtgagcaggt catagaaaag gacactaaag ccttaaggac aggcctggcc 250attacctctg cagctccttt ggcttgttga gtcaaaaaac atgggagggg 300ccaggcacgg tgactcacac ctgtaatccc agcattttgg gagaccgagg 350tgagcagatc acttgaggtc aggagttcga gaccagcctg gccaacatgg 400agaaaccccc atctctacta aaaatacaaa aattagccag gagtggtggc 450aggtgcctgt aatcccagct actcaggtgg ctgagccagg agaatcgctt 500gaatccagga ggcggaggat gcagtcagct gagtgcaccg ctgcactcca 550gcctgggtga cagaatgaga ctctgtctca aacaaacaaa cacgggagga 600ggggtagata ctgcttctct gcaacctcct taactctgca tcctcttctt 650ccagggctgc ccctgatggg gcctggcaat gactgagcag gcccagcccc 700agaggacaag gaagagaagg catattgagg agggcaagaa gtgacgcccg 750gtgtagaatg actgccctgg gagggtggtt ccttgggccc tggcagggtt 800gctgaccctt accctgcaaa acacaaagag caggactcca gactctcctt 850gtgaatggtc ccctgccctg cagctccacc atgaggcttc tcgtggcccc 900actcttgcta gcttgggtgg ctggtgccac tgccactgtg cccgtggtac 950cctggcatgt tccctgcccc cctcagtgtg cctgccagat ccggccctgg 1000tatacgcccc gctcgtccta ccgcgaggct accactgtgg actgcaatga 1050cctattcctg acggcagtcc ccccggcact ccccgcaggc acacagaccc 1100tgctcctgca gagcaacagc attgtccgtg tggaccagag tgagctgggc 1150tacctggcca atctcacaga gctggacctg tcccagaaca gcttttcgga 1200tgcccgagac tgtgatttcc atgccctgcc ccagctgctg agcctgcacc 1250tagaggagaa ccagctgacc cggctggagg accacagctt tgcagggctg 1300gccagcctac aggaactcta tctcaaccac aaccagctct accgcatcgc 1350ccccagggcc ttttctggcc tcagcaactt gctgcggctg cacctcaact 1400ccaacctcct gagggccatt gacagccgct ggtttgaaat gctgcccaac 1450ttggagatac tcatgattgg cggcaacaag gtagatgcca tcctggacat 1500gaacttccgg cccctggcca acctgcgtag cctggtgcta gcaggcatga 1550acctgcggga gatctccgac tatgccctgg aggggctgca aagcctggag 1600agcctctcct tctatgacaa ccagctggcc cgggtgccca ggcgggcact 1650ggaacaggtg cccgggctca agttcctaga cctcaacaag aacccgctcc 1700agcgggtagg gccgggggac tttgccaaca tgctgcacct taaggagctg 1750ggactgaaca acatggagga gctggtctcc atcgacaagt ttgccctggt 1800gaacctcccc gagctgacca agctggacat caccaataac ccacggctgt 1850ccttcatcca cccccgcgcc ttccaccacc tgccccagat ggagaccctc 1900atgctcaaca acaacgctct cagtgccttg caccagcaga cggtggagtc 1950cctgcccaac ctgcaggagg taggtctcca cggcaacccc atccgctgtg 2000actgtgtcat ccgctgggcc aatgccacgg gcacccgtgt ccgcttcatc 2050gagccgcaat ccaccctgtg tgcggagcct ccggacctcc agcgcctccc 2100ggtccgtgag gtgcccttcc gggagatgac ggaccactgt ttgcccctca 2150tctccccacg aagcttcccc ccaagcctcc aggtagccag tggagagagc 2200atggtgctgc attgccgggc actggccgaa cccgaacccg agatctactg 2250ggtcactcca gctgggcttc gactgacacc tgcccatgca ggcaggaggt 2300accgggtgta ccccgagggg accctggagc tgcggagggt gacagcagaa 2350gaggcagggc tatacacctg tgtggcccag aacctggtgg gggctgacac 2400taagacggtt agtgtggttg tgggccgtgc tctcctccag ccaggcaggg 2450acgaaggaca ggggctggag ctccgggtgc aggagaccca cccctatcac 2500atcctgctat cttgggtcac cccacccaac acagtgtcca ccaacctcac 2550ctggtccagt gcctcctccc tccggggcca gggggccaca gctctggccc 2600gcctgcctcg gggaacccac agctacaaca ttacccgcct ccttcaggcc 2650acggagtact gggcctgcct gcaagtggcc tttgctgatg cccacaccca 2700gttggcttgt gtatgggcca ggaccaaaga ggccacttct tgccacagag 2750ccttagggga tcgtcctggg ctcattgcca tcctggctct cgctgtcctt 2800ctcctggcag ctgggctagc ggcccacctt ggcacaggcc aacccaggaa 2850gggtgtgggt gggaggcggc ctctccctcc agcctgggct ttctggggct 2900ggagtgcccc ttctgtccgg gttgtgtctg ctcccctcgt cctgccctgg 2950aatccaggga ggaagctgcc cagatcctca gaaggggaga cactgttgcc 3000accattgtct caaaattctt gaagctcagc ctgttctcag cagtagagaa 3050atcactagga ctacttttta ccaaaagaga agcagtctgg gccagatgcc 3100ctgccaggaa agggacatgg acccacgtgc ttgaggcctg gcagctgggc 3150caagacagat ggggctttgt ggccctgggg gtgcttctgc agccttgaaa 3200aagttgccct tacctcctag ggtcacctct gctgccattc tgaggaacat 3250ctccaaggaa caggagggac tttggctaga gcctcctgcc tccccatctt 3300ctctctgccc agaggctcct gggcctggct tggctgtccc ctacctgtgt 3350ccccgggctg caccccttcc tcttctcttt ctctgtacag tctcagttgc 3400ttgctcttgt gcctcctggg caagggctga aggaggccac tccatctcac 3450ctcggggggc tgccctcaat gtgggagtga ccccagccag

atctgaagga 3500 catttgggag agggatgccc aggaacgcct catctcagcagcctgggctc 3550 ggcattccga agctgacttt ctataggcaa ttttgtacctttgtggagaa 3600 atgtgtcacc tcccccaacc cgattcactc ttttctcctgttttgtaaaa 3650 aataaaaata aataataaca ataaaaaaa 3679 245 713 PRTHomo Sapien 245 Met Arg Leu Leu Val Ala Pro Leu Leu Leu Ala Trp ValAla Gly 1 5 10 15 Ala Thr Ala Thr Val Pro Val Val Pro Trp His ValPro Cys Pro 20 25 30 Pro Gln Cys Ala Cys Gln Ile Arg Pro Trp TyrThr Pro Arg Ser 35 40 45 Ser Tyr Arg Glu Ala Thr Thr Val Asp CysAsn Asp Leu Phe Leu 50 55 60 Thr Ala Val Pro Pro Ala Leu Pro AlaGly Thr Gln Thr Leu Leu 65 70 75 Leu Gln Ser Asn Ser Ile Val ArgVal Asp Gln Ser Glu Leu Gly 80 85 90 Tyr Leu Ala Asn Leu Thr GluLeu Asp Leu Ser Gln Asn Ser Phe 95 100 105 Ser Asp Ala Arg Asp CysAsp Phe His Ala Leu Pro Gln Leu Leu 110 115 120 Ser Leu His Leu GluGlu Asn Gln Leu Thr Arg Leu Glu Asp His 125 130 135 Ser Phe Ala GlyLeu Ala Ser Leu Gln Glu Leu Tyr Leu Asn His 140 145 150 Asn Gln LeuTyr Arg Ile Ala Pro Arg Ala Phe Ser Gly Leu Ser 155 160 165 Asn LeuLeu Arg Leu His Leu Asn Ser Asn Leu Leu Arg Ala Ile 170 175 180 AspSer Arg Trp Phe Glu Met Leu Pro Asn Leu Glu Ile Leu Met 185 190 195Ile Gly Gly Asn Lys Val Asp Ala Ile Leu Asp Met Asn Phe Arg 200 205210 Pro Leu Ala Asn Leu Arg Ser Leu Val Leu Ala Gly Met Asn Leu 215220 225 Arg Glu Ile Ser Asp Tyr Ala Leu Glu Gly Leu Gln Ser Leu Glu230 235 240 Ser Leu Ser Phe Tyr Asp Asn Gln Leu Ala Arg Val Pro ArgArg 245 250 255 Ala Leu Glu Gln Val Pro Gly Leu Lys Phe Leu Asp LeuAsn Lys 260 265 270 Asn Pro Leu Gln Arg Val Gly Pro Gly Asp Phe AlaAsn Met Leu 275 280 285 His Leu Lys Glu Leu Gly Leu Asn Asn Met GluGlu Leu Val Ser 290 295 300 Ile Asp Lys Phe Ala Leu Val Asn Leu ProGlu Leu Thr Lys Leu 305 310 315 Asp Ile Thr Asn Asn Pro Arg Leu SerPhe Ile His Pro Arg Ala 320 325 330 Phe His His Leu Pro Gln Met GluThr Leu Met Leu Asn Asn Asn 335 340 345 Ala Leu Ser Ala Leu His GlnGln Thr Val Glu Ser Leu Pro Asn 350 355 360 Leu Gln Glu Val Gly LeuHis Gly Asn Pro Ile Arg Cys Asp Cys 365 370 375 Val Ile Arg Trp AlaAsn Ala Thr Gly Thr Arg Val Arg Phe Ile 380 385 390 Glu Pro Gln SerThr Leu Cys Ala Glu Pro Pro Asp Leu Gln Arg 395 400 405 Leu Pro ValArg Glu Val Pro Phe Arg Glu Met Thr Asp His Cys 410 415 420 Leu ProLeu Ile Ser Pro Arg Ser Phe Pro Pro Ser Leu Gln Val 425 430 435 AlaSer Gly Glu Ser Met Val Leu His Cys Arg Ala Leu Ala Glu 440 445 450Pro Glu Pro Glu Ile Tyr Trp Val Thr Pro Ala Gly Leu Arg Leu 455 460465 Thr Pro Ala His Ala Gly Arg Arg Tyr Arg Val Tyr Pro Glu Gly 470475 480 Thr Leu Glu Leu Arg Arg Val Thr Ala Glu Glu Ala Gly Leu Tyr485 490 495 Thr Cys Val Ala Gln Asn Leu Val Gly Ala Asp Thr Lys ThrVal 500 505 510 Ser Val Val Val Gly Arg Ala Leu Leu Gln Pro Gly ArgAsp Glu 515 520 525 Gly Gln Gly Leu Glu Leu Arg Val Gln Glu Thr HisPro Tyr His 530 535 540 Ile Leu Leu Ser Trp Val Thr Pro Pro Asn ThrVal Ser Thr Asn 545 550 555 Leu Thr Trp Ser Ser Ala Ser Ser Leu ArgGly Gln Gly Ala Thr 560 565 570 Ala Leu Ala Arg Leu Pro Arg Gly ThrHis Ser Tyr Asn Ile Thr 575 580 585 Arg Leu Leu Gln Ala Thr Glu TyrTrp Ala Cys Leu Gln Val Ala 590 595 600 Phe Ala Asp Ala His Thr GlnLeu Ala Cys Val Trp Ala Arg Thr 605 610 615 Lys Glu Ala Thr Ser CysHis Arg Ala Leu Gly Asp Arg Pro Gly 620 625 630 Leu Ile Ala Ile LeuAla Leu Ala Val Leu Leu Leu Ala Ala Gly 635 640 645 Leu Ala Ala HisLeu Gly Thr Gly Gln Pro Arg Lys Gly Val Gly 650 655 660 Gly Arg ArgPro Leu Pro Pro Ala Trp Ala Phe Trp Gly Trp Ser 665 670 675 Ala ProSer Val Arg Val Val Ser Ala Pro Leu Val Leu Pro Trp 680 685 690 AsnPro Gly Arg Lys Leu Pro Arg Ser Ser Glu Gly Glu Thr Leu 695 700 705Leu Pro Pro Leu Ser Gln Asn Ser 710 246 22 DNA Artificial SequenceSynthetic Oligonucleotide Probe 246 aacaaggtaa gatgccatcc tg 22 24724 DNA Artificial Sequence Synthetic Oligonucleotide Probe 247aaacttgtcg atggagacca gctc 24 248 45 DNA Artificial SequenceSynthetic Oligonucleotide Probe 248 aggggctgca aagcctggagagcctctcct tctatgacaa ccagc 45 249 3401 DNA Homo Sapien 249gcaagccaag gcgctgtttg agaaggtgaa gaagttccgg acccatgtgg 50aggaggggga cattgtgtac cgcctctaca tgcggcagac catcatcaag 100gtgatcaagt tcatcctcat catctgctac accgtctact acgtgcacaa 150catcaagttc gacgtggact gcaccgtgga cattgagagc ctgacgggct 200accgcaccta ccgctgtgcc caccccctgg ccacactctt caagatcctg 250gcgtccttct acatcagcct agtcatcttc tacggcctca tctgcatgta 300cacactgtgg tggatgctac ggcgctccct caagaagtac tcgtttgagt 350cgatccgtga ggagagcagc tacagcgaca tccccgacgt caagaacgac 400ttcgccttca tgctgcacct cattgaccaa tacgacccgc tctactccaa 450gcgcttcgcc gtcttcctgt cggaggtgag tgagaacaag ctgcggcagc 500tgaacctcaa caacgagtgg acgctggaca agctccggca gcggctcacc 550aagaacgcgc aggacaagct ggagctgcac ctgttcatgc tcagtggcat 600ccctgacact gtgtttgacc tggtggagct ggaggtcctc aagctggagc 650tgatccccga cgtgaccatc ccgcccagca ttgcccagct cacgggcctc 700aaggagctgt ggctctacca cacagcggcc aagattgaag cgcctgcgct 750ggccttcctg cgcgagaacc tgcgggcgct gcacatcaag ttcaccgaca 800tcaaggagat cccgctgtgg atctatagcc tgaagacact ggaggagctg 850cacctgacgg gcaacctgag cgcggagaac aaccgctaca tcgtcatcga 900cgggctgcgg gagctcaaac gcctcaaggt gctgcggctc aagagcaacc 950taagcaagct gccacaggtg gtcacagatg tgggcgtgca cctgcagaag 1000ctgtccatca acaatgaggg caccaagctc atcgtcctca acagcctcaa 1050gaagatggcg aacctgactg agctggagct gatccgctgc gacctggagc 1100gcatccccca ctccatcttc agcctccaca acctgcagga gattgacctc 1150aaggacaaca acctcaagac catcgaggag atcatcagct tccagcacct 1200gcaccgcctc acctgcctta agctgtggta caaccacatc gcctacatcc 1250ccatccagat cggcaacctc accaacctgg agcgcctcta cctgaaccgc 1300aacaagatcg agaagatccc cacccagctc ttctactgcc gcaagctgcg 1350ctacctggac ctcagccaca acaacctgac cttcctccct gccgacatcg 1400gcctcctgca gaacctccag aacctagcca tcacggccaa ccggatcgag 1450acgctccctc cggagctctt ccagtgccgg aagctgcggg ccctgcacct 1500gggcaacaac gtgctgcagt cactgccctc cagggtgggc gagctgacca 1550acctgacgca gatcgagctg cggggcaacc ggctggagtg cctgcctgtg 1600gagctgggcg agtgcccact gctcaagcgc agcggcttgg tggtggagga 1650ggacctgttc aacacactgc cacccgaggt gaaggagcgg ctgtggaggg 1700ctgacaagga gcaggcctga gcgaggccgg cccagcacag caagcagcag 1750gaccgctgcc cagtcctcag gcccggaggg gcaggcctag cttctcccag 1800aactcccgga cagccaggac agcctcgcgg ctgggcagga gcctggggcc 1850gcttgtgagt caggccagag cgagaggaca gtatctgtgg ggctggcccc 1900ttttctccct ctgagactca cgtcccccag ggcaagtgct tgtggaggag 1950agcaagtctc aagagcgcag tatttggata atcagggtct cctccctgga 2000ggccagctct gccccagggg ctgagctgcc accagaggtc ctgggaccct 2050cactttagtt cttggtattt atttttctcc atctcccacc tccttcatcc 2100agataactta tacattccca agaaagttca gcccagatgg aaggtgttca 2150gggaaaggtg ggctgccttt tccccttgtc cttatttagc gatgccgccg 2200ggcatttaac acccacctgg acttcagcag agtggtccgg ggcgaaccag 2250ccatgggacg gtcacccagc agtgccgggc tgggctctgc ggtgcggtcc 2300acgggagagc aggcctccag ctggaaaggc caggcctgga gcttgcctct 2350tcagtttttg tggcagtttt agttttttgt tttttttttt tttaatcaaa 2400aaacaatttt ttttaaaaaa aagctttgaa aatggatggt ttgggtatta 2450aaaagaaaaa aaaaacttaa aaaaaaaaag acactaacgg ccagtgagtt 2500ggagtctcag ggcagggtgg cagtttccct tgagcaaagc agccagacgt 2550tgaactgtgt ttcctttccc tgggcgcagg gtgcagggtg tcttccggat 2600ctggtgtgac cttggtccag gagttctatt tgttcctggg gagggaggtt 2650tttttgtttg ttttttgggt ttttttggtg tcttgttttc tttctcctcc 2700atgtgtcttg gcaggcactc atttctgtgg ctgtcggcca gagggaatgt 2750tctggagctg ccaaggaggg aggagactcg ggttggctaa tccccggatg 2800aacggtgctc cattcgcacc tcccctcctc gtgcctgccc tgcctctcca 2850cgcacagtgt taaggagcca agaggagcca cttcgcccag actttgtttc 2900cccacctcct gcggcatggg tgtgtccagt gccaccgctg gcctccgctg 2950cttccatcag ccctgtcgcc acctggtcct tcatgaagag cagacactta 3000gaggctggtc gggaatgggg aggtcgcccc tgggagggca ggcgttggtt 3050ccaagccggt tcccgtccct ggcgcctgga gtgcacacag cccagtcggc 3100acctggtggc tggaagccaa cctgctttag atcactcggg tccccacctt 3150agaagggtcc ccgccttaga tcaatcacgt ggacactaag gcacgtttta 3200gagtctcttg tcttaatgat tatgtccatc cgtctgtccg tccatttgtg 3250ttttctgcgt cgtgtcattg gatataatcc tcagaaataa tgcacactag 3300cctctgacaa ccatgaagca aaaatccgtt acatgtgggt ctgaacttgt 3350agactcggtc acagtatcaa ataaaatcta taacagaaaa aaaaaaaaaa 3400 a 3401250 546 PRT Homo Sapien 250 Met Arg Gln Thr Ile Ile Lys Val Ile LysPhe Ile Leu Ile Ile 1 5 10 15 Cys Tyr Thr Val Tyr Tyr Val His AsnIle Lys Phe Asp Val Asp 20 25 30 Cys Thr Val Asp Ile Glu Ser LeuThr Gly Tyr Arg Thr Tyr Arg 35 40 45 Cys Ala His Pro Leu Ala ThrLeu Phe Lys Ile Leu Ala Ser Phe 50 55 60 Tyr Ile Ser Leu Val IlePhe Tyr Gly Leu Ile Cys Met Tyr Thr 65 70 75 Leu Trp Trp Met LeuArg Arg Ser Leu Lys Lys Tyr Ser Phe Glu 80 85 90 Ser Ile Arg GluGlu Ser Ser Tyr Ser Asp Ile Pro Asp Val Lys 95 100 105 Asn Asp PheAla Phe Met Leu His Leu Ile Asp Gln Tyr Asp Pro 110 115 120 Leu TyrSer Lys Arg Phe Ala Val Phe Leu Ser Glu Val Ser Glu 125 130 135 AsnLys Leu Arg Gln Leu Asn Leu Asn Asn Glu Trp Thr Leu Asp 140 145 150Lys Leu Arg Gln Arg Leu Thr Lys Asn Ala Gln Asp Lys Leu Glu 155 160165 Leu His Leu Phe Met Leu Ser Gly Ile Pro Asp Thr Val Phe Asp 170175 180 Leu Val Glu Leu Glu Val Leu Lys Leu Glu Leu Ile Pro Asp Val185 190 195 Thr Ile Pro Pro Ser Ile Ala Gln Leu Thr Gly Leu Lys GluLeu 200 205 210 Trp Leu Tyr His Thr Ala Ala Lys Ile Glu Ala Pro AlaLeu Ala 215 220 225 Phe Leu Arg Glu Asn Leu Arg Ala Leu His Ile LysPhe Thr Asp 230 235 240 Ile Lys Glu Ile Pro Leu Trp Ile Tyr Ser LeuLys Thr Leu Glu 245 250 255 Glu Leu His Leu Thr Gly Asn Leu Ser AlaGlu Asn Asn Arg Tyr 260 265 270 Ile Val Ile Asp Gly Leu Arg Glu LeuLys Arg Leu Lys Val Leu 275 280 285 Arg Leu Lys Ser Asn Leu Ser LysLeu Pro Gln Val Val Thr Asp 290 295 300 Val Gly Val His Leu Gln LysLeu Ser Ile Asn Asn Glu Gly Thr 305 310 315 Lys Leu Ile Val Leu AsnSer Leu Lys Lys Met Ala Asn Leu Thr 320 325 330 Glu Leu Glu Leu IleArg Cys Asp Leu Glu Arg Ile Pro His Ser 335 340 345 Ile Phe Ser LeuHis Asn Leu Gln Glu Ile Asp Leu Lys Asp Asn 350 355 360 Asn Leu LysThr Ile Glu Glu Ile Ile Ser Phe Gln His Leu His 365 370 375 Arg LeuThr Cys Leu Lys Leu Trp Tyr Asn His Ile Ala Tyr Ile 380 385 390 ProIle Gln Ile Gly Asn Leu Thr Asn Leu Glu Arg Leu Tyr Leu 395 400 405Asn Arg Asn Lys Ile Glu Lys Ile Pro Thr Gln Leu Phe Tyr Cys 410 415420 Arg Lys Leu Arg Tyr Leu Asp Leu Ser His Asn Asn Leu Thr Phe 425430 435 Leu Pro Ala Asp Ile Gly Leu Leu Gln Asn Leu Gln Asn Leu Ala440 445 450 Ile Thr Ala Asn Arg Ile Glu Thr Leu Pro Pro Glu Leu PheGln 455 460 465 Cys Arg Lys Leu Arg Ala Leu His Leu Gly Asn Asn ValLeu Gln 470 475 480 Ser Leu Pro Ser Arg Val Gly Glu Leu Thr Asn LeuThr Gln Ile 485 490 495 Glu Leu Arg Gly Asn Arg Leu Glu Cys Leu ProVal Glu Leu Gly 500 505 510 Glu Cys Pro Leu Leu Lys Arg Ser Gly LeuVal Val Glu Glu Asp 515 520 525 Leu Phe Asn Thr Leu Pro Pro Glu ValLys Glu Arg Leu Trp Arg 530 535 540 Ala Asp Lys Glu Gln Ala 545 25120 DNA Artificial Sequence Synthetic Oligonucleotide Probe 251caacaatgag ggcaccaagc 20 252 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 252 gatggctagg ttctggaggt tctg 24 253 47 DNAArtificial Sequence Synthetic Oligonucleotide Probe 253 caacctgcaggagattgacc tcaaggacaa caacctcaag accatcg 47 254 1650 DNA HomoSapien 254 gcctgttgct gatgctgccg tgcggtactt gtcatggagc tggcactgcg50 gcgctctccc gtcccgcggt ggttgctgct gctgccgctg ctgctgggcc 100tgaacgcagg agctgtcatt gactggccca cagaggaggg caaggaagta 150tgggattatg tgacggtccg caaggatgcc tacatgttct ggtggctcta 200ttatgccacc aactcctgca agaacttctc agaactgccc ctggtcatgt 250ggcttcaggg cggtccaggc ggttctagca ctggatttgg aaactttgag 300gaaattgggc cccttgacag tgatctcaaa ccacggaaaa ccacctggct 350ccaggctgcc agtctcctat ttgtggataa tcccgtgggc actgggttca 400gttatgtgaa tggtagtggt gcctatgcca aggacctggc tatggtggct 450tcagacatga tggttctcct gaagaccttc ttcagttgcc acaaagaatt 500ccagacagtt ccattctaca ttttctcaga gtcctatgga ggaaaaatgg 550cagctggcat tggtctagag ctttataagg ccattcagcg agggaccatc 600aagtgcaact ttgcgggggt tgccttgggt gattcctgga tctcccctgt 650tgattcggtg ctctcctggg gaccttacct gtacagcatg tctcttctcg 700aagacaaagg tctggcagag gtgtctaagg ttgcagagca agtactgaat 750gccgtaaata aggggctcta cagagaggcc acagagctgt gggggaaagc 800agaaatgatc attgaacaga acacagatgg ggtgaacttc tataacatct 850taactaaaag cactcccacg tctacaatgg agtcgagtct agaattcaca 900cagagccacc tagtttgtct ttgtcagcgc cacgtgagac acctacaacg 950agatgcctta agccagctca tgaatggccc catcagaaag aagctcaaaa 1000ttattcctga ggatcaatcc tggggaggcc aggctaccaa cgtctttgtg 1050aacatggagg aggacttcat gaagccagtc attagcattg tggacgagtt 1100gctggaggca gggatcaacg tgacggtgta taatggacag ctggatctca 1150tcgtagatac catgggtcag gaggcctggg tgcggaaact gaagtggcca 1200gaactgccta aattcagtca gctgaagtgg aaggccctgt acagtgaccc 1250taaatctttg gaaacatctg cttttgtcaa gtcctacaag aaccttgctt 1300tctactggat tctgaaagct ggtcatatgg ttccttctga

ccaaggggac 1350 atggctctga agatgatgag actggtgact cagcaagaataggatggatg 1400 gggctggaga tgagctggtt tggccttggg gcacagagctgagctgaggc 1450 cgctgaagct gtaggaagcg ccattcttcc ctgtatctaactggggctgt 1500 gatcaagaag gttctgacca gcttctgcag aggataaaatcattgtctct 1550 ggaggcaatt tggaaattat ttctgcttct taaaaaaacctaagattttt 1600 taaaaaattg atttgttttg atcaaaataa aggatgataatagatattaa 1650 255 452 PRT Homo Sapien 255 Met Glu Leu Ala Leu ArgArg Ser Pro Val Pro Arg Trp Leu Leu 1 5 10 15 Leu Leu Pro Leu LeuLeu Gly Leu Asn Ala Gly Ala Val Ile Asp 20 25 30 Trp Pro Thr GluGlu Gly Lys Glu Val Trp Asp Tyr Val Thr Val 35 40 45 Arg Lys AspAla Tyr Met Phe Trp Trp Leu Tyr Tyr Ala Thr Asn 50 55 60 Ser CysLys Asn Phe Ser Glu Leu Pro Leu Val Met Trp Leu Gln 65 70 75 GlyGly Pro Gly Gly Ser Ser Thr Gly Phe Gly Asn Phe Glu Glu 80 85 90Ile Gly Pro Leu Asp Ser Asp Leu Lys Pro Arg Lys Thr Thr Trp 95 100105 Leu Gln Ala Ala Ser Leu Leu Phe Val Asp Asn Pro Val Gly Thr 110115 120 Gly Phe Ser Tyr Val Asn Gly Ser Gly Ala Tyr Ala Lys Asp Leu125 130 135 Ala Met Val Ala Ser Asp Met Met Val Leu Leu Lys Thr PhePhe 140 145 150 Ser Cys His Lys Glu Phe Gln Thr Val Pro Phe Tyr IlePhe Ser 155 160 165 Glu Ser Tyr Gly Gly Lys Met Ala Ala Gly Ile GlyLeu Glu Leu 170 175 180 Tyr Lys Ala Ile Gln Arg Gly Thr Ile Lys CysAsn Phe Ala Gly 185 190 195 Val Ala Leu Gly Asp Ser Trp Ile Ser ProVal Asp Ser Val Leu 200 205 210 Ser Trp Gly Pro Tyr Leu Tyr Ser MetSer Leu Leu Glu Asp Lys 215 220 225 Gly Leu Ala Glu Val Ser Lys ValAla Glu Gln Val Leu Asn Ala 230 235 240 Val Asn Lys Gly Leu Tyr ArgGlu Ala Thr Glu Leu Trp Gly Lys 245 250 255 Ala Glu Met Ile Ile GluGln Asn Thr Asp Gly Val Asn Phe Tyr 260 265 270 Asn Ile Leu Thr LysSer Thr Pro Thr Ser Thr Met Glu Ser Ser 275 280 285 Leu Glu Phe ThrGln Ser His Leu Val Cys Leu Cys Gln Arg His 290 295 300 Val Arg HisLeu Gln Arg Asp Ala Leu Ser Gln Leu Met Asn Gly 305 310 315 Pro IleArg Lys Lys Leu Lys Ile Ile Pro Glu Asp Gln Ser Trp 320 325 330 GlyGly Gln Ala Thr Asn Val Phe Val Asn Met Glu Glu Asp Phe 335 340 345Met Lys Pro Val Ile Ser Ile Val Asp Glu Leu Leu Glu Ala Gly 350 355360 Ile Asn Val Thr Val Tyr Asn Gly Gln Leu Asp Leu Ile Val Asp 365370 375 Thr Met Gly Gln Glu Ala Trp Val Arg Lys Leu Lys Trp Pro Glu380 385 390 Leu Pro Lys Phe Ser Gln Leu Lys Trp Lys Ala Leu Tyr SerAsp 395 400 405 Pro Lys Ser Leu Glu Thr Ser Ala Phe Val Lys Ser TyrLys Asn 410 415 420 Leu Ala Phe Tyr Trp Ile Leu Lys Ala Gly His MetVal Pro Ser 425 430 435 Asp Gln Gly Asp Met Ala Leu Lys Met Met ArgLeu Val Thr Gln 440 445 450 Gln Glu 256 1100 DNA Homo Sapien 256ggccgcggga gaggaggcca tgggcgcgcg cggggcgctg ctgctggcgc 50tgctgctggc tcgggctgga ctcaggaagc cggagtcgca ggaggcggcg 100ccgttatcag gaccatgcgg ccgacgggtc atcacgtcgc gcatcgtggg 150tggagaggac gccgaactcg ggcgttggcc gtggcagggg agcctgcgcc 200tgtgggattc ccacgtatgc ggagtgagcc tgctcagcca ccgctgggca 250ctcacggcgg cgcactgctt tgaaacctat agtgacctta gtgatccctc 300cgggtggatg gtccagtttg gccagctgac ttccatgcca tccttctgga 350gcctgcaggc ctactacacc cgttacttcg tatcgaatat ctatctgagc 400cctcgctacc tggggaattc accctatgac attgccttgg tgaagctgtc 450tgcacctgtc acctacacta aacacatcca gcccatctgt ctccaggcct 500ccacatttga gtttgagaac cggacagact gctgggtgac tggctggggg 550tacatcaaag aggatgaggc actgccatct ccccacaccc tccaggaagt 600tcaggtcgcc atcataaaca actctatgtg caaccacctc ttcctcaagt 650acagtttccg caaggacatc tttggagaca tggtttgtgc tggcaacgcc 700caaggcggga aggatgcctg cttcggtgac tcaggtggac ccttggcctg 750taacaagaat ggactgtggt atcagattgg agtcgtgagc tggggagtgg 800gctgtggtcg gcccaatcgg cccggtgtct acaccaatat cagccaccac 850tttgagtgga tccagaagct gatggcccag agtggcatgt cccagccaga 900cccctcctgg ccactactct ttttccctct tctctgggct ctcccactcc 950tggggccggt ctgagcctac ctgagcccat gcagcctggg gccactgcca 1000agtcaggccc tggttctctt ctgtcttgtt tggtaataaa cacattccag 1050ttgatgcctt gcagggcatt cttcaaaaaa aaaaaaaaaa aaaaaaaaaa 1100 257 314PRT Homo Sapien 257 Met Gly Ala Arg Gly Ala Leu Leu Leu Ala Leu LeuLeu Ala Arg 1 5 10 15 Ala Gly Leu Arg Lys Pro Glu Ser Gln Glu AlaAla Pro Leu Ser 20 25 30 Gly Pro Cys Gly Arg Arg Val Ile Thr SerArg Ile Val Gly Gly 35 40 45 Glu Asp Ala Glu Leu Gly Arg Trp ProTrp Gln Gly Ser Leu Arg 50 55 60 Leu Trp Asp Ser His Val Cys GlyVal Ser Leu Leu Ser His Arg 65 70 75 Trp Ala Leu Thr Ala Ala HisCys Phe Glu Thr Tyr Ser Asp Leu 80 85 90 Ser Asp Pro Ser Gly TrpMet Val Gln Phe Gly Gln Leu Thr Ser 95 100 105 Met Pro Ser Phe TrpSer Leu Gln Ala Tyr Tyr Thr Arg Tyr Phe 110 115 120 Val Ser Asn IleTyr Leu Ser Pro Arg Tyr Leu Gly Asn Ser Pro 125 130 135 Tyr Asp IleAla Leu Val Lys Leu Ser Ala Pro Val Thr Tyr Thr 140 145 150 Lys HisIle Gln Pro Ile Cys Leu Gln Ala Ser Thr Phe Glu Phe 155 160 165 GluAsn Arg Thr Asp Cys Trp Val Thr Gly Trp Gly Tyr Ile Lys 170 175 180Glu Asp Glu Ala Leu Pro Ser Pro His Thr Leu Gln Glu Val Gln 185 190195 Val Ala Ile Ile Asn Asn Ser Met Cys Asn His Leu Phe Leu Lys 200205 210 Tyr Ser Phe Arg Lys Asp Ile Phe Gly Asp Met Val Cys Ala Gly215 220 225 Asn Ala Gln Gly Gly Lys Asp Ala Cys Phe Gly Asp Ser GlyGly 230 235 240 Pro Leu Ala Cys Asn Lys Asn Gly Leu Trp Tyr Gln IleGly Val 245 250 255 Val Ser Trp Gly Val Gly Cys Gly Arg Pro Asn ArgPro Gly Val 260 265 270 Tyr Thr Asn Ile Ser His His Phe Glu Trp IleGln Lys Leu Met 275 280 285 Ala Gln Ser Gly Met Ser Gln Pro Asp ProSer Trp Pro Leu Leu 290 295 300 Phe Phe Pro Leu Leu Trp Ala Leu ProLeu Leu Gly Pro Val 305 310 258 2427 DNA Homo Sapien 258 cccacgcgtccgcggacgcg tgggaagggc agaatgggac tccaagcctg 50 cctcctagggctctttgccc tcatcctctc tggcaaatgc agttacagcc 100 cggagcccgaccagcggagg acgctgcccc caggctgggt gtccctgggc 150 cgtgcggaccctgaggaaga gctgagtctc acctttgccc tgagacagca 200 gaatgtggaaagactctcgg agctggtgca ggctgtgtcg gatcccagct 250 ctcctcaatacggaaaatac ctgaccctag agaatgtggc tgatctggtg 300 aggccatccccactgaccct ccacacggtg caaaaatggc tcttggcagc 350 cggagcccagaagtgccatt ctgtgatcac acaggacttt ctgacttgct 400 ggctgagcatccgacaagca gagctgctgc tccctggggc tgagtttcat 450 cactatgtgggaggacctac ggaaacccat gttgtaaggt ccccacatcc 500 ctaccagcttccacaggcct tggcccccca tgtggacttt gtggggggac 550 tgcaccgttttcccccaaca tcatccctga ggcaacgtcc tgagccgcag 600 gtgacagggactgtaggcct gcatctgggg gtaaccccct ctgtgatccg 650 taagcgatacaacttgacct cacaagacgt gggctctggc accagcaata 700 acagccaagcctgtgcccag ttcctggagc agtatttcca tgactcagac 750 ctggctcagttcatgcgcct cttcggtggc aactttgcac atcaggcatc 800 agtagcccgtgtggttggac aacagggccg gggccgggcc gggattgagg 850 ccagtctagatgtgcagtac ctgatgagtg ctggtgccaa catctccacc 900 tgggtctacagtagccctgg ccggcatgag ggacaggagc ccttcctgca 950 gtggctcatgctgctcagta atgagtcagc cctgccacat gtgcatactg 1000 tgagctatggagatgatgag gactccctca gcagcgccta catccagcgg 1050 gtcaacactgagctcatgaa ggctgccgct cggggtctca ccctgctctt 1100 cgcctcaggtgacagtgggg ccgggtgttg gtctgtctct ggaagacacc 1150 agttccgccctaccttccct gcctccagcc cctatgtcac cacagtggga 1200 ggcacatccttccaggaacc tttcctcatc acaaatgaaa ttgttgacta 1250 tatcagtggtggtggcttca gcaatgtgtt cccacggcct tcataccagg 1300 aggaagctgtaacgaagttc ctgagctcta gcccccacct gccaccatcc 1350 agttacttcaatgccagtgg ccgtgcctac ccagatgtgg ctgcactttc 1400 tgatggctactgggtggtca gcaacagagt gcccattcca tgggtgtccg 1450 gaacctcggcctctactcca gtgtttgggg ggatcctatc cttgatcaat 1500 gagcacaggatccttagtgg ccgcccccct cttggctttc tcaacccaag 1550 gctctaccagcagcatgggg caggtctctt tgatgtaacc cgtggctgcc 1600 atgagtcctgtctggatgaa gaggtagagg gccagggttt ctgctctggt 1650 cctggctgggatcctgtaac aggctgggga acaccaactt cccagctttg 1700 ctgaagactctactcaaccc ctgacccttt cctatcagga gagatggctt 1750 gtcccctgccctgaagctgg cagttcagtc ccttattctg ccctgttgga 1800 agccctgctgaaccctcaac tattgactgc tgcagacagc ttatctccct 1850 aaccctgaaatgctgtgagc ttgacttgac tcccaaccct accatgctcc 1900 atcatactcaggtctcccta ctcctgcctt agattcctca ataagatgct 1950 gtaactagcattttttgaat gcctctccct ccgcatctca tctttctctt 2000 ttcaatcaggcttttccaaa gggttgtata cagactctgt gcactatttc 2050 acttgatattcattccccaa ttcactgcaa ggagacctct actgtcaccg 2100 tttactctttcctaccctga catccagaaa caatggcctc cagtgcatac 2150 ttctcaatctttgctttatg gcctttccat catagttgcc cactccctct 2200 ccttacttagcttccaggtc ttaacttctc tgactactct tgtcttcctc 2250 tctcatcaatttctgcttct tcatggaatg ctgaccttca ttgctccatt 2300 tgtagatttttgctcttctc agtttactca ttgtcccctg gaacaaatca 2350 ctgacatctacaaccattac catctcacta aataagactt tctatccaat 2400 aatgattgatacctcaaatg taaaaaa 2427 259 556 PRT Homo Sapien 259 Met Gly Leu GlnAla Cys Leu Leu Gly Leu Phe Ala Leu Ile Leu 1 5 10 15 Ser Gly LysCys Ser Tyr Ser Pro Glu Pro Asp Gln Arg Arg Thr 20 25 30 Leu ProPro Gly Trp Val Ser Leu Gly Arg Ala Asp Pro Glu Glu 35 40 45 GluLeu Ser Leu Thr Phe Ala Leu Arg Gln Gln Asn Val Glu Arg 50 55 60Leu Ser Glu Leu Val Gln Ala Val Ser Asp Pro Ser Ser Pro Gln 65 7075 Tyr Gly Lys Tyr Leu Thr Leu Glu Asn Val Ala Asp Leu Val Arg 8085 90 Pro Ser Pro Leu Thr Leu His Thr Val Gln Lys Trp Leu Leu Ala95 100 105 Ala Gly Ala Gln Lys Cys His Ser Val Ile Thr Gln Asp PheLeu 110 115 120 Thr Cys Trp Leu Ser Ile Arg Gln Ala Glu Leu Leu LeuPro Gly 125 130 135 Ala Glu Phe His His Tyr Val Gly Gly Pro Thr GluThr His Val 140 145 150 Val Arg Ser Pro His Pro Tyr Gln Leu Pro GlnAla Leu Ala Pro 155 160 165 His Val Asp Phe Val Gly Gly Leu His ArgPhe Pro Pro Thr Ser 170 175 180 Ser Leu Arg Gln Arg Pro Glu Pro GlnVal Thr Gly Thr Val Gly 185 190 195 Leu His Leu Gly Val Thr Pro SerVal Ile Arg Lys Arg Tyr Asn 200 205 210 Leu Thr Ser Gln Asp Val GlySer Gly Thr Ser Asn Asn Ser Gln 215 220 225 Ala Cys Ala Gln Phe LeuGlu Gln Tyr Phe His Asp Ser Asp Leu 230 235 240 Ala Gln Phe Met ArgLeu Phe Gly Gly Asn Phe Ala His Gln Ala 245 250 255 Ser Val Ala ArgVal Val Gly Gln Gln Gly Arg Gly Arg Ala Gly 260 265 270 Ile Glu AlaSer Leu Asp Val Gln Tyr Leu Met Ser Ala Gly Ala 275 280 285 Asn IleSer Thr Trp Val Tyr Ser Ser Pro Gly Arg His Glu Gly 290 295 300 GlnGlu Pro Phe Leu Gln Trp Leu Met Leu Leu Ser Asn Glu Ser 305 310 315Ala Leu Pro His Val His Thr Val Ser Tyr Gly Asp Asp Glu Asp 320 325330 Ser Leu Ser Ser Ala Tyr Ile Gln Arg Val Asn Thr Glu Leu Met 335340 345 Lys Ala Ala Ala Arg Gly Leu Thr Leu Leu Phe Ala Ser Gly Asp350 355 360 Ser Gly Ala Gly Cys Trp Ser Val Ser Gly Arg His Gln PheArg 365 370 375 Pro Thr Phe Pro Ala Ser Ser Pro Tyr Val Thr Thr ValGly Gly 380 385 390 Thr Ser Phe Gln Glu Pro Phe Leu Ile Thr Asn GluIle Val Asp 395 400 405 Tyr Ile Ser Gly Gly Gly Phe Ser Asn Val PhePro Arg Pro Ser 410 415 420 Tyr Gln Glu Glu Ala Val Thr Lys Phe LeuSer Ser Ser Pro His 425 430 435 Leu Pro Pro Ser Ser Tyr Phe Asn AlaSer Gly Arg Ala Tyr Pro 440 445 450 Asp Val Ala Ala Leu Ser Asp GlyTyr Trp Val Val Ser Asn Arg 455 460 465 Val Pro Ile Pro Trp Val SerGly Thr Ser Ala Ser Thr Pro Val 470 475 480 Phe Gly Gly Ile Leu SerLeu Ile Asn Glu His Arg Ile Leu Ser 485 490 495 Gly Arg Pro Pro LeuGly Phe Leu Asn Pro Arg Leu Tyr Gln Gln 500 505 510 His Gly Ala GlyLeu Phe Asp Val Thr Arg Gly Cys His Glu Ser 515 520 525 Cys Leu AspGlu Glu Val Glu Gly Gln Gly Phe Cys Ser Gly Pro 530 535 540 Gly TrpAsp Pro Val Thr Gly Trp Gly Thr Pro Thr Ser Gln Leu 545 550 555 Cys260 1638 DNA Homo Sapien 260 gccgcgcgct ctctcccggc gcccacacctgtctgagcgg cgcagcgagc 50 cgcggcccgg gcgggctgct cggcgcggaacagtgctcgg catggcaggg 100 attccagggc tcctcttcct tctcttctttctgctctgtg ctgttgggca 150 agtgagccct tacagtgccc cctggaaacccacttggcct gcataccgcc 200 tccctgtcgt cttgccccag tctaccctcaatttagccaa gccagacttt 250 ggagccgaag ccaaattaga agtatcttcttcatgtggac cccagtgtca 300 taagggaact ccactgccca cttacgaagaggccaagcaa tatctgtctt 350 atgaaacgct ctatgccaat ggcagccgcacagagacgca ggtgggcatc 400 tacatcctca gcagtagtgg agatggggcccaacaccgag actcagggtc 450 ttcaggaaag tctcgaagga agcggcagatttatggctat gacagcaggt 500 tcagcatttt tgggaaggac ttcctgctcaactacccttt ctcaacatca 550 gtgaagttat ccacgggctg caccggcaccctggtggcag agaagcatgt 600 cctcacagct gcccactgca tacacgatggaaaaacctat gtgaaaggaa 650 cccagaagct tcgagtgggc ttcctaaagcccaagtttaa agatggtggt 700 cgaggggcca acgactccac ttcagccatgcccgagcaga tgaaatttca 750 gtggatccgg gtgaaacgca cccatgtgcccaagggttgg atcaagggca 800 atgccaatga catcggcatg gattatgattatgccctcct ggaactcaaa 850 aagccccaca agagaaaatt tatgaagattggggtgagcc ctcctgctaa 900 gcagctgcca gggggcagaa ttcacttctctggttatgac aatgaccgac 950 caggcaattt ggtgtatcgc ttctgtgacgtcaaagacga gacctatgac 1000 ttgctctacc agcaatgcga tgcccagccaggggccagcg ggtctggggt 1050 ctatgtgagg atgtggaaga gacagcagcagaagtgggag cgaaaaatta 1100 ttggcatttt ttcagggcac cagtgggtggacatgaatgg ttccccacag 1150 gatttcaacg tggctgtcag aatcactcctctcaaatatg cccagatttg 1200 ctattggatt aaaggaaact acctggattgtagggagggg tgacacagtg 1250 ttccctcctg gcagcaatta agggtcttcatgttcttatt ttaggagagg 1300 ccaaattgtt ttttgtcatt ggcgtgcacacgtgtgtgtg tgtgtgtgtg 1350 tgtgtgtaag gtgtcttata atcttttacc

tatttcttac aattgcaaga 1400 tgactggctt tactatttga aaactggtttgtgtatcata tcatatatca 1450 tttaagcagt ttgaaggcat acttttgcatagaaataaaa aaaatactga 1500 tttggggcaa tgaggaatat ttgacaattaagttaatctt cacgtttttg 1550 caaactttga tttttatttc atctgaacttgtttcaaaga tttatattaa 1600 atatttggca tacaagagat atgaaaaaaaaaaaaaaa 1638 261 383 PRT Homo Sapien 261 Met Ala Gly Ile Pro GlyLeu Leu Phe Leu Leu Phe Phe Leu Leu 1 5 10 15 Cys Ala Val Gly GlnVal Ser Pro Tyr Ser Ala Pro Trp Lys Pro 20 25 30 Thr Trp Pro AlaTyr Arg Leu Pro Val Val Leu Pro Gln Ser Thr 35 40 45 Leu Asn LeuAla Lys Pro Asp Phe Gly Ala Glu Ala Lys Leu Glu 50 55 60 Val SerSer Ser Cys Gly Pro Gln Cys His Lys Gly Thr Pro Leu 65 70 75 ProThr Tyr Glu Glu Ala Lys Gln Tyr Leu Ser Tyr Glu Thr Leu 80 85 90Tyr Ala Asn Gly Ser Arg Thr Glu Thr Gln Val Gly Ile Tyr Ile 95 100105 Leu Ser Ser Ser Gly Asp Gly Ala Gln His Arg Asp Ser Gly Ser 110115 120 Ser Gly Lys Ser Arg Arg Lys Arg Gln Ile Tyr Gly Tyr Asp Ser125 130 135 Arg Phe Ser Ile Phe Gly Lys Asp Phe Leu Leu Asn Tyr ProPhe 140 145 150 Ser Thr Ser Val Lys Leu Ser Thr Gly Cys Thr Gly ThrLeu Val 155 160 165 Ala Glu Lys His Val Leu Thr Ala Ala His Cys IleHis Asp Gly 170 175 180 Lys Thr Tyr Val Lys Gly Thr Gln Lys Leu ArgVal Gly Phe Leu 185 190 195 Lys Pro Lys Phe Lys Asp Gly Gly Arg GlyAla Asn Asp Ser Thr 200 205 210 Ser Ala Met Pro Glu Gln Met Lys PheGln Trp Ile Arg Val Lys 215 220 225 Arg Thr His Val Pro Lys Gly TrpIle Lys Gly Asn Ala Asn Asp 230 235 240 Ile Gly Met Asp Tyr Asp TyrAla Leu Leu Glu Leu Lys Lys Pro 245 250 255 His Lys Arg Lys Phe MetLys Ile Gly Val Ser Pro Pro Ala Lys 260 265 270 Gln Leu Pro Gly GlyArg Ile His Phe Ser Gly Tyr Asp Asn Asp 275 280 285 Arg Pro Gly AsnLeu Val Tyr Arg Phe Cys Asp Val Lys Asp Glu 290 295 300 Thr Tyr AspLeu Leu Tyr Gln Gln Cys Asp Ala Gln Pro Gly Ala 305 310 315 Ser GlySer Gly Val Tyr Val Arg Met Trp Lys Arg Gln Gln Gln 320 325 330 LysTrp Glu Arg Lys Ile Ile Gly Ile Phe Ser Gly His Gln Trp 335 340 345Val Asp Met Asn Gly Ser Pro Gln Asp Phe Asn Val Ala Val Arg 350 355360 Ile Thr Pro Leu Lys Tyr Ala Gln Ile Cys Tyr Trp Ile Lys Gly 365370 375 Asn Tyr Leu Asp Cys Arg Glu Gly 380 262 1378 DNA HomoSapien 262 gcatcgccct gggtctctcg agcctgctgc ctgctccccc gccccaccag50 ccatggtggt ttctggagcg cccccagccc tgggtggggg ctgtctcggc 100accttcacct ccctgctgct gctggcgtcg acagccatcc tcaatgcggc 150caggatacct gttcccccag cctgtgggaa gccccagcag ctgaaccggg 200ttgtgggcgg cgaggacagc actgacagcg agtggccctg gatcgtgagc 250atccagaaga atgggaccca ccactgcgca ggttctctgc tcaccagccg 300ctgggtgatc actgctgccc actgtttcaa ggacaacctg aacaaaccat 350acctgttctc tgtgctgctg ggggcctggc agctggggaa ccctggctct 400cggtcccaga aggtgggtgt tgcctgggtg gagccccacc ctgtgtattc 450ctggaaggaa ggtgcctgtg cagacattgc cctggtgcgt ctcgagcgct 500ccatacagtt ctcagagcgg gtcctgccca tctgcctacc tgatgcctct 550atccacctcc ctccaaacac ccactgctgg atctcaggct gggggagcat 600ccaagatgga gttcccttgc cccaccctca gaccctgcag aagctgaagg 650ttcctatcat cgactcggaa gtctgcagcc atctgtactg gcggggagca 700ggacagggac ccatcactga ggacatgctg tgtgccggct acttggaggg 750ggagcgggat gcttgtctgg gcgactccgg gggccccctc atgtgccagg 800tggacggcgc ctggctgctg gccggcatca tcagctgggg cgagggctgt 850gccgagcgca acaggcccgg ggtctacatc agcctctctg cgcaccgctc 900ctgggtggag aagatcgtgc aaggggtgca gctccgcggg cgcgctcagg 950ggggtggggc cctcagggca ccgagccagg gctctggggc cgccgcgcgc 1000tcctagggcg cagcgggacg cggggctcgg atctgaaagg cggccagatc 1050cacatctgga tctggatctg cggcggcctc gggcggtttc ccccgccgta 1100aataggctca tctacctcta cctctggggg cccggacggc tgctgcggaa 1150aggaaacccc ctccccgacc cgcccgacgg cctcaggccc ccctccaagg 1200catcaggccc cgcccaacgg cctcatgtcc ccgcccccac gacttccggc 1250cccgcccccg ggccccagcg cttttgtgta tataaatgtt aatgattttt 1300ataggtattt gtaaccctgc ccacatatct tatttattcc tccaatttca 1350ataaattatt tattctccaa aaaaaaaa 1378 263 317 PRT Homo Sapien 263 MetVal Val Ser Gly Ala Pro Pro Ala Leu Gly Gly Gly Cys Leu 1 5 10 15Gly Thr Phe Thr Ser Leu Leu Leu Leu Ala Ser Thr Ala Ile Leu 20 2530 Asn Ala Ala Arg Ile Pro Val Pro Pro Ala Cys Gly Lys Pro Gln 3540 45 Gln Leu Asn Arg Val Val Gly Gly Glu Asp Ser Thr Asp Ser Glu50 55 60 Trp Pro Trp Ile Val Ser Ile Gln Lys Asn Gly Thr His HisCys 65 70 75 Ala Gly Ser Leu Leu Thr Ser Arg Trp Val Ile Thr AlaAla His 80 85 90 Cys Phe Lys Asp Asn Leu Asn Lys Pro Tyr Leu PheSer Val Leu 95 100 105 Leu Gly Ala Trp Gln Leu Gly Asn Pro Gly SerArg Ser Gln Lys 110 115 120 Val Gly Val Ala Trp Val Glu Pro His ProVal Tyr Ser Trp Lys 125 130 135 Glu Gly Ala Cys Ala Asp Ile Ala LeuVal Arg Leu Glu Arg Ser 140 145 150 Ile Gln Phe Ser Glu Arg Val LeuPro Ile Cys Leu Pro Asp Ala 155 160 165 Ser Ile His Leu Pro Pro AsnThr His Cys Trp Ile Ser Gly Trp 170 175 180 Gly Ser Ile Gln Asp GlyVal Pro Leu Pro His Pro Gln Thr Leu 185 190 195 Gln Lys Leu Lys ValPro Ile Ile Asp Ser Glu Val Cys Ser His 200 205 210 Leu Tyr Trp ArgGly Ala Gly Gln Gly Pro Ile Thr Glu Asp Met 215 220 225 Leu Cys AlaGly Tyr Leu Glu Gly Glu Arg Asp Ala Cys Leu Gly 230 235 240 Asp SerGly Gly Pro Leu Met Cys Gln Val Asp Gly Ala Trp Leu 245 250 255 LeuAla Gly Ile Ile Ser Trp Gly Glu Gly Cys Ala Glu Arg Asn 260 265 270Arg Pro Gly Val Tyr Ile Ser Leu Ser Ala His Arg Ser Trp Val 275 280285 Glu Lys Ile Val Gln Gly Val Gln Leu Arg Gly Arg Ala Gln Gly 290295 300 Gly Gly Ala Leu Arg Ala Pro Ser Gln Gly Ser Gly Ala Ala Ala305 310 315 Arg Ser 264 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 264 gtccgcaagg atgcctacat gttc 24 265 19 DNAArtificial Sequence Synthetic Oligonucleotide Probe 265 gcagaggtgtctaaggttg 19 266 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 266 agctctagac caatgccagc ttcc 24 267 45 DNAArtificial Sequence Synthetic Oligonucleotide Probe 267 gccaccaactcctgcaagaa cttctcagaa ctgcccctgg tcatg 45 268 25 DNA ArtificialSequence Synthetic Oligonucleotide Probe 268 ggggaattca ccctatgacattgcc 25 269 24 DNA Artificial Sequence Synthetic OligonucleotideProbe 269 gaatgccctg caagcatcaa ctgg 24 270 50 DNA ArtificialSequence Synthetic Oligonucleotide Probe 270 gcacctgtca cctacactaaacacatccag cccatctgtc tccaggcctc 50 271 26 DNA Artificial SequenceSynthetic Oligonucleotide Probe 271 gcggaagggc agaatgggac tccaag 26272 18 DNA Artificial Sequence Synthetic Oligonucleotide Probe 272cagccctgcc acatgtgc 18 273 18 DNA Artificial Sequence SyntheticOligonucleotide Probe 273 tactgggtgg tcagcaac 18 274 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 274 ggcgaagagcagggtgagac cccg 24 275 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 275 gccctcatcc tctctggcaa atgcagttacagcccggagc ccgac 45 276 21 DNA Artificial Sequence SyntheticOligonucleotide Probe 276 gggcagggat tccagggctc c 21 277 18 DNAArtificial Sequence Synthetic Oligonucleotide Probe 277 ggctatgacagcaggttc 18 278 18 DNA Artificial Sequence SyntheticOligonucleotide Probe 278 tgacaatgac cgaccagg 18 279 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 279 gcatcgcattgctggtagag caag 24 280 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 280 ttacagtgcc ccctggaaac ccacttggcctgcataccgc ctccc 45 281 34 DNA Artificial Sequence SyntheticOligonucleotide Probe 281 cgtctcgagc gctccataca gttcccttgc ccca 34282 61 DNA Artificial Sequence Synthetic Oligonucleotide Probe 282tggaggggga gcgggatgct tgtctgggcg actccggggg ccccctcatg 50tgccaggtgg a 61 283 119 DNA Artificial Sequence SyntheticOligonucleotide Probe 283 ccctcagacc ctgcagaagc tgaaggttcctatcatcgac tcggaagtct 50 gcagccatct gtactggcgg ggagcaggacagggacccat cactgaggac 100 atgctgtgtg ccggctact 119 284 1875 DNAHomo Sapien 284 gacggctggc caccatgcac ggctcctgca gtttcctgatgcttctgctg 50 ccgctactgc tactgctggt ggccaccaca ggccccgttggagccctcac 100 agatgaggag aaacgtttga tggtggagct gcacaacctctaccgggccc 150 aggtatcccc gacggcctca gacatgctgc acatgagatgggacgaggag 200 ctggccgcct tcgccaaggc ctacgcacgg cagtgcgtgtggggccacaa 250 caaggagcgc gggcgccgcg gcgagaatct gttcgccatcacagacgagg 300 gcatggacgt gccgctggcc atggaggagt ggcaccacgagcgtgagcac 350 tacaacctca gcgccgccac ctgcagccca ggccagatgtgcggccacta 400 cacgcaggtg gtatgggcca agacagagag gatcggctgtggttcccact 450 tctgtgagaa gctccagggt gttgaggaga ccaacatcgaattactggtg 500 tgcaactatg agcctccggg gaacgtgaag gggaaacggccctaccagga 550 ggggactccg tgctcccaat gtccctctgg ctaccactgcaagaactccc 600 tctgtgaacc catcggaagc ccggaagatg ctcaggatttgccttacctg 650 gtaactgagg ccccatcctt ccgggcgact gaagcatcagactctaggaa 700 aatgggtact ccttcttccc tagcaacggg gattccggctttcttggtaa 750 cagaggtctc aggctccctg gcaaccaagg ctctgcctgctgtggaaacc 800 caggccccaa cttccttagc aacgaaagac ccgccctccatggcaacaga 850 ggctccacct tgcgtaacaa ctgaggtccc ttccattttggcagctcaca 900 gcctgccctc cttggatgag gagccagtta ccttccccaaatcgacccat 950 gttcctatcc caaaatcagc agacaaagtg acagacaaaacaaaagtgcc 1000 ctctaggagc ccagagaact ctctggaccc caagatgtccctgacagggg 1050 caagggaact cctaccccat gcccaggagg aggctgaggctgaggctgag 1100 ttgcctcctt ccagtgaggt cttggcctca gtttttccagcccaggacaa 1150 gccaggtgag ctgcaggcca cactggacca cacggggcacacctcctcca 1200 agtccctgcc caatttcccc aatacctctg ccaccgctaatgccacgggt 1250 gggcgtgccc tggctctgca gtcgtccttg ccaggtgcagagggccctga 1300 caagcctagc gttgtgtcag ggctgaactc gggccctggtcatgtgtggg 1350 gccctctcct gggactactg ctcctgcctc ctctggtgttggctggaatc 1400 ttctgaatgg gataccactc aaagggtgaa gaggtcagctgtcctcctgt 1450 catcttcccc accctgtccc cagcccctaa acaagatacttcttggttaa 1500 ggccctccgg aagggaaagg ctacggggca tgtgcctcatcacaccatcc 1550 atcctggagg cacaaggcct ggctggctgc gagctcaggaggccgcctga 1600 ggactgcaca ccgggcccac acctctcctg cccctccctcctgagtcctg 1650 ggggtgggag gatttgaggg agctcactgc ctacctggcctggggctgtc 1700 tgcccacaca gcatgtgcgc tctccctgag tgcctgtgtagctggggatg 1750 gggattccta ggggcagatg aaggacaagc cccactggagtggggttctt 1800 tgagtggggg aggcagggac gagggaagga aagtaactcctgactctcca 1850 ataaaaacct gtccaacctg tgaaa 1875 285 463 PRT HomoSapien 285 Met His Gly Ser Cys Ser Phe Leu Met Leu Leu Leu Pro LeuLeu 1 5 10 15 Leu Leu Leu Val Ala Thr Thr Gly Pro Val Gly Ala LeuThr Asp 20 25 30 Glu Glu Lys Arg Leu Met Val Glu Leu His Asn LeuTyr Arg Ala 35 40 45 Gln Val Ser Pro Thr Ala Ser Asp Met Leu HisMet Arg Trp Asp 50 55 60 Glu Glu Leu Ala Ala Phe Ala Lys Ala TyrAla Arg Gln Cys Val 65 70 75 Trp Gly His Asn Lys Glu Arg Gly ArgArg Gly Glu Asn Leu Phe 80 85 90 Ala Ile Thr Asp Glu Gly Met AspVal Pro Leu Ala Met Glu Glu 95 100 105 Trp His His Glu Arg Glu HisTyr Asn Leu Ser Ala Ala Thr Cys 110 115 120 Ser Pro Gly Gln Met CysGly His Tyr Thr Gln Val Val Trp Ala 125 130 135 Lys Thr Glu Arg IleGly Cys Gly Ser His Phe Cys Glu Lys Leu 140 145 150 Gln Gly Val GluGlu Thr Asn Ile Glu Leu Leu Val Cys Asn Tyr 155 160 165 Glu Pro ProGly Asn Val Lys Gly Lys Arg Pro Tyr Gln Glu Gly 170 175 180 Thr ProCys Ser Gln Cys Pro Ser Gly Tyr His Cys Lys Asn Ser 185 190 195 LeuCys Glu Pro Ile Gly Ser Pro Glu Asp Ala Gln Asp Leu Pro 200 205 210Tyr Leu Val Thr Glu Ala Pro Ser Phe Arg Ala Thr Glu Ala Ser 215 220225 Asp Ser Arg Lys Met Gly Thr Pro Ser Ser Leu Ala Thr Gly Ile 230235 240 Pro Ala Phe Leu Val Thr Glu Val Ser Gly Ser Leu Ala Thr Lys245 250 255 Ala Leu Pro Ala Val Glu Thr Gln Ala Pro Thr Ser Leu AlaThr 260 265 270 Lys Asp Pro Pro Ser Met Ala Thr Glu Ala Pro Pro CysVal Thr 275 280 285 Thr Glu Val Pro Ser Ile Leu Ala Ala His Ser LeuPro Ser Leu 290 295 300 Asp Glu Glu Pro Val Thr Phe Pro Lys Ser ThrHis Val Pro Ile 305 310 315 Pro Lys Ser Ala Asp Lys Val Thr Asp LysThr Lys Val Pro Ser 320 325 330 Arg Ser Pro Glu Asn Ser Leu Asp ProLys Met Ser Leu Thr Gly 335 340 345 Ala Arg Glu Leu Leu Pro His AlaGln Glu Glu Ala Glu Ala Glu 350 355 360 Ala Glu Leu Pro Pro Ser SerGlu Val Leu Ala Ser Val Phe Pro 365 370 375 Ala Gln Asp Lys Pro GlyGlu Leu Gln Ala Thr Leu Asp His Thr 380 385 390 Gly His Thr Ser SerLys Ser Leu Pro Asn Phe Pro Asn Thr Ser 395 400 405 Ala Thr Ala AsnAla Thr Gly Gly Arg Ala Leu Ala Leu Gln Ser 410 415 420 Ser Leu ProGly Ala Glu Gly Pro Asp Lys Pro Ser Val Val Ser 425 430 435 Gly LeuAsn Ser Gly Pro Gly His Val Trp Gly Pro Leu Leu Gly 440 445 450 LeuLeu Leu Leu Pro Pro Leu Val Leu Ala Gly Ile Phe 455 460 286 19 DNAArtificial Sequence Synthetic Oligonucleotide Probe 286 tcctgcagtttcctgatgc 19 287 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 287 ctcatattgc acaccagtaa ttcg 24 288 45 DNAArtificial Sequence Synthetic Oligonucleotide Probe 288 atgaggagaaacgtttgatg gtggagctgc acaacctcta ccggg 45 289 3662 DNA Homo Sapien289 gtaactgaag tcaggctttt catttgggaa gccccctcaa cagaattcgg 50tcattctcca agttatggtg gacgtacttc tgttgttctc cctctgcttg 100ctttttcaca

ttagcagacc ggacttaagt cacaacagat tatctttcat 150 caaggcaagttccatgagcc accttcaaag ccttcgagaa gtgaaactga 200 acaacaatgaattggagacc attccaaatc tgggaccagt ctcggcaaat 250 attacacttctctccttggc tggaaacagg attgttgaaa tactccctga 300 acatctgaaagagtttcagt cccttgaaac tttggacctt agcagcaaca 350 atatttcagagctccaaact gcatttccag ccctacagct caaatatctg 400 tatctcaacagcaaccgagt cacatcaatg gaacctgggt attttgacaa 450 tttggccaacacactccttg tgttaaagct gaacaggaac cgaatctcag 500 ctatcccacccaagatgttt aaactgcccc aactgcaaca tctcgaattg 550 aaccgaaacaagattaaaaa tgtagatgga ctgacattcc aaggccttgg 600 tgctctgaagtctctgaaaa tgcaaagaaa tggagtaacg aaacttatgg 650 atggagctttttgggggctg agcaacatgg aaattttgca gctggaccat 700 aacaacctaacagagattac caaaggctgg ctttacggct tgctgatgct 750 gcaggaacttcatctcagcc aaaatgccat caacaggatc agccctgatg 800 cctgggagttctgccagaag ctcagtgagc tggacctaac tttcaatcac 850 ttatcaaggttagatgattc aagcttcctt ggcctaagct tactaaatac 900 actgcacattgggaacaaca gagtcagcta cattgctgat tgtgccttcc 950 gggggctttccagtttaaag actttggatc tgaagaacaa tgaaatttcc 1000 tggactattgaagacatgaa tggtgctttc tctgggcttg acaaactgag 1050 gcgactgatactccaaggaa atcggatccg ttctattact aaaaaagcct 1100 tcactggtttggatgcattg gagcatctag acctgagtga caacgcaatc 1150 atgtctttacaaggcaatgc attttcacaa atgaagaaac tgcaacaatt 1200 gcatttaaatacatcaagcc ttttgtgcga ttgccagcta aaatggctcc 1250 cacagtgggtggcggaaaac aactttcaga gctttgtaaa tgccagttgt 1300 gcccatcctcagctgctaaa aggaagaagc atttttgctg ttagcccaga 1350 tggctttgtgtgtgatgatt ttcccaaacc ccagatcacg gttcagccag 1400 aaacacagtcggcaataaaa ggttccaatt tgagtttcat ctgctcagct 1450 gccagcagcagtgattcccc aatgactttt gcttggaaaa aagacaatga 1500 actactgcatgatgctgaaa tggaaaatta tgcacacctc cgggcccaag 1550 gtggcgaggtgatggagtat accaccatcc ttcggctgcg cgaggtggaa 1600 tttgccagtgaggggaaata tcagtgtgtc atctccaatc actttggttc 1650 atcctactctgtcaaagcca agcttacagt aaatatgctt ccctcattca 1700 ccaagacccccatggatctc accatccgag ctggggccat ggcacgcttg 1750 gagtgtgctgctgtggggca cccagccccc cagatagcct ggcagaagga 1800 tgggggcacagacttcccag ctgcacggga gagacgcatg catgtgatgc 1850 ccgaggatgacgtgttcttt atcgtggatg tgaagataga ggacattggg 1900 gtatacagctgcacagctca gaacagtgca ggaagtattt cagcaaatgc 1950 aactctgactgtcctagaaa caccatcatt tttgcggcca ctgttggacc 2000 gaactgtaaccaagggagaa acagccgtcc tacagtgcat tgctggagga 2050 agccctccccctaaactgaa ctggaccaaa gatgatagcc cattggtggt 2100 aaccgagaggcacttttttg cagcaggcaa tcagcttctg attattgtgg 2150 actcagatgtcagtgatgct gggaaataca catgtgagat gtctaacacc 2200 cttggcactgagagaggaaa cgtgcgcctc agtgtgatcc ccactccaac 2250 ctgcgactcccctcagatga cagccccatc gttagacgat gacggatggg 2300 ccactgtgggtgtcgtgatc atagccgtgg tttgctgtgt ggtgggcacg 2350 tcactcgtgtgggtggtcat catataccac acaaggcgga ggaatgaaga 2400 ttgcagcattaccaacacag atgagaccaa cttgccagca gatattccta 2450 gttatttgtcatctcaggga acgttagctg acaggcagga tgggtacgtg 2500 tcttcagaaagtggaagcca ccaccagttt gtcacatctt caggtgctgg 2550 atttttcttaccacaacatg acagtagtgg gacctgccat attgacaata 2600 gcagtgaagctgatgtggaa gctgccacag atctgttcct ttgtccgttt 2650 ttgggatccacaggccctat gtatttgaag ggaaatgtgt atggctcaga 2700 tccttttgaaacatatcata caggttgcag tcctgaccca agaacagttt 2750 taatggaccactatgagccc agttacataa agaaaaagga gtgctaccca 2800 tgttctcatccttcagaaga atcctgcgaa cggagcttca gtaatatatc 2850 gtggccttcacatgtgagga agctacttaa cactagttac tctcacaatg 2900 aaggacctggaatgaaaaat ctgtgtctaa acaagtcctc tttagatttt 2950 agtgcaaatccagagccagc gtcggttgcc tcgagtaatt ctttcatggg 3000 tacctttggaaaagctctca ggagacctca cctagatgcc tattcaagct 3050 ttggacagccatcagattgt cagccaagag ccttttattt gaaagctcat 3100 tcttccccagacttggactc tgggtcagag gaagatggga aagaaaggac 3150 agattttcaggaagaaaatc acatttgtac ctttaaacag actttagaaa 3200 actacaggactccaaatttt cagtcttatg acttggacac atagactgaa 3250 tgagaccaaaggaaaagctt aacatactac ctcaagtgaa cttttattta 3300 aaagagagagaatcttatgt tttttaaatg gagttatgaa ttttaaaagg 3350 ataaaaatgctttatttata cagatgaacc aaaattacaa aaagttatga 3400 aaatttttatactgggaatg atgctcatat aagaatacct ttttaaacta 3450 ttttttaactttgttttatg caaaaaagta tcttacgtaa attaatgata 3500 taaatcatgattattttatg tatttttata atgccagatt tctttttatg 3550 gaaaatgagttactaaagca ttttaaataa tacctgcctt gtaccatttt 3600 ttaaatagaagttacttcat tatattttgc acattatatt taataaaatg 3650 tgtcaatttg aa 3662290 1059 PRT Homo Sapien 290 Met Val Asp Val Leu Leu Leu Phe SerLeu Cys Leu Leu Phe His 1 5 10 15 Ile Ser Arg Pro Asp Leu Ser HisAsn Arg Leu Ser Phe Ile Lys 20 25 30 Ala Ser Ser Met Ser His LeuGln Ser Leu Arg Glu Val Lys Leu 35 40 45 Asn Asn Asn Glu Leu GluThr Ile Pro Asn Leu Gly Pro Val Ser 50 55 60 Ala Asn Ile Thr LeuLeu Ser Leu Ala Gly Asn Arg Ile Val Glu 65 70 75 Ile Leu Pro GluHis Leu Lys Glu Phe Gln Ser Leu Glu Thr Leu 80 85 90 Asp Leu SerSer Asn Asn Ile Ser Glu Leu Gln Thr Ala Phe Pro 95 100 105 Ala LeuGln Leu Lys Tyr Leu Tyr Leu Asn Ser Asn Arg Val Thr 110 115 120 SerMet Glu Pro Gly Tyr Phe Asp Asn Leu Ala Asn Thr Leu Leu 125 130 135Val Leu Lys Leu Asn Arg Asn Arg Ile Ser Ala Ile Pro Pro Lys 140 145150 Met Phe Lys Leu Pro Gln Leu Gln His Leu Glu Leu Asn Arg Asn 155160 165 Lys Ile Lys Asn Val Asp Gly Leu Thr Phe Gln Gly Leu Gly Ala170 175 180 Leu Lys Ser Leu Lys Met Gln Arg Asn Gly Val Thr Lys LeuMet 185 190 195 Asp Gly Ala Phe Trp Gly Leu Ser Asn Met Glu Ile LeuGln Leu 200 205 210 Asp His Asn Asn Leu Thr Glu Ile Thr Lys Gly TrpLeu Tyr Gly 215 220 225 Leu Leu Met Leu Gln Glu Leu His Leu Ser GlnAsn Ala Ile Asn 230 235 240 Arg Ile Ser Pro Asp Ala Trp Glu Phe CysGln Lys Leu Ser Glu 245 250 255 Leu Asp Leu Thr Phe Asn His Leu SerArg Leu Asp Asp Ser Ser 260 265 270 Phe Leu Gly Leu Ser Leu Leu AsnThr Leu His Ile Gly Asn Asn 275 280 285 Arg Val Ser Tyr Ile Ala AspCys Ala Phe Arg Gly Leu Ser Ser 290 295 300 Leu Lys Thr Leu Asp LeuLys Asn Asn Glu Ile Ser Trp Thr Ile 305 310 315 Glu Asp Met Asn GlyAla Phe Ser Gly Leu Asp Lys Leu Arg Arg 320 325 330 Leu Ile Leu GlnGly Asn Arg Ile Arg Ser Ile Thr Lys Lys Ala 335 340 345 Phe Thr GlyLeu Asp Ala Leu Glu His Leu Asp Leu Ser Asp Asn 350 355 360 Ala IleMet Ser Leu Gln Gly Asn Ala Phe Ser Gln Met Lys Lys 365 370 375 LeuGln Gln Leu His Leu Asn Thr Ser Ser Leu Leu Cys Asp Cys 380 385 390Gln Leu Lys Trp Leu Pro Gln Trp Val Ala Glu Asn Asn Phe Gln 395 400405 Ser Phe Val Asn Ala Ser Cys Ala His Pro Gln Leu Leu Lys Gly 410415 420 Arg Ser Ile Phe Ala Val Ser Pro Asp Gly Phe Val Cys Asp Asp425 430 435 Phe Pro Lys Pro Gln Ile Thr Val Gln Pro Glu Thr Gln SerAla 440 445 450 Ile Lys Gly Ser Asn Leu Ser Phe Ile Cys Ser Ala AlaSer Ser 455 460 465 Ser Asp Ser Pro Met Thr Phe Ala Trp Lys Lys AspAsn Glu Leu 470 475 480 Leu His Asp Ala Glu Met Glu Asn Tyr Ala HisLeu Arg Ala Gln 485 490 495 Gly Gly Glu Val Met Glu Tyr Thr Thr IleLeu Arg Leu Arg Glu 500 505 510 Val Glu Phe Ala Ser Glu Gly Lys TyrGln Cys Val Ile Ser Asn 515 520 525 His Phe Gly Ser Ser Tyr Ser ValLys Ala Lys Leu Thr Val Asn 530 535 540 Met Leu Pro Ser Phe Thr LysThr Pro Met Asp Leu Thr Ile Arg 545 550 555 Ala Gly Ala Met Ala ArgLeu Glu Cys Ala Ala Val Gly His Pro 560 565 570 Ala Pro Gln Ile AlaTrp Gln Lys Asp Gly Gly Thr Asp Phe Pro 575 580 585 Ala Ala Arg GluArg Arg Met His Val Met Pro Glu Asp Asp Val 590 595 600 Phe Phe IleVal Asp Val Lys Ile Glu Asp Ile Gly Val Tyr Ser 605 610 615 Cys ThrAla Gln Asn Ser Ala Gly Ser Ile Ser Ala Asn Ala Thr 620 625 630 LeuThr Val Leu Glu Thr Pro Ser Phe Leu Arg Pro Leu Leu Asp 635 640 645Arg Thr Val Thr Lys Gly Glu Thr Ala Val Leu Gln Cys Ile Ala 650 655660 Gly Gly Ser Pro Pro Pro Lys Leu Asn Trp Thr Lys Asp Asp Ser 665670 675 Pro Leu Val Val Thr Glu Arg His Phe Phe Ala Ala Gly Asn Gln680 685 690 Leu Leu Ile Ile Val Asp Ser Asp Val Ser Asp Ala Gly LysTyr 695 700 705 Thr Cys Glu Met Ser Asn Thr Leu Gly Thr Glu Arg GlyAsn Val 710 715 720 Arg Leu Ser Val Ile Pro Thr Pro Thr Cys Asp SerPro Gln Met 725 730 735 Thr Ala Pro Ser Leu Asp Asp Asp Gly Trp AlaThr Val Gly Val 740 745 750 Val Ile Ile Ala Val Val Cys Cys Val ValGly Thr Ser Leu Val 755 760 765 Trp Val Val Ile Ile Tyr His Thr ArgArg Arg Asn Glu Asp Cys 770 775 780 Ser Ile Thr Asn Thr Asp Glu ThrAsn Leu Pro Ala Asp Ile Pro 785 790 795 Ser Tyr Leu Ser Ser Gln GlyThr Leu Ala Asp Arg Gln Asp Gly 800 805 810 Tyr Val Ser Ser Glu SerGly Ser His His Gln Phe Val Thr Ser 815 820 825 Ser Gly Ala Gly PhePhe Leu Pro Gln His Asp Ser Ser Gly Thr 830 835 840 Cys His Ile AspAsn Ser Ser Glu Ala Asp Val Glu Ala Ala Thr 845 850 855 Asp Leu PheLeu Cys Pro Phe Leu Gly Ser Thr Gly Pro Met Tyr 860 865 870 Leu LysGly Asn Val Tyr Gly Ser Asp Pro Phe Glu Thr Tyr His 875 880 885 ThrGly Cys Ser Pro Asp Pro Arg Thr Val Leu Met Asp His Tyr 890 895 900Glu Pro Ser Tyr Ile Lys Lys Lys Glu Cys Tyr Pro Cys Ser His 905 910915 Pro Ser Glu Glu Ser Cys Glu Arg Ser Phe Ser Asn Ile Ser Trp 920925 930 Pro Ser His Val Arg Lys Leu Leu Asn Thr Ser Tyr Ser His Asn935 940 945 Glu Gly Pro Gly Met Lys Asn Leu Cys Leu Asn Lys Ser SerLeu 950 955 960 Asp Phe Ser Ala Asn Pro Glu Pro Ala Ser Val Ala SerSer Asn 965 970 975 Ser Phe Met Gly Thr Phe Gly Lys Ala Leu Arg ArgPro His Leu 980 985 990 Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser AspCys Gln Pro Arg 995 1000 1005 Ala Phe Tyr Leu Lys Ala His Ser SerPro Asp Leu Asp Ser Gly 1010 1015 1020 Ser Glu Glu Asp Gly Lys GluArg Thr Asp Phe Gln Glu Glu Asn 1025 1030 1035 His Ile Cys Thr PheLys Gln Thr Leu Glu Asn Tyr Arg Thr Pro 1040 1045 1050 Asn Phe GlnSer Tyr Asp Leu Asp Thr 1055 291 2906 DNA Homo Sapien 291ggggagagga attgaccatg taaaaggaga cttttttttt tggtggtggt 50ggctgttggg tgccttgcaa aaatgaagga tgcaggacgc agctttctcc 100tggaaccgaa cgcaatggat aaactgattg tgcaagagag aaggaagaac 150gaagcttttt cttgtgagcc ctggatctta acacaaatgt gtatatgtgc 200acacagggag cattcaagaa tgaaataaac cagagttaga cccgcggggg 250ttggtgtgtt ctgacataaa taaataatct taaagcagct gttcccctcc 300ccacccccaa aaaaaaggat gattggaaat gaagaaccga ggattcacaa 350agaaaaaagt atgttcattt ttctctataa aggagaaagt gagccaagga 400gatatttttg gaatgaaaag tttggggctt ttttagtaaa gtaaagaact 450ggtgtggtgg tgttttcctt tctttttgaa tttcccacaa gaggagagga 500aattaataat acatctgcaa agaaatttca gagaagaaaa gttgaccgcg 550gcagattgag gcattgattg ggggagagaa accagcagag cacagttgga 600tttgtgccta tgttgactaa aattgacgga taattgcagt tggatttttc 650ttcatcaacc tccttttttt taaattttta ttccttttgg tatcaagatc 700atgcgttttc tcttgttctt aaccacctgg atttccatct ggatgttgct 750gtgatcagtc tgaaatacaa ctgtttgaat tccagaagga ccaacaccag 800ataaattatg aatgttgaac aagatgacct tacatccaca gcagataatg 850ataggtccta ggtttaacag ggccctattt gaccccctgc ttgtggtgct 900gctggctctt caacttcttg tggtggctgg tctggtgcgg gctcagacct 950gcccttctgt gtgctcctgc agcaaccagt tcagcaaggt gatttgtgtt 1000cggaaaaacc tgcgtgaggt tccggatggc atctccacca acacacggct 1050gctgaacctc catgagaacc aaatccagat catcaaagtg aacagcttca 1100agcacttgag gcacttggaa atcctacagt tgagtaggaa ccatatcaga 1150accattgaaa ttggggcttt caatggtctg gcgaacctca acactctgga 1200actctttgac aatcgtctta ctaccatccc gaatggagct tttgtatact 1250tgtctaaact gaaggagctc tggttgcgaa acaaccccat tgaaagcatc 1300ccttcttatg cttttaacag aattccttct ttgcgccgac tagacttagg 1350ggaattgaaa agactttcat acatctcaga aggtgccttt gaaggtctgt 1400ccaacttgag gtatttgaac cttgccatgt gcaaccttcg ggaaatccct 1450aacctcacac cgctcataaa actagatgag ctggatcttt ctgggaatca 1500tttatctgcc atcaggcctg gctctttcca gggtttgatg caccttcaaa 1550aactgtggat gatacagtcc cagattcaag tgattgaacg gaatgccttt 1600gacaaccttc agtcactagt ggagatcaac ctggcacaca ataatctaac 1650attactgcct catgacctct tcactccctt gcatcatcta gagcggatac 1700atttacatca caacccttgg aactgtaact gtgacatact gtggctcagc 1750tggtggataa aagacatggc cccctcgaac acagcttgtt gtgcccggtg 1800taacactcct cccaatctaa aggggaggta cattggagag ctcgaccaga 1850attacttcac atgctatgct ccggtgattg tggagccccc tgcagacctc 1900aatgtcactg aaggcatggc agctgagctg aaatgtcggg cctccacatc 1950cctgacatct gtatcttgga ttactccaaa tggaacagtc atgacacatg 2000gggcgtacaa agtgcggata gctgtgctca gtgatggtac gttaaatttc 2050acaaatgtaa ctgtgcaaga tacaggcatg tacacatgta tggtgagtaa 2100ttccgttggg aatactactg cttcagccac cctgaatgtt actgcagcaa 2150ccactactcc tttctcttac ttttcaaccg tcacagtaga gactatggaa 2200ccgtctcagg atgaggcacg gaccacagat aacaatgtgg gtcccactcc 2250agtggtcgac tgggagacca ccaatgtgac cacctctctc acaccacaga 2300gcacaaggtc gacagagaaa accttcacca tcccagtgac tgatataaac 2350agtgggatcc caggaattga tgaggtcatg aagactacca aaatcatcat 2400tgggtgtttt gtggccatca cactcatggc tgcagtgatg ctggtcattt 2450tctacaagat gaggaagcag caccatcggc aaaaccatca cgccccaaca 2500aggactgttg aaattattaa tgtggatgat gagattacgg gagacacacc 2550catggaaagc cacctgccca tgcctgctat cgagcatgag cacctaaatc 2600actataactc atacaaatct cccttcaacc acacaacaac agttaacaca 2650ataaattcaa tacacagttc agtgcatgaa ccgttattga tccgaatgaa 2700ctctaaagac aatgtacaag agactcaaat ctaaaacatt tacagagtta 2750caaaaaacaa acaatcaaaa aaaaagacag tttattaaaa atgacacaaa 2800tgactgggct aaatctactg tttcaaaaaa gtgtctttac aaaaaaacaa 2850aaaagaaaag aaatttattt attaaaaatt ctattgtgat ctaaagcaga 2900 caaaaa2906 292 640 PRT Homo Sapien 292 Met Leu Asn Lys Met Thr Leu HisPro Gln Gln Ile Met Ile Gly 1 5 10 15 Pro Arg Phe Asn Arg Ala LeuPhe Asp Pro Leu Leu Val Val Leu 20 25 30 Leu Ala Leu Gln Leu

Leu Val Val Ala Gly Leu Val Arg Ala Gln 35 40 45 Thr Cys Pro SerVal Cys Ser Cys Ser Asn Gln Phe Ser Lys Val 50 55 60 Ile Cys ValArg Lys Asn Leu Arg Glu Val Pro Asp Gly Ile Ser 65 70 75 Thr AsnThr Arg Leu Leu Asn Leu His Glu Asn Gln Ile Gln Ile 80 85 90 IleLys Val Asn Ser Phe Lys His Leu Arg His Leu Glu Ile Leu 95 100 105Gln Leu Ser Arg Asn His Ile Arg Thr Ile Glu Ile Gly Ala Phe 110 115120 Asn Gly Leu Ala Asn Leu Asn Thr Leu Glu Leu Phe Asp Asn Arg 125130 135 Leu Thr Thr Ile Pro Asn Gly Ala Phe Val Tyr Leu Ser Lys Leu140 145 150 Lys Glu Leu Trp Leu Arg Asn Asn Pro Ile Glu Ser Ile ProSer 155 160 165 Tyr Ala Phe Asn Arg Ile Pro Ser Leu Arg Arg Leu AspLeu Gly 170 175 180 Glu Leu Lys Arg Leu Ser Tyr Ile Ser Glu Gly AlaPhe Glu Gly 185 190 195 Leu Ser Asn Leu Arg Tyr Leu Asn Leu Ala MetCys Asn Leu Arg 200 205 210 Glu Ile Pro Asn Leu Thr Pro Leu Ile LysLeu Asp Glu Leu Asp 215 220 225 Leu Ser Gly Asn His Leu Ser Ala IleArg Pro Gly Ser Phe Gln 230 235 240 Gly Leu Met His Leu Gln Lys LeuTrp Met Ile Gln Ser Gln Ile 245 250 255 Gln Val Ile Glu Arg Asn AlaPhe Asp Asn Leu Gln Ser Leu Val 260 265 270 Glu Ile Asn Leu Ala HisAsn Asn Leu Thr Leu Leu Pro His Asp 275 280 285 Leu Phe Thr Pro LeuHis His Leu Glu Arg Ile His Leu His His 290 295 300 Asn Pro Trp AsnCys Asn Cys Asp Ile Leu Trp Leu Ser Trp Trp 305 310 315 Ile Lys AspMet Ala Pro Ser Asn Thr Ala Cys Cys Ala Arg Cys 320 325 330 Asn ThrPro Pro Asn Leu Lys Gly Arg Tyr Ile Gly Glu Leu Asp 335 340 345 GlnAsn Tyr Phe Thr Cys Tyr Ala Pro Val Ile Val Glu Pro Pro 350 355 360Ala Asp Leu Asn Val Thr Glu Gly Met Ala Ala Glu Leu Lys Cys 365 370375 Arg Ala Ser Thr Ser Leu Thr Ser Val Ser Trp Ile Thr Pro Asn 380385 390 Gly Thr Val Met Thr His Gly Ala Tyr Lys Val Arg Ile Ala Val395 400 405 Leu Ser Asp Gly Thr Leu Asn Phe Thr Asn Val Thr Val GlnAsp 410 415 420 Thr Gly Met Tyr Thr Cys Met Val Ser Asn Ser Val GlyAsn Thr 425 430 435 Thr Ala Ser Ala Thr Leu Asn Val Thr Ala Ala ThrThr Thr Pro 440 445 450 Phe Ser Tyr Phe Ser Thr Val Thr Val Glu ThrMet Glu Pro Ser 455 460 465 Gln Asp Glu Ala Arg Thr Thr Asp Asn AsnVal Gly Pro Thr Pro 470 475 480 Val Val Asp Trp Glu Thr Thr Asn ValThr Thr Ser Leu Thr Pro 485 490 495 Gln Ser Thr Arg Ser Thr Glu LysThr Phe Thr Ile Pro Val Thr 500 505 510 Asp Ile Asn Ser Gly Ile ProGly Ile Asp Glu Val Met Lys Thr 515 520 525 Thr Lys Ile Ile Ile GlyCys Phe Val Ala Ile Thr Leu Met Ala 530 535 540 Ala Val Met Leu ValIle Phe Tyr Lys Met Arg Lys Gln His His 545 550 555 Arg Gln Asn HisHis Ala Pro Thr Arg Thr Val Glu Ile Ile Asn 560 565 570 Val Asp AspGlu Ile Thr Gly Asp Thr Pro Met Glu Ser His Leu 575 580 585 Pro MetPro Ala Ile Glu His Glu His Leu Asn His Tyr Asn Ser 590 595 600 TyrLys Ser Pro Phe Asn His Thr Thr Thr Val Asn Thr Ile Asn 605 610 615Ser Ile His Ser Ser Val His Glu Pro Leu Leu Ile Arg Met Asn 620 625630 Ser Lys Asp Asn Val Gln Glu Thr Gln Ile 635 640 293 4053 DNAHomo Sapien 293 agccgacgct gctcaagctg caactctgtt gcagttggcagttcttttcg 50 gtttccctcc tgctgtttgg gggcatgaaa gggcttcgccgccgggagta 100 aaagaaggaa ttgaccgggc agcgcgaggg aggagcgcgcacgcgaccgc 150 gagggcgggc gtgcaccctc ggctggaagt ttgtgccgggccccgagcgc 200 gcgccggctg ggagcttcgg gtagagacct aggccgctggaccgcgatga 250 gcgcgccgag cctccgtgcg cgcgccgcgg ggttggggctgctgctgtgc 300 gcggtgctgg ggcgcgctgg ccggtccgac agcggcggtcgcggggaact 350 cgggcagccc tctggggtag ccgccgagcg cccatgccccactacctgcc 400 gctgcctcgg ggacctgctg gactgcagtc gtaagcggctagcgcgtctt 450 cccgagccac tcccgtcctg ggtcgctcgg ctggacttaagtcacaacag 500 attatctttc atcaaggcaa gttccatgag ccaccttcaaagccttcgag 550 aagtgaaact gaacaacaat gaattggaga ccattccaaatctgggacca 600 gtctcggcaa atattacact tctctccttg gctggaaacaggattgttga 650 aatactccct gaacatctga aagagtttca gtcccttgaaactttggacc 700 ttagcagcaa caatatttca gagctccaaa ctgcatttccagccctacag 750 ctcaaatatc tgtatctcaa cagcaaccga gtcacatcaatggaacctgg 800 gtattttgac aatttggcca acacactcct tgtgttaaagctgaacagga 850 accgaatctc agctatccca cccaagatgt ttaaactgccccaactgcaa 900 catctcgaat tgaaccgaaa caagattaaa aatgtagatggactgacatt 950 ccaaggcctt ggtgctctga agtctctgaa aatgcaaagaaatggagtaa 1000 cgaaacttat ggatggagct ttttgggggc tgagcaacatggaaattttg 1050 cagctggacc ataacaacct aacagagatt accaaaggctggctttacgg 1100 cttgctgatg ctgcaggaac ttcatctcag ccaaaatgccatcaacagga 1150 tcagccctga tgcctgggag ttctgccaga agctcagtgagctggaccta 1200 actttcaatc acttatcaag gttagatgat tcaagcttccttggcctaag 1250 cttactaaat acactgcaca ttgggaacaa cagagtcagctacattgctg 1300 attgtgcctt ccgggggctt tccagtttaa agactttggatctgaagaac 1350 aatgaaattt cctggactat tgaagacatg aatggtgctttctctgggct 1400 tgacaaactg aggcgactga tactccaagg aaatcggatccgttctatta 1450 ctaaaaaagc cttcactggt ttggatgcat tggagcatctagacctgagt 1500 gacaacgcaa tcatgtcttt acaaggcaat gcattttcacaaatgaagaa 1550 actgcaacaa ttgcatttaa atacatcaag ccttttgtgcgattgccagc 1600 taaaatggct cccacagtgg gtggcggaaa acaactttcagagctttgta 1650 aatgccagtt gtgcccatcc tcagctgcta aaaggaagaagcatttttgc 1700 tgttagccca gatggctttg tgtgtgatga ttttcccaaaccccagatca 1750 cggttcagcc agaaacacag tcggcaataa aaggttccaatttgagtttc 1800 atctgctcag ctgccagcag cagtgattcc ccaatgacttttgcttggaa 1850 aaaagacaat gaactactgc atgatgctga aatggaaaattatgcacacc 1900 tccgggccca aggtggcgag gtgatggagt ataccaccatccttcggctg 1950 cgcgaggtgg aatttgccag tgaggggaaa tatcagtgtgtcatctccaa 2000 tcactttggt tcatcctact ctgtcaaagc caagcttacagtaaatatgc 2050 ttccctcatt caccaagacc cccatggatc tcaccatccgagctggggcc 2100 atggcacgct tggagtgtgc tgctgtgggg cacccagccccccagatagc 2150 ctggcagaag gatgggggca cagacttccc agctgcacgggagagacgca 2200 tgcatgtgat gcccgaggat gacgtgttct ttatcgtggatgtgaagata 2250 gaggacattg gggtatacag ctgcacagct cagaacagtgcaggaagtat 2300 ttcagcaaat gcaactctga ctgtcctaga aacaccatcatttttgcggc 2350 cactgttgga ccgaactgta accaagggag aaacagccgtcctacagtgc 2400 attgctggag gaagccctcc ccctaaactg aactggaccaaagatgatag 2450 cccattggtg gtaaccgaga ggcacttttt tgcagcaggcaatcagcttc 2500 tgattattgt ggactcagat gtcagtgatg ctgggaaatacacatgtgag 2550 atgtctaaca cccttggcac tgagagagga aacgtgcgcctcagtgtgat 2600 ccccactcca acctgcgact cccctcagat gacagccccatcgttagacg 2650 atgacggatg ggccactgtg ggtgtcgtga tcatagccgtggtttgctgt 2700 gtggtgggca cgtcactcgt gtgggtggtc atcatataccacacaaggcg 2750 gaggaatgaa gattgcagca ttaccaacac agatgagaccaacttgccag 2800 cagatattcc tagttatttg tcatctcagg gaacgttagctgacaggcag 2850 gatgggtacg tgtcttcaga aagtggaagc caccaccagtttgtcacatc 2900 ttcaggtgct ggatttttct taccacaaca tgacagtagtgggacctgcc 2950 atattgacaa tagcagtgaa gctgatgtgg aagctgccacagatctgttc 3000 ctttgtccgt ttttgggatc cacaggccct atgtatttgaagggaaatgt 3050 gtatggctca gatccttttg aaacatatca tacaggttgcagtcctgacc 3100 caagaacagt tttaatggac cactatgagc ccagttacataaagaaaaag 3150 gagtgctacc catgttctca tccttcagaa gaatcctgcgaacggagctt 3200 cagtaatata tcgtggcctt cacatgtgag gaagctacttaacactagtt 3250 actctcacaa tgaaggacct ggaatgaaaa atctgtgtctaaacaagtcc 3300 tctttagatt ttagtgcaaa tccagagcca gcgtcggttgcctcgagtaa 3350 ttctttcatg ggtacctttg gaaaagctct caggagacctcacctagatg 3400 cctattcaag ctttggacag ccatcagatt gtcagccaagagccttttat 3450 ttgaaagctc attcttcccc agacttggac tctgggtcagaggaagatgg 3500 gaaagaaagg acagattttc aggaagaaaa tcacatttgtacctttaaac 3550 agactttaga aaactacagg actccaaatt ttcagtcttatgacttggac 3600 acatagactg aatgagacca aaggaaaagc ttaacatactacctcaagtg 3650 aacttttatt taaaagagag agaatcttat gttttttaaatggagttatg 3700 aattttaaaa ggataaaaat gctttattta tacagatgaaccaaaattac 3750 aaaaagttat gaaaattttt atactgggaa tgatgctcatataagaatac 3800 ctttttaaac tattttttaa ctttgtttta tgcaaaaaagtatcttacgt 3850 aaattaatga tataaatcat gattatttta tgtatttttataatgccaga 3900 tttcttttta tggaaaatga gttactaaag cattttaaataatacctgcc 3950 ttgtaccatt ttttaaatag aagttacttc attatattttgcacattata 4000 tttaataaaa tgtgtcaatt tgaaaaaaaa aaaaaaaaaaaaaaaaaaaa 4050 aaa 4053 294 1119 PRT Homo Sapien 294 Met Ser AlaPro Ser Leu Arg Ala Arg Ala Ala Gly Leu Gly Leu 1 5 10 15 Leu LeuCys Ala Val Leu Gly Arg Ala Gly Arg Ser Asp Ser Gly 20 25 30 GlyArg Gly Glu Leu Gly Gln Pro Ser Gly Val Ala Ala Glu Arg 35 40 45Pro Cys Pro Thr Thr Cys Arg Cys Leu Gly Asp Leu Leu Asp Cys 50 5560 Ser Arg Lys Arg Leu Ala Arg Leu Pro Glu Pro Leu Pro Ser Trp 6570 75 Val Ala Arg Leu Asp Leu Ser His Asn Arg Leu Ser Phe Ile Lys80 85 90 Ala Ser Ser Met Ser His Leu Gln Ser Leu Arg Glu Val LysLeu 95 100 105 Asn Asn Asn Glu Leu Glu Thr Ile Pro Asn Leu Gly ProVal Ser 110 115 120 Ala Asn Ile Thr Leu Leu Ser Leu Ala Gly Asn ArgIle Val Glu 125 130 135 Ile Leu Pro Glu His Leu Lys Glu Phe Gln SerLeu Glu Thr Leu 140 145 150 Asp Leu Ser Ser Asn Asn Ile Ser Glu LeuGln Thr Ala Phe Pro 155 160 165 Ala Leu Gln Leu Lys Tyr Leu Tyr LeuAsn Ser Asn Arg Val Thr 170 175 180 Ser Met Glu Pro Gly Tyr Phe AspAsn Leu Ala Asn Thr Leu Leu 185 190 195 Val Leu Lys Leu Asn Arg AsnArg Ile Ser Ala Ile Pro Pro Lys 200 205 210 Met Phe Lys Leu Pro GlnLeu Gln His Leu Glu Leu Asn Arg Asn 215 220 225 Lys Ile Lys Asn ValAsp Gly Leu Thr Phe Gln Gly Leu Gly Ala 230 235 240 Leu Lys Ser LeuLys Met Gln Arg Asn Gly Val Thr Lys Leu Met 245 250 255 Asp Gly AlaPhe Trp Gly Leu Ser Asn Met Glu Ile Leu Gln Leu 260 265 270 Asp HisAsn Asn Leu Thr Glu Ile Thr Lys Gly Trp Leu Tyr Gly 275 280 285 LeuLeu Met Leu Gln Glu Leu His Leu Ser Gln Asn Ala Ile Asn 290 295 300Arg Ile Ser Pro Asp Ala Trp Glu Phe Cys Gln Lys Leu Ser Glu 305 310315 Leu Asp Leu Thr Phe Asn His Leu Ser Arg Leu Asp Asp Ser Ser 320325 330 Phe Leu Gly Leu Ser Leu Leu Asn Thr Leu His Ile Gly Asn Asn335 340 345 Arg Val Ser Tyr Ile Ala Asp Cys Ala Phe Arg Gly Leu SerSer 350 355 360 Leu Lys Thr Leu Asp Leu Lys Asn Asn Glu Ile Ser TrpThr Ile 365 370 375 Glu Asp Met Asn Gly Ala Phe Ser Gly Leu Asp LysLeu Arg Arg 380 385 390 Leu Ile Leu Gln Gly Asn Arg Ile Arg Ser IleThr Lys Lys Ala 395 400 405 Phe Thr Gly Leu Asp Ala Leu Glu His LeuAsp Leu Ser Asp Asn 410 415 420 Ala Ile Met Ser Leu Gln Gly Asn AlaPhe Ser Gln Met Lys Lys 425 430 435 Leu Gln Gln Leu His Leu Asn ThrSer Ser Leu Leu Cys Asp Cys 440 445 450 Gln Leu Lys Trp Leu Pro GlnTrp Val Ala Glu Asn Asn Phe Gln 455 460 465 Ser Phe Val Asn Ala SerCys Ala His Pro Gln Leu Leu Lys Gly 470 475 480 Arg Ser Ile Phe AlaVal Ser Pro Asp Gly Phe Val Cys Asp Asp 485 490 495 Phe Pro Lys ProGln Ile Thr Val Gln Pro Glu Thr Gln Ser Ala 500 505 510 Ile Lys GlySer Asn Leu Ser Phe Ile Cys Ser Ala Ala Ser Ser 515 520 525 Ser AspSer Pro Met Thr Phe Ala Trp Lys Lys Asp Asn Glu Leu 530 535 540 LeuHis Asp Ala Glu Met Glu Asn Tyr Ala His Leu Arg Ala Gln 545 550 555Gly Gly Glu Val Met Glu Tyr Thr Thr Ile Leu Arg Leu Arg Glu 560 565570 Val Glu Phe Ala Ser Glu Gly Lys Tyr Gln Cys Val Ile Ser Asn 575580 585 His Phe Gly Ser Ser Tyr Ser Val Lys Ala Lys Leu Thr Val Asn590 595 600 Met Leu Pro Ser Phe Thr Lys Thr Pro Met Asp Leu Thr IleArg 605 610 615 Ala Gly Ala Met Ala Arg Leu Glu Cys Ala Ala Val GlyHis Pro 620 625 630 Ala Pro Gln Ile Ala Trp Gln Lys Asp Gly Gly ThrAsp Phe Pro 635 640 645 Ala Ala Arg Glu Arg Arg Met His Val Met ProGlu Asp Asp Val 650 655 660 Phe Phe Ile Val Asp Val Lys Ile Glu AspIle Gly Val Tyr Ser 665 670 675 Cys Thr Ala Gln Asn Ser Ala Gly SerIle Ser Ala Asn Ala Thr 680 685 690 Leu Thr Val Leu Glu Thr Pro SerPhe Leu Arg Pro Leu Leu Asp 695 700 705 Arg Thr Val Thr Lys Gly GluThr Ala Val Leu Gln Cys Ile Ala 710 715 720 Gly Gly Ser Pro Pro ProLys Leu Asn Trp Thr Lys Asp Asp Ser 725 730 735 Pro Leu Val Val ThrGlu Arg His Phe Phe Ala Ala Gly Asn Gln 740 745 750 Leu Leu Ile IleVal Asp Ser Asp Val Ser Asp Ala Gly Lys Tyr 755 760 765 Thr Cys GluMet Ser Asn Thr Leu Gly Thr Glu Arg Gly Asn Val 770 775 780 Arg LeuSer Val Ile Pro Thr Pro Thr Cys Asp Ser Pro Gln Met 785 790 795 ThrAla Pro Ser Leu Asp Asp Asp Gly Trp Ala Thr Val Gly Val 800 805 810Val Ile Ile Ala Val Val Cys Cys Val Val Gly Thr Ser Leu Val 815 820825 Trp Val Val Ile Ile Tyr His Thr Arg Arg Arg Asn Glu Asp Cys 830835 840 Ser Ile Thr Asn Thr Asp Glu Thr Asn Leu Pro Ala Asp Ile Pro845 850 855 Ser Tyr Leu Ser Ser Gln Gly Thr Leu Ala Asp Arg Gln AspGly 860 865 870 Tyr Val Ser Ser Glu Ser Gly Ser His His Gln Phe ValThr Ser 875 880 885 Ser Gly Ala Gly Phe Phe Leu Pro Gln His Asp SerSer Gly Thr 890 895 900 Cys His Ile Asp Asn Ser Ser Glu Ala Asp ValGlu Ala Ala Thr 905 910 915 Asp Leu Phe Leu Cys Pro Phe Leu Gly SerThr Gly Pro Met Tyr 920 925 930 Leu Lys Gly Asn Val Tyr Gly

Ser Asp Pro Phe Glu Thr Tyr His 935 940 945 Thr Gly Cys Ser Pro AspPro Arg Thr Val Leu Met Asp His Tyr 950 955 960 Glu Pro Ser Tyr IleLys Lys Lys Glu Cys Tyr Pro Cys Ser His 965 970 975 Pro Ser Glu GluSer Cys Glu Arg Ser Phe Ser Asn Ile Ser Trp 980 985 990 Pro Ser HisVal Arg Lys Leu Leu Asn Thr Ser Tyr Ser His Asn 995 1000 1005 GluGly Pro Gly Met Lys Asn Leu Cys Leu Asn Lys Ser Ser Leu 1010 10151020 Asp Phe Ser Ala Asn Pro Glu Pro Ala Ser Val Ala Ser Ser Asn1025 1030 1035 Ser Phe Met Gly Thr Phe Gly Lys Ala Leu Arg Arg ProHis Leu 1040 1045 1050 Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser AspCys Gln Pro Arg 1055 1060 1065 Ala Phe Tyr Leu Lys Ala His Ser SerPro Asp Leu Asp Ser Gly 1070 1075 1080 Ser Glu Glu Asp Gly Lys GluArg Thr Asp Phe Gln Glu Glu Asn 1085 1090 1095 His Ile Cys Thr PheLys Gln Thr Leu Glu Asn Tyr Arg Thr Pro 1100 1105 1110 Asn Phe GlnSer Tyr Asp Leu Asp Thr 1115 295 18 DNA Artificial SequenceSynthetic Oligonucleotide Probe 295 ggaaccgaat ctcagcta 18 296 19DNA Artificial Sequence Synthetic Oligonucleotide Probe 296cctaaactga actggacca 19 297 19 DNA Artificial Sequence SyntheticOligonucleotide Probe 297 ggctggagac actgaacct 19 298 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 298 acagctgcacagctcagaac agtg 24 299 22 DNA Artificial Sequence SyntheticOligonucleotide Probe 299 cattcccagt ataaaaattt tc 22 300 18 DNAArtificial Sequence Synthetic Oligonucleotide Probe 300 gggtcttggtgaatgagg 18 301 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 301 gtgcctctcg gttaccacca atgg 24 302 50 DNAArtificial Sequence Synthetic Oligonucleotide Probe 302 gcggccactgttggaccgaa ctgtaaccaa gggagaaaca gccgtcctac 50 303 28 DNAArtificial Sequence Synthetic Oligonucleotide Probe 303 gcctttgacaaccttcagtc actagtgg 28 304 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 304 ccccatgtgt ccatgactgt tccc 24 305 45 DNAArtificial Sequence Synthetic Oligonucleotide Probe 305 tactgcctcatgacctcttc actcccttgc atcatcttag agcgg 45 306 24 DNA ArtificialSequence Synthetic Oligonucleotide Probe 306 actccaagga aatcggatccgttc 24 307 24 DNA Artificial Sequence Synthetic oligonucleotideprobe 307 ttagcagctg aggatgggca caac 24 308 24 DNA ArtificialSequence Synthetic Oligonucleotide Probe 308 actccaagga aatcggatccgttc 24 309 50 DNA Artificial Sequence Synthetic OligonucleotideProbe 309 gccttcactg gtttggatgc attggagcat ctagacctga gtgacaacgc 50310 3296 DNA Homo Sapien 310 caaaacttgc gtcgcggaga gcgcccagcttgacttgaat ggaaggagcc 50 cgagcccgcg gagcgcagct gagactgggggagcgcgttc ggcctgtggg 100 gcgccgctcg gcgccggggc gcagcagggaaggggaagct gtggtctgcc 150 ctgctccacg aggcgccact ggtgtgaaccgggagagccc ctgggtggtc 200 ccgtccccta tccctccttt atatagaaaccttccacact gggaaggcag 250 cggcgaggca ggagggctca tggtgagcaaggaggccggc tgatctgcag 300 gcgcacagca ttccgagttt acagatttttacagatacca aatggaaggc 350 gaggaggcag aacagcctgc ctggttccatcagccctggc gcccaggcgc 400 atctgactcg gcaccccctg caggcaccatggcccagagc cgggtgctgc 450 tgctcctgct gctgctgccg ccacagctgcacctgggacc tgtgcttgcc 500 gtgagggccc caggatttgg ccgaagtggcggccacagcc tgagccccga 550 agagaacgaa tttgcggagg aggagccggtgctggtactg agccctgagg 600 agcccgggcc tggcccagcc gcggtcagctgcccccgaga ctgtgcctgt 650 tcccaggagg gcgtcgtgga ctgtggcggtattgacctgc gtgagttccc 700 gggggacctg cctgagcaca ccaaccacctatctctgcag aacaaccagc 750 tggaaaagat ctaccctgag gagctctcccggctgcaccg gctggagaca 800 ctgaacctgc aaaacaaccg cctgacttcccgagggctcc cagagaaggc 850 gtttgagcat ctgaccaacc tcaattacctgtacttggcc aataacaagc 900 tgaccttggc accccgcttc ctgccaaacgccctgatcag tgtggacttt 950 gctgccaact atctcaccaa gatctatgggctcacctttg gccagaagcc 1000 aaacttgagg tctgtgtacc tgcacaacaacaagctggca gacgccgggc 1050 tgccggacaa catgttcaac ggctccagcaacgtcgaggt cctcatcctg 1100 tccagcaact tcctgcgcca cgtgcccaagcacctgccgc ctgccctgta 1150 caagctgcac ctcaagaaca acaagctggagaagatcccc ccgggggcct 1200 tcagcgagct gagcagcctg cgcgagctatacctgcagaa caactacctg 1250 actgacgagg gcctggacaa cgagaccttctggaagctct ccagcctgga 1300 gtacctggat ctgtccagca acaacctgtctcgggtccca gctgggctgc 1350 cgcgcagcct ggtgctgctg cacttggagaagaacgccat ccggagcgtg 1400 gacgcgaatg tgctgacccc catccgcagcctggagtacc tgctgctgca 1450 cagcaaccag ctgcgggagc agggcatccacccactggcc ttccagggcc 1500 tcaagcggtt gcacacggtg cacctgtacaacaacgcgct ggagcgcgtg 1550 cccagtggcc tgcctcgccg cgtgcgcaccctcatgatcc tgcacaacca 1600 gatcacaggc attggccgcg aagactttgccaccacctac ttcctggagg 1650 agctcaacct cagctacaac cgcatcaccagcccacaggt gcaccgcgac 1700 gccttccgca agctgcgcct gctgcgctcgctggacctgt cgggcaaccg 1750 gctgcacacg ctgccacctg ggctgcctcgaaatgtccat gtgctgaagg 1800 tcaagcgcaa tgagctggct gccttggcacgaggggcgct ggcgggcatg 1850 gctcagctgc gtgagctgta cctcaccagcaaccgactgc gcagccgagc 1900 cctgggcccc cgtgcctggg tggacctcgcccatctgcag ctgctggaca 1950 tcgccgggaa tcagctcaca gagatccccgaggggctccc cgagtcactt 2000 gagtacctgt acctgcagaa caacaagattagtgcggtgc ccgccaatgc 2050 cttcgactcc acgcccaacc tcaaggggatctttctcagg tttaacaagc 2100 tggctgtggg ctccgtggtg gacagtgccttccggaggct gaagcacctg 2150 caggtcttgg acattgaagg caacttagagtttggtgaca tttccaagga 2200 ccgtggccgc ttggggaagg aaaaggaggaggaggaagag gaggaggagg 2250 aggaagagga aacaagatag tgacaaggtgatgcagatgt gacctaggat 2300 gatggaccgc cggactcttt tctgcagcacacgcctgtgt gctgtgagcc 2350 ccccactctg ccgtgctcac acagacacacccagctgcac acatgaggca 2400 tcccacatga cacgggctga cacagtctcatatccccacc ccttcccacg 2450 gcgtgtccca cggccagaca catgcacacacatcacaccc tcaaacaccc 2500 agctcagcca cacacaacta ccctccaaaccaccacagtc tctgtcacac 2550 ccccactacc gctgccacgc cctctgaatcatgcagggaa gggtctgccc 2600 ctgccctggc acacacaggc acccattccctccccctgct gacatgtgta 2650 tgcgtatgca tacacaccac acacacacacatgcacaagt catgtgcgaa 2700 cagccctcca aagcctatgc cacagacagctcttgcccca gccagaatca 2750 gccatagcag ctcgccgtct gccctgtccatctgtccgtc cgttccctgg 2800 agaagacaca agggtatcca tgctctgtggccaggtgcct gccaccctct 2850 ggaactcaca aaagctggct tttattcctttcccatccta tggggacagg 2900 agccttcagg actgctggcc tggcctggcccaccctgctc ctccaggtgc 2950 tgggcagtca ctctgctaag agtccctccctgccacgccc tggcaggaca 3000 caggcacttt tccaatgggc aagcccagtggaggcaggat gggagagccc 3050 cctgggtgct gctggggcct tggggcaggagtgaagcaga ggtgatgggg 3100 ctgggctgag ccagggagga aggacccagctgcacctagg agacaccttt 3150 gttcttcagg cctgtggggg aagttccgggtgcctttatt ttttattctt 3200 ttctaaggaa aaaaatgata aaaatctcaaagctgatttt tcttgttata 3250 gaaaaactaa tataaaagca ttatccctatccctgcaaaa aaaaaa 3296 311 22 DNA Artificial Sequence SyntheticOligonucleotide Probe 311 gcattggccg cgagactttg cc 22 312 22 DNAArtificial Sequence Synthetic Oligonucleotide Probe 312 gcggccacggtccttggaaa tg 22 313 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 313 tggaggagct caacctcagc tacaaccgcatcaccagccc acagg 45 314 3003 DNA Homo Sapien 314 gggagggggctccgggcgcc gcgcagcaga cctgctccgg ccgcgcgcct 50 cgccgctgtcctccgggagc ggcagcagta gcccgggcgg cgagggctgg 100 gggttcctcgagactctcag aggggcgcct cccatcggcg cccaccaccc 150 caacctgttcctcgcgcgcc actgcgctgc gccccaggac ccgctgccca 200 acatggattttctcctggcg ctggtgctgg tatcctcgct ctacctgcag 250 gcggccgccgagttcgacgg gaggtggccc aggcaaatag tgtcatcgat 300 tggcctatgtcgttatggtg ggaggattga ctgctgctgg ggctgggctc 350 gccagtcttggggacagtgt cagcctgtgt gccaaccacg atgcaaacat 400 ggtgaatgtatcgggccaaa caagtgcaag tgtcatcctg gttatgctgg 450 aaaaacctgtaatcaagatc taaatgagtg tggcctgaag ccccggccct 500 gtaagcacaggtgcatgaac acttacggca gctacaagtg ctactgtctc 550 aacggatatatgctcatgcc ggatggttcc tgctcaagtg ccctgacctg 600 ctccatggcaaactgtcagt atggctgtga tgttgttaaa ggacaaatac 650 ggtgccagtgcccatcccct ggcctgcacc tggctcctga tgggaggacc 700 tgtgtagatgttgatgaatg tgctacagga agagcctcct gccctagatt 750 taggcaatgtgtcaacactt ttgggagcta catctgcaag tgtcataaag 800 gcttcgatctcatgtatatt ggaggcaaat atcaatgtca tgacatagac 850 gaatgctcacttggtcagta tcagtgcagc agctttgctc gatgttataa 900 cgtacgtgggtcctacaagt gcaaatgtaa agaaggatac cagggtgatg 950 gactgacttgtgtgtatatc ccaaaagtta tgattgaacc ttcaggtcca 1000 attcatgtaccaaagggaaa tggtaccatt ttaaagggtg acacaggaaa 1050 taataattggattcctgatg ttggaagtac ttggtggcct ccgaagacac 1100 catatattcctcctatcatt accaacaggc ctacttctaa gccaacaaca 1150 agacctacaccaaagccaac accaattcct actccaccac caccaccacc 1200 cctgccaacagagctcagaa cacctctacc acctacaacc ccagaaaggc 1250 caaccaccggactgacaact atagcaccag ctgccagtac acctccagga 1300 gggattacagttgacaacag ggtacagaca gaccctcaga aacccagagg 1350 agatgtgttcagtgttctgg tacacagttg taattttgac catggacttt 1400 gtggatggatcagggagaaa gacaatgact tgcactggga accaatcagg 1450 gacccagcaggtggacaata tctgacagtg tcggcagcca aagccccagg 1500 gggaaaagctgcacgcttgg tgctacctct cggccgcctc atgcattcag 1550 gggacctgtgcctgtcattc aggcacaagg tgacggggct gcactctggc 1600 acactccaggtgtttgtgag aaaacacggt gcccacggag cagccctgtg 1650 gggaagaaatggtggccatg gctggaggca aacacagatc accttgcgag 1700 gggctgacatcaagagcgaa tcacaaagat gattaaaggg ttggaaaaaa 1750 agatctatgatggaaaatta aaggaactgg gattattgag cctggagaag 1800 agaagactgaggggcaaacc attgatggtt ttcaagtata tgaagggttg 1850 gcacagagagggtggcgacc agctgttctc catatgcact aagaatagaa 1900 caagaggaaactggcttaga ctagagtata agggagcatt tcttggcagg 1950 ggccattgttagaatacttc ataaaaaaag aagtgtgaaa atctcagtat 2000 ctctctctctttctaaaaaa ttagataaaa atttgtctat ttaagatggt 2050 taaagatgttcttacccaag gaaaagtaac aaattataga atttcccaaa 2100 agatgttttgatcctactag tagtatgcag tgaaaatctt tagaactaaa 2150 taatttggacaaggcttaat ttaggcattt ccctcttgac ctcctaatgg 2200 agagggattgaaaggggaag agcccaccaa atgctgagct cactgaaata 2250 tctctcccttatggcaatcc tagcagtatt aaagaaaaaa ggaaactatt 2300 tattccaaatgagagtatga tggacagata ttttagtatc tcagtaatgt 2350 cctagtgtggcggtggtttt caatgtttct tcatggtaaa ggtataagcc 2400 tttcatttgttcaatggatg atgtttcaga tttttttttt tttaagagat 2450 ccttcaaggaacacagttca gagagatttt catcgggtgc attctctctg 2500 cttcgtgtgtgacaagttat cttggctgct gagaaagagt gccctgcccc 2550 acaccggcagacctttcctt cacctcatca gtatgattca gtttctctta 2600 tcaattggactctcccaggt tccacagaac agtaatattt tttgaacaat 2650 aggtacaatagaaggtcttc tgtcatttaa cctggtaaag gcagggctgg 2700 agggggaaaataaatcatta agcctttgag taacggcaga atatatggct 2750 gtagatccatttttaatggt tcatttcctt tatggtcata taactgcaca 2800 gctgaagatgaaaggggaaa ataaatgaaa attttacttt tcgatgccaa 2850 tgatacattgcactaaactg atggaagaag ttatccaaag tactgtataa 2900 catcttgtttattatttaat gttttctaaa ataaaaaatg ttagtggttt 2950 tccaaatggcctaataaaaa caattatttg taaataaaaa cactgttagt 3000 aat 3003 315 509PRT Homo Sapien 315 Met Asp Phe Leu Leu Ala Leu Val Leu Val Ser SerLeu Tyr Leu 1 5 10 15 Gln Ala Ala Ala Glu Phe Asp Gly Arg Trp ProArg Gln Ile Val 20 25 30 Ser Ser Ile Gly Leu Cys Arg Tyr Gly GlyArg Ile Asp Cys Cys 35 40 45 Trp Gly Trp Ala Arg Gln Ser Trp GlyGln Cys Gln Pro Val Cys 50 55 60 Gln Pro Arg Cys Lys His Gly GluCys Ile Gly Pro Asn Lys Cys 65 70 75 Lys Cys His Pro Gly Tyr AlaGly Lys Thr Cys Asn Gln Asp Leu 80 85 90 Asn Glu Cys Gly Leu LysPro Arg Pro Cys Lys His Arg Cys Met 95 100 105 Asn Thr Tyr Gly SerTyr Lys Cys Tyr Cys Leu Asn Gly Tyr Met 110 115 120 Leu Met Pro AspGly Ser Cys Ser Ser Ala Leu Thr Cys Ser Met 125 130 135 Ala Asn CysGln Tyr Gly Cys Asp Val Val Lys Gly Gln Ile Arg 140 145 150 Cys GlnCys Pro Ser Pro Gly Leu His Leu Ala Pro Asp Gly Arg 155 160 165 ThrCys Val Asp Val Asp Glu Cys Ala Thr Gly Arg Ala Ser Cys 170 175 180Pro Arg Phe Arg Gln Cys Val Asn Thr Phe Gly Ser Tyr Ile Cys 185 190195 Lys Cys His Lys Gly Phe Asp Leu Met Tyr Ile Gly Gly Lys Tyr 200205 210 Gln Cys His Asp Ile Asp Glu Cys Ser Leu Gly Gln Tyr Gln Cys215 220 225 Ser Ser Phe Ala Arg Cys Tyr Asn Val Arg Gly Ser Tyr LysCys 230 235 240 Lys Cys Lys Glu Gly Tyr Gln Gly Asp Gly Leu Thr CysVal Tyr 245 250 255 Ile Pro Lys Val Met Ile Glu Pro Ser Gly Pro IleHis Val Pro 260 265 270 Lys Gly Asn Gly Thr Ile Leu Lys Gly Asp ThrGly Asn Asn Asn 275 280 285 Trp Ile Pro Asp Val Gly Ser Thr Trp TrpPro Pro Lys Thr Pro 290 295 300 Tyr Ile Pro Pro Ile Ile Thr Asn ArgPro Thr Ser Lys Pro Thr 305 310 315 Thr Arg Pro Thr Pro Lys Pro ThrPro Ile Pro Thr Pro Pro Pro 320 325 330 Pro Pro Pro Leu Pro Thr GluLeu Arg Thr Pro Leu Pro Pro Thr 335 340 345 Thr Pro Glu Arg Pro ThrThr Gly Leu Thr Thr Ile Ala Pro Ala 350 355 360 Ala Ser Thr Pro ProGly Gly Ile Thr Val Asp Asn Arg Val Gln 365 370 375 Thr Asp Pro GlnLys Pro Arg Gly Asp Val Phe Ser Val Leu Val 380 385 390 His Ser CysAsn Phe Asp His Gly Leu Cys Gly Trp Ile Arg Glu 395 400 405 Lys AspAsn Asp Leu His Trp Glu Pro Ile Arg Asp Pro Ala Gly 410 415 420 GlyGln Tyr Leu Thr Val Ser Ala Ala Lys Ala Pro Gly Gly Lys 425 430 435Ala Ala Arg Leu Val Leu Pro Leu Gly Arg Leu Met His Ser Gly 440 445450 Asp Leu Cys Leu Ser Phe Arg His Lys Val Thr Gly Leu His Ser 455460 465 Gly Thr Leu Gln Val Phe Val Arg Lys His Gly Ala His Gly Ala470 475 480 Ala Leu Trp Gly Arg Asn Gly Gly His Gly Trp Arg Gln ThrGln 485 490 495 Ile Thr Leu Arg Gly Ala Asp Ile Lys Ser Glu Ser GlnArg 500 505 316 24 DNA Artificial Sequence SyntheticOligonucleotide Probe 316 gatggttcct gctcaagtgc cctg 24 317 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 317 ttgcacttgtaggacccacg tacg 24 318 50 DNA Artificial Sequence SyntheticOligonucleotide Probe 318 ctgatgggag gacctgtgta gatgttgatgaatgtgctac aggaagagcc 50 319 2110 DNA Homo Sapien 319 cttctttgaaaaggattatc acctgatcag gttctctctg catttgcccc 50 tttagattgtgaaatgtggc tcaaggtctt cacaactttc ctttcctttg 100 caacaggtgcttgctcgggg ctgaaggtga cagtgccatc acacactgtc 150 catggcgtcagaggtcaggc cctctaccta cccgtccact atggcttcca 200 cactccagcatcagacatcc agatcatatg gctatttgag agaccccaca 250

caatgcccaa atacttactg ggctctgtga ataagtctgt ggttcctgac 300ttggaatacc aacacaagtt caccatgatg ccacccaatg catctctgct 350tatcaaccca ctgcagttcc ctgatgaagg caattacatc gtgaaggtca 400acattcaggg aaatggaact ctatctgcca gtcagaagat acaagtcacg 450gttgatgatc ctgtcacaaa gccagtggtg cagattcatc ctccctctgg 500ggctgtggag tatgtgggga acatgaccct gacatgccat gtggaagggg 550gcactcggct agcttaccaa tggctaaaaa atgggagacc tgtccacacc 600agctccacct actccttttc tccccaaaac aatacccttc atattgctcc 650agtaaccaag gaagacattg ggaattacag ctgcctggtg aggaaccctg 700tcagtgaaat ggaaagtgat atcattatgc ccatcatata ttatggacct 750tatggacttc aagtgaattc tgataaaggg ctaaaagtag gggaagtgtt 800tactgttgac cttggagagg ccatcctatt tgattgttct gctgattctc 850atccccccaa cacctactcc tggattagga ggactgacaa tactacatat 900atcattaagc atgggcctcg cttagaagtt gcatctgaga aagtagccca 950gaagacaatg gactatgtgt gctgtgctta caacaacata accggcaggc 1000aagatgaaac tcatttcaca gttatcatca cttccgtagg actggagaag 1050cttgcacaga aaggaaaatc attgtcacct ttagcaagta taactggaat 1100atcactattt ttgattatat ccatgtgtct tctcttccta tggaaaaaat 1150atcaacccta caaagttata aaacagaaac tagaaggcag gccagaaaca 1200gaatacagga aagctcaaac attttcaggc catgaagatg ctctggatga 1250cttcggaata tatgaatttg ttgcttttcc agatgtttct ggtgtttcca 1300ggattccaag caggtctgtt ccagcctctg attgtgtatc ggggcaagat 1350ttgcacagta cagtgtatga agttattcag cacatccctg cccagcagca 1400agaccatcca gagtgaactt tcatgggcta aacagtacat tcgagtgaaa 1450ttctgaagaa acattttaag gaaaaacagt ggaaaagtat attaatctgg 1500aatcagtgaa gaaaccagga ccaacacctc ttactcatta ttcctttaca 1550tgcagaatag aggcatttat gcaaattgaa ctgcaggttt ttcagcatat 1600acacaatgtc ttgtgcaaca gaaaaacatg ttggggaaat attcctcagt 1650ggagagtcgt tctcatgctg acggggagaa cgaaagtgac aggggtttcc 1700tcataagttt tgtatgaaat atctctacaa acctcaatta gttctactct 1750acactttcac tatcatcaac actgagacta tcctgtctca cctacaaatg 1800tggaaacttt acattgttcg atttttcagc agactttgtt ttattaaatt 1850tttattagtg ttaagaatgc taaatttatg tttcaatttt atttccaaat 1900ttctatcttg ttatttgtac aacaaagtaa taaggatggt tgtcacaaaa 1950acaaaactat gccttctctt ttttttcaat caccagtagt atttttgaga 2000agacttgtga acacttaagg aaatgactat taaagtctta tttttatttt 2050tttcaaggaa agatggattc aaataaatta ttctgttttt gcttttaaaa 2100aaaaaaaaaa 2110 320 450 PRT Homo Sapien 320 Met Trp Leu Lys Val PheThr Thr Phe Leu Ser Phe Ala Thr Gly 1 5 10 15 Ala Cys Ser Gly LeuLys Val Thr Val Pro Ser His Thr Val His 20 25 30 Gly Val Arg GlyGln Ala Leu Tyr Leu Pro Val His Tyr Gly Phe 35 40 45 His Thr ProAla Ser Asp Ile Gln Ile Ile Trp Leu Phe Glu Arg 50 55 60 Pro HisThr Met Pro Lys Tyr Leu Leu Gly Ser Val Asn Lys Ser 65 70 75 ValVal Pro Asp Leu Glu Tyr Gln His Lys Phe Thr Met Met Pro 80 85 90Pro Asn Ala Ser Leu Leu Ile Asn Pro Leu Gln Phe Pro Asp Glu 95 100105 Gly Asn Tyr Ile Val Lys Val Asn Ile Gln Gly Asn Gly Thr Leu 110115 120 Ser Ala Ser Gln Lys Ile Gln Val Thr Val Asp Asp Pro Val Thr125 130 135 Lys Pro Val Val Gln Ile His Pro Pro Ser Gly Ala Val GluTyr 140 145 150 Val Gly Asn Met Thr Leu Thr Cys His Val Glu Gly GlyThr Arg 155 160 165 Leu Ala Tyr Gln Trp Leu Lys Asn Gly Arg Pro ValHis Thr Ser 170 175 180 Ser Thr Tyr Ser Phe Ser Pro Gln Asn Asn ThrLeu His Ile Ala 185 190 195 Pro Val Thr Lys Glu Asp Ile Gly Asn TyrSer Cys Leu Val Arg 200 205 210 Asn Pro Val Ser Glu Met Glu Ser AspIle Ile Met Pro Ile Ile 215 220 225 Tyr Tyr Gly Pro Tyr Gly Leu GlnVal Asn Ser Asp Lys Gly Leu 230 235 240 Lys Val Gly Glu Val Phe ThrVal Asp Leu Gly Glu Ala Ile Leu 245 250 255 Phe Asp Cys Ser Ala AspSer His Pro Pro Asn Thr Tyr Ser Trp 260 265 270 Ile Arg Arg Thr AspAsn Thr Thr Tyr Ile Ile Lys His Gly Pro 275 280 285 Arg Leu Glu ValAla Ser Glu Lys Val Ala Gln Lys Thr Met Asp 290 295 300 Tyr Val CysCys Ala Tyr Asn Asn Ile Thr Gly Arg Gln Asp Glu 305 310 315 Thr HisPhe Thr Val Ile Ile Thr Ser Val Gly Leu Glu Lys Leu 320 325 330 AlaGln Lys Gly Lys Ser Leu Ser Pro Leu Ala Ser Ile Thr Gly 335 340 345Ile Ser Leu Phe Leu Ile Ile Ser Met Cys Leu Leu Phe Leu Trp 350 355360 Lys Lys Tyr Gln Pro Tyr Lys Val Ile Lys Gln Lys Leu Glu Gly 365370 375 Arg Pro Glu Thr Glu Tyr Arg Lys Ala Gln Thr Phe Ser Gly His380 385 390 Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr Glu Phe Val AlaPhe 395 400 405 Pro Asp Val Ser Gly Val Ser Arg Ile Pro Ser Arg SerVal Pro 410 415 420 Ala Ser Asp Cys Val Ser Gly Gln Asp Leu His SerThr Val Tyr 425 430 435 Glu Val Ile Gln His Ile Pro Ala Gln Gln GlnAsp His Pro Glu 440 445 450 321 25 DNA Artificial SequenceSynthetic Oligonucleotide Probe 321 gatcctgtca caaagccagt ggtgc 25322 24 DNA Artificial Sequence Synthetic Oligonucleotide Probe 322cactgacagg gttcctcacc cagg 24 323 45 DNA Artificial SequenceSynthetic Oligonucleotide Probe 323 ctccctctgg gctgtggagtatgtggggaa catgaccctg acatg 45 324 2397 DNA Homo Sapien 324gcaagcggcg aaatggcgcc ctccgggagt cttgcagttc ccctggcagt 50cctggtgctg ttgctttggg gtgctccctg gacgcacggg cggcggagca 100acgttcgcgt catcacggac gagaactgga gagaactgct ggaaggagac 150tggatgatag aattttatgc cccgtggtgc cctgcttgtc aaaatcttca 200accggaatgg gaaagttttg ctgaatgggg agaagatctt gaggttaata 250ttgcgaaagt agatgtcaca gagcagccag gactgagtgg acggtttatc 300ataactgctc ttcctactat ttatcattgt aaagatggtg aatttaggcg 350ctatcagggt ccaaggacta agaaggactt cataaacttt ataagtgata 400aagagtggaa gagtattgag cccgtttcat catggtttgg tccaggttct 450gttctgatga gtagtatgtc agcactcttt cagctatcta tgtggatcag 500gacgtgccat aactacttta ttgaagacct tggattgcca gtgtggggat 550catatactgt ttttgcttta gcaactctgt tttccggact gttattagga 600ctctgtatga tatttgtggc agattgcctt tgtccttcaa aaaggcgcag 650accacagcca tacccatacc cttcaaaaaa attattatca gaatctgcac 700aacctttgaa aaaagtggag gaggaacaag aggcggatga agaagatgtt 750tcagaagaag aagctgaaag taaagaagga acaaacaaag actttccaca 800gaatgccata agacaacgct ctctgggtcc atcattggcc acagataaat 850cctagttaaa ttttatagtt atcttaatat tatgattttg ataaaaacag 900aagattgatc attttgtttg gtttgaagtg aactgtgact tttttgaata 950ttgcagggtt cagtctagat tgtcattaaa ttgaagagtc tacattcaga 1000acataaaagc actaggtata caagtttgaa atatgattta agcacagtat 1050gatggtttaa atagttctct aatttttgaa aaatcgtgcc aagcaataag 1100atttatgtat atttgtttaa taataaccta tttcaagtct gagttttgaa 1150aatttacatt tcccaagtat tgcattattg aggtatttaa gaagattatt 1200ttagagaaaa atatttctca tttgatataa tttttctctg tttcactgtg 1250tgaaaaaaag aagatatttc ccataaatgg gaagtttgcc cattgtctca 1300agaaatgtgt atttcagtga caatttcgtg gtctttttag aggtatattc 1350caaaatttcc ttgtattttt aggttatgca actaataaaa actaccttac 1400attaattaat tacagttttc tacacatggt aatacaggat atgctactga 1450tttaggaagt ttttaagttc atggtattct cttgattcca acaaagtttg 1500attttctctt gtatttttct tacttactat gggttacatt ttttattttt 1550caaattggat gataatttct tggaaacatt ttttatgttt tagtaaacag 1600tatttttttg ttgtttcaaa ctgaagttta ctgagagatc catcaaattg 1650aacaatctgt tgtaatttaa aattttggcc acttttttca gattttacat 1700cattcttgct gaacttcaac ttgaaattgt tttttttttc tttttggatg 1750tgaaggtgaa cattcctgat ttttgtctga tgtgaaaaag ccttggtatt 1800ttacattttg aaaattcaaa gaagcttaat ataaaagttt gcattctact 1850caggaaaaag catcttcttg tatatgtctt aaatgtattt ttgtcctcat 1900atacagaaag ttcttaattg attttacagt ctgtaatgct tgatgtttta 1950aaataataac atttttatat tttttaaaag acaaacttca tattatcctg 2000tgttctttcc tgactggtaa tattgtgtgg gatttcacag gtaaaagtca 2050gtaggatgga acattttagt gtatttttac tccttaaaga gctagaatac 2100atagttttca ccttaaaaga agggggaaaa tcataaatac aatgaatcaa 2150ctgaccatta cgtagtagac aatttctgta atgtcccctt ctttctaggc 2200tctgttgctg tgtgaatcca ttagatttac agtatcgtaa tatacaagtt 2250ttctttaaag ccctctcctt tagaatttaa aatattgtac cattaaagag 2300tttggatgtg taacttgtga tgccttagaa aaatatccta agcacaaaat 2350aaacctttct aaccacttca ttaaagctga aaaaaaaaaa aaaaaaa 2397 325 280PRT Homo Sapien 325 Met Ala Pro Ser Gly Ser Leu Ala Val Pro Leu AlaVal Leu Val 1 5 10 15 Leu Leu Leu Trp Gly Ala Pro Trp Thr His GlyArg Arg Ser Asn 20 25 30 Val Arg Val Ile Thr Asp Glu Asn Trp ArgGlu Leu Leu Glu Gly 35 40 45 Asp Trp Met Ile Glu Phe Tyr Ala ProTrp Cys Pro Ala Cys Gln 50 55 60 Asn Leu Gln Pro Glu Trp Glu SerPhe Ala Glu Trp Gly Glu Asp 65 70 75 Leu Glu Val Asn Ile Ala LysVal Asp Val Thr Glu Gln Pro Gly 80 85 90 Leu Ser Gly Arg Phe IleIle Thr Ala Leu Pro Thr Ile Tyr His 95 100 105 Cys Lys Asp Gly GluPhe Arg Arg Tyr Gln Gly Pro Arg Thr Lys 110 115 120 Lys Asp Phe IleAsn Phe Ile Ser Asp Lys Glu Trp Lys Ser Ile 125 130 135 Glu Pro ValSer Ser Trp Phe Gly Pro Gly Ser Val Leu Met Ser 140 145 150 Ser MetSer Ala Leu Phe Gln Leu Ser Met Trp Ile Arg Thr Cys 155 160 165 HisAsn Tyr Phe Ile Glu Asp Leu Gly Leu Pro Val Trp Gly Ser 170 175 180Tyr Thr Val Phe Ala Leu Ala Thr Leu Phe Ser Gly Leu Leu Leu 185 190195 Gly Leu Cys Met Ile Phe Val Ala Asp Cys Leu Cys Pro Ser Lys 200205 210 Arg Arg Arg Pro Gln Pro Tyr Pro Tyr Pro Ser Lys Lys Leu Leu215 220 225 Ser Glu Ser Ala Gln Pro Leu Lys Lys Val Glu Glu Glu GlnGlu 230 235 240 Ala Asp Glu Glu Asp Val Ser Glu Glu Glu Ala Glu SerLys Glu 245 250 255 Gly Thr Asn Lys Asp Phe Pro Gln Asn Ala Ile ArgGln Arg Ser 260 265 270 Leu Gly Pro Ser Leu Ala Thr Asp Lys Ser 275280 326 23 DNA Artificial Sequence Synthetic Oligonucleotide Probe326 tgaggtgggc aagcggcgaa atg 23 327 20 DNA Artificial SequenceSynthetic Oligonucleotide Probe 327 tatgtggatc aggacgtgcc 20 328 21DNA Artificial Sequence Synthetic Oligonucleotide Probe 328tgcagggttc agtctagatt g 21 329 25 DNA Artificial Sequence SyntheticOligonucleotide Probe 329 ttgaaggaca aaggcaatct gccac 25 330 45 DNAArtificial Sequence Synthetic Oligonucleotide Probe 330 ggagtcttgcagttcccctg gcagtcctgg tgctgttgct ttggg 45 331 2168 DNA Homo Sapien331 gcgagtgtcc agctgcggag acccgtgata attcgttaac taattcaaca 50aacgggaccc ttctgtgtgc cagaaaccgc aagcagttgc taacccagtg 100ggacaggcgg attggaagag cgggaaggtc ctggcccaga gcagtgtgac 150acttccctct gtgaccatga aactctgggt gtctgcattg ctgatggcct 200ggtttggtgt cctgagctgt gtgcaggccg aattcttcac ctctattggg 250cacatgactg acctgattta tgcagagaaa gagctggtgc agtctctgaa 300agagtacatc cttgtggagg aagccaagct ttccaagatt aagagctggg 350ccaacaaaat ggaagccttg actagcaagt cagctgctga tgctgagggc 400tacctggctc accctgtgaa tgcctacaaa ctggtgaagc ggctaaacac 450agactggcct gcgctggagg accttgtcct gcaggactca gctgcaggtt 500ttatcgccaa cctctctgtg cagcggcagt tcttccccac tgatgaggac 550gagataggag ctgccaaagc cctgatgaga cttcaggaca catacaggct 600ggacccaggc acaatttcca gaggggaact tccaggaacc aagtaccagg 650caatgctgag tgtggatgac tgctttggga tgggccgctc ggcctacaat 700gaaggggact attatcatac ggtgttgtgg atggagcagg tgctaaagca 750gcttgatgcc ggggaggagg ccaccacaac caagtcacag gtgctggact 800acctcagcta tgctgtcttc cagttgggtg atctgcaccg tgccctggag 850ctcacccgcc gcctgctctc ccttgaccca agccacgaac gagctggagg 900gaatctgcgg tactttgagc agttattgga ggaagagaga gaaaaaacgt 950taacaaatca gacagaagct gagctagcaa ccccagaagg catctatgag 1000aggcctgtgg actacctgcc tgagagggat gtttacgaga gcctctgtcg 1050tggggagggt gtcaaactga caccccgtag acagaagagg cttttctgta 1100ggtaccacca tggcaacagg gccccacagc tgctcattgc ccccttcaaa 1150gaggaggacg agtgggacag cccgcacatc gtcaggtact acgatgtcat 1200gtctgatgag gaaatcgaga ggatcaagga gatcgcaaaa cctaaacttg 1250cacgagccac cgttcgtgat cccaagacag gagtcctcac tgtcgccagc 1300taccgggttt ccaaaagctc ctggctagag gaagatgatg accctgttgt 1350ggcccgagta aatcgtcgga tgcagcatat cacagggtta acagtaaaga 1400ctgcagaatt gttacaggtt gcaaattatg gagtgggagg acagtatgaa 1450ccgcacttcg acttctctag gcgacctttt gacagcggcc tcaaaacaga 1500ggggaatagg ttagcgacgt ttcttaacta catgagtgat gtagaagctg 1550gtggtgccac cgtcttccct gatctggggg ctgcaatttg gcctaagaag 1600ggtacagctg tgttctggta caacctcttg cggagcgggg aaggtgacta 1650ccgaacaaga catgctgcct gccctgtgct tgtgggctgc aagtgggtct 1700ccaataagtg gttccatgaa cgaggacagg agttcttgag accttgtgga 1750tcaacagaag ttgactgaca tccttttctg tccttcccct tcctggtcct 1800tcagcccatg tcaacgtgac agacaccttt gtatgttcct ttgtatgttc 1850ctatcaggct gatttttgga gaaatgaatg tttgtctgga gcagagggag 1900accatactag ggcgactcct gtgtgactga agtcccagcc cttccattca 1950gcctgtgcca tccctggccc caaggctagg atcaaagtgg ctgcagcaga 2000gttagctgtc tagcgcctag caaggtgcct ttgtacctca ggtgttttag 2050gtgtgagatg tttcagtgaa ccaaagttct gataccttgt ttacatgttt 2100gtttttatgg catttctatc tattgtggct ttaccaaaaa ataaaatgtc 2150cctaccagaa aaaaaaaa 2168 332 533 PRT Homo Sapien 332 Met Lys LeuTrp Val Ser Ala Leu Leu Met Ala Trp Phe Gly Val 1 5 10 15 Leu SerCys Val Gln Ala Glu Phe Phe Thr Ser Ile Gly His Met 20 25 30 ThrAsp Leu Ile Tyr Ala Glu Lys Glu Leu Val Gln Ser Leu Lys 35 40 45Glu Tyr Ile Leu Val Glu Glu Ala Lys Leu Ser Lys Ile Lys Ser 50 5560 Trp Ala Asn Lys Met Glu Ala Leu Thr Ser Lys Ser Ala Ala Asp 6570 75 Ala Glu Gly Tyr Leu Ala His Pro Val Asn Ala Tyr Lys Leu Val80 85 90 Lys Arg Leu Asn Thr Asp Trp Pro Ala Leu Glu Asp Leu ValLeu 95 100 105 Gln Asp Ser Ala Ala Gly Phe Ile Ala Asn Leu Ser ValGln Arg 110 115 120 Gln Phe Phe Pro Thr Asp Glu Asp Glu Ile Gly AlaAla Lys Ala 125 130 135 Leu Met Arg Leu Gln Asp Thr Tyr Arg Leu AspPro Gly Thr Ile 140 145 150 Ser Arg Gly Glu Leu Pro Gly Thr Lys TyrGln Ala Met Leu Ser 155 160 165 Val Asp Asp Cys Phe Gly Met Gly ArgSer Ala Tyr Asn Glu Gly 170 175 180 Asp Tyr Tyr His Thr Val Leu TrpMet Glu Gln Val Leu Lys Gln 185 190 195 Leu Asp Ala Gly Glu Glu AlaThr Thr Thr Lys Ser Gln Val Leu 200 205 210 Asp Tyr Leu Ser TyrAla

Val Phe Gln Leu Gly Asp Leu His Arg 215 220 225 Ala Leu Glu Leu ThrArg Arg Leu Leu Ser Leu Asp Pro Ser His 230 235 240 Glu Arg Ala GlyGly Asn Leu Arg Tyr Phe Glu Gln Leu Leu Glu 245 250 255 Glu Glu ArgGlu Lys Thr Leu Thr Asn Gln Thr Glu Ala Glu Leu 260 265 270 Ala ThrPro Glu Gly Ile Tyr Glu Arg Pro Val Asp Tyr Leu Pro 275 280 285 GluArg Asp Val Tyr Glu Ser Leu Cys Arg Gly Glu Gly Val Lys 290 295 300Leu Thr Pro Arg Arg Gln Lys Arg Leu Phe Cys Arg Tyr His His 305 310315 Gly Asn Arg Ala Pro Gln Leu Leu Ile Ala Pro Phe Lys Glu Glu 320325 330 Asp Glu Trp Asp Ser Pro His Ile Val Arg Tyr Tyr Asp Val Met335 340 345 Ser Asp Glu Glu Ile Glu Arg Ile Lys Glu Ile Ala Lys ProLys 350 355 360 Leu Ala Arg Ala Thr Val Arg Asp Pro Lys Thr Gly ValLeu Thr 365 370 375 Val Ala Ser Tyr Arg Val Ser Lys Ser Ser Trp LeuGlu Glu Asp 380 385 390 Asp Asp Pro Val Val Ala Arg Val Asn Arg ArgMet Gln His Ile 395 400 405 Thr Gly Leu Thr Val Lys Thr Ala Glu LeuLeu Gln Val Ala Asn 410 415 420 Tyr Gly Val Gly Gly Gln Tyr Glu ProHis Phe Asp Phe Ser Arg 425 430 435 Arg Pro Phe Asp Ser Gly Leu LysThr Glu Gly Asn Arg Leu Ala 440 445 450 Thr Phe Leu Asn Tyr Met SerAsp Val Glu Ala Gly Gly Ala Thr 455 460 465 Val Phe Pro Asp Leu GlyAla Ala Ile Trp Pro Lys Lys Gly Thr 470 475 480 Ala Val Phe Trp TyrAsn Leu Leu Arg Ser Gly Glu Gly Asp Tyr 485 490 495 Arg Thr Arg HisAla Ala Cys Pro Val Leu Val Gly Cys Lys Trp 500 505 510 Val Ser AsnLys Trp Phe His Glu Arg Gly Gln Glu Phe Leu Arg 515 520 525 Pro CysGly Ser Thr Glu Val Asp 530 333 18 DNA Artificial SequenceSynthetic Oligonucleotide Probe 333 ccaggcacaa tttccaga 18 334 19DNA Artificial Sequence Synthetic Oligonucleotide Probe 334ggacccttct gtgtgccag 19 335 19 DNA Artificial Sequence SyntheticOligonucleotide Probe 335 ggtctcaaga actcctgtc 19 336 24 DNAArtificial Sequence Synthetic Oligonucleotide Probe 336 acactcagcattgcctggta cttg 24 337 45 DNA Artificial Sequence SyntheticOligonucleotide Probe 337 gggcacatga ctgacctgat ttatgcagagaaagagctgg tgcag 45 338 2789 DNA Homo Sapien 338 gcagtattgagttttacttc ctcctctttt tagtggaaga cagaccataa 50 tcccagtgtgagtgaaattg attgtttcat ttattaccgt tttggctggg 100 ggttagttccgacaccttca cagttgaaga gcaggcagaa ggagttgtga 150 agacaggacaatcttcttgg ggatgctggt cctggaagcc agcgggcctt 200 gctctgtctttggcctcatt gaccccaggt tctctggtta aaactgaaag 250 cctactactggcctggtgcc catcaatcca ttgatccttg aggctgtgcc 300 cctggggcacccacctggca gggcctacca ccatgcgact gagctccctg 350 ttggctctgctgcggccagc gcttcccctc atcttagggc tgtctctggg 400 gtgcagcctgagcctcctgc gggtttcctg gatccagggg gagggagaag 450 atccctgtgtcgaggctgta ggggagcgag gagggccaca gaatccagat 500 tcgagagctcggctagacca aagtgatgaa gacttcaaac cccggattgt 550 cccctactacagggacccca acaagcccta caagaaggtg ctcaggactc 600 ggtacatccagacagagctg ggctcccgtg agcggttgct ggtggctgtc 650 ctgacctcccgagctacact gtccactttg gccgtggctg tgaaccgtac 700 ggtggcccatcacttccctc ggttactcta cttcactggg cagcgggggg 750 cccgggctccagcagggatg caggtggtgt ctcatgggga tgagcggccc 800 gcctggctcatgtcagagac cctgcgccac cttcacacac actttggggc 850 cgactacgactggttcttca tcatgcagga tgacacatat gtgcaggccc 900 cccgcctggcagcccttgct ggccacctca gcatcaacca agacctgtac 950 ttaggccgggcagaggagtt cattggcgca ggcgagcagg cccggtactg 1000 tcatgggggctttggctacc tgttgtcacg gagtctcctg cttcgtctgc 1050 ggccacatctggatggctgc cgaggagaca ttctcagtgc ccgtcctgac 1100 gagtggcttggacgctgcct cattgactct ctgggcgtcg gctgtgtctc 1150 acagcaccaggggcagcagt atcgctcatt tgaactggcc aaaaataggg 1200 accctgagaaggaagggagc tcggctttcc tgagtgcctt cgccgtgcac 1250 cctgtctccgaaggtaccct catgtaccgg ctccacaaac gcttcagcgc 1300 tctggagttggagcgggctt acagtgaaat agaacaactg caggctcaga 1350 tccggaacctgaccgtgctg acccccgaag gggaggcagg gctgagctgg 1400 cccgttgggctccctgctcc tttcacacca cactctcgct ttgaggtgct 1450 gggctgggactacttcacag agcagcacac cttctcctgt gcagatgggg 1500 ctcccaagtgcccactacag ggggctagca gggcggacgt gggtgatgcg 1550 ttggagactgccctggagca gctcaatcgg cgctatcagc cccgcctgcg 1600 cttccagaagcagcgactgc tcaacggcta tcggcgcttc gacccagcac 1650 ggggcatggagtacaccctg gacctgctgt tggaatgtgt gacacagcgt 1700 gggcaccggcgggccctggc tcgcagggtc agcctgctgc ggccactgag 1750 ccgggtggaaatcctaccta tgccctatgt cactgaggcc acccgagtgc 1800 agctggtgctgccactcctg gtggctgaag ctgctgcagc cccggctttc 1850 ctcgaggcgtttgcagccaa tgtcctggag ccacgagaac atgcattgct 1900 caccctgttgctggtctacg ggccacgaga aggtggccgt ggagctccag 1950 acccatttcttggggtgaag gctgcagcag cggagttaga gcgacggtac 2000 cctgggacgaggctggcctg gctcgctgtg cgagcagagg ccccttccca 2050 ggtgcgactcatggacgtgg tctcgaagaa gcaccctgtg gacactctct 2100 tcttccttaccaccgtgtgg acaaggcctg ggcccgaagt cctcaaccgc 2150 tgtcgcatgaatgccatctc tggctggcag gccttctttc cagtccattt 2200 ccaggagttcaatcctgccc tgtcaccaca gagatcaccc ccagggcccc 2250 cgggggctggccctgacccc ccctcccctc ctggtgctga cccctcccgg 2300 ggggctcctataggggggag atttgaccgg caggcttctg cggagggctg 2350 cttctacaacgctgactacc tggcggcccg agcccggctg gcaggtgaac 2400 tggcaggccaggaagaggag gaagccctgg aggggctgga ggtgatggat 2450 gttttcctccggttctcagg gctccacctc tttcgggccg tagagccagg 2500 gctggtgcagaagttctccc tgcgagactg cagcccacgg ctcagtgaag 2550 aactctaccaccgctgccgc ctcagcaacc tggaggggct agggggccgt 2600 gcccagctggctatggctct ctttgagcag gagcaggcca atagcactta 2650 gcccgcctgggggccctaac ctcattacct ttcctttgtc tgcctcagcc 2700 ccaggaagggcaaggcaaga tggtggacag atagagaatt gttgctgtat 2750 tttttaaatatgaaaatgtt attaaacatg tcttctgcc 2789 339 772 PRT Homo Sapien 339Met Arg Leu Ser Ser Leu Leu Ala Leu Leu Arg Pro Ala Leu Pro 1 5 1015 Leu Ile Leu Gly Leu Ser Leu Gly Cys Ser Leu Ser Leu Leu Arg 2025 30 Val Ser Trp Ile Gln Gly Glu Gly Glu Asp Pro Cys Val Glu Ala35 40 45 Val Gly Glu Arg Gly Gly Pro Gln Asn Pro Asp Ser Arg AlaArg 50 55 60 Leu Asp Gln Ser Asp Glu Asp Phe Lys Pro Arg Ile ValPro Tyr 65 70 75 Tyr Arg Asp Pro Asn Lys Pro Tyr Lys Lys Val LeuArg Thr Arg 80 85 90 Tyr Ile Gln Thr Glu Leu Gly Ser Arg Glu ArgLeu Leu Val Ala 95 100 105 Val Leu Thr Ser Arg Ala Thr Leu Ser ThrLeu Ala Val Ala Val 110 115 120 Asn Arg Thr Val Ala His His Phe ProArg Leu Leu Tyr Phe Thr 125 130 135 Gly Gln Arg Gly Ala Arg Ala ProAla Gly Met Gln Val Val Ser 140 145 150 His Gly Asp Glu Arg Pro AlaTrp Leu Met Ser Glu Thr Leu Arg 155 160 165 His Leu His Thr His PheGly Ala Asp Tyr Asp Trp Phe Phe Ile 170 175 180 Met Gln Asp Asp ThrTyr Val Gln Ala Pro Arg Leu Ala Ala Leu 185 190 195 Ala Gly His LeuSer Ile Asn Gln Asp Leu Tyr Leu Gly Arg Ala 200 205 210 Glu Glu PheIle Gly Ala Gly Glu Gln Ala Arg Tyr Cys His Gly 215 220 225 Gly PheGly Tyr Leu Leu Ser Arg Ser Leu Leu Leu Arg Leu Arg 230 235 240 ProHis Leu Asp Gly Cys Arg Gly Asp Ile Leu Ser Ala Arg Pro 245 250 255Asp Glu Trp Leu Gly Arg Cys Leu Ile Asp Ser Leu Gly Val Gly 260 265270 Cys Val Ser Gln His Gln Gly Gln Gln Tyr Arg Ser Phe Glu Leu 275280 285 Ala Lys Asn Arg Asp Pro Glu Lys Glu Gly Ser Ser Ala Phe Leu290 295 300 Ser Ala Phe Ala Val His Pro Val Ser Glu Gly Thr Leu MetTyr 305 310 315 Arg Leu His Lys Arg Phe Ser Ala Leu Glu Leu Glu ArgAla Tyr 320 325 330 Ser Glu Ile Glu Gln Leu Gln Ala Gln Ile Arg AsnLeu Thr Val 335 340 345 Leu Thr Pro Glu Gly Glu Ala Gly Leu Ser TrpPro Val Gly Leu 350 355 360 Pro Ala Pro Phe Thr Pro His Ser Arg PheGlu Val Leu Gly Trp 365 370 375 Asp Tyr Phe Thr Glu Gln His Thr PheSer Cys Ala Asp Gly Ala 380 385 390 Pro Lys Cys Pro Leu Gln Gly AlaSer Arg Ala Asp Val Gly Asp 395 400 405 Ala Leu Glu Thr Ala Leu GluGln Leu Asn Arg Arg Tyr Gln Pro 410 415 420 Arg Leu Arg Phe Gln LysGln Arg Leu Leu Asn Gly Tyr Arg Arg 425 430 435 Phe Asp Pro Ala ArgGly Met Glu Tyr Thr Leu Asp Leu Leu Leu 440 445 450 Glu Cys Val ThrGln Arg Gly His Arg Arg Ala Leu Ala Arg Arg 455 460 465 Val Ser LeuLeu Arg Pro Leu Ser Arg Val Glu Ile Leu Pro Met 470 475 480 Pro TyrVal Thr Glu Ala Thr Arg Val Gln Leu Val Leu Pro Leu 485 490 495 LeuVal Ala Glu Ala Ala Ala Ala Pro Ala Phe Leu Glu Ala Phe 500 505 510Ala Ala Asn Val Leu Glu Pro Arg Glu His Ala Leu Leu Thr Leu 515 520525 Leu Leu Val Tyr Gly Pro Arg Glu Gly Gly Arg Gly Ala Pro Asp 530535 540 Pro Phe Leu Gly Val Lys Ala Ala Ala Ala Glu Leu Glu Arg Arg545 550 555 Tyr Pro Gly Thr Arg Leu Ala Trp Leu Ala Val Arg Ala GluAla 560 565 570 Pro Ser Gln Val Arg Leu Met Asp Val Val Ser Lys LysHis Pro 575 580 585 Val Asp Thr Leu Phe Phe Leu Thr Thr Val Trp ThrArg Pro Gly 590 595 600 Pro Glu Val Leu Asn Arg Cys Arg Met Asn AlaIle Ser Gly Trp 605 610 615 Gln Ala Phe Phe Pro Val His Phe Gln GluPhe Asn Pro Ala Leu 620 625 630 Ser Pro Gln Arg Ser Pro Pro Gly ProPro Gly Ala Gly Pro Asp 635 640 645 Pro Pro Ser Pro Pro Gly Ala AspPro Ser Arg Gly Ala Pro Ile 650 655 660 Gly Gly Arg Phe Asp Arg GlnAla Ser Ala Glu Gly Cys Phe Tyr 665 670 675 Asn Ala Asp Tyr Leu AlaAla Arg Ala Arg Leu Ala Gly Glu Leu 680 685 690 Ala Gly Gln Glu GluGlu Glu Ala Leu Glu Gly Leu Glu Val Met 695 700 705 Asp Val Phe LeuArg Phe Ser Gly Leu His Leu Phe Arg Ala Val 710 715 720 Glu Pro GlyLeu Val Gln Lys Phe Ser Leu Arg Asp Cys Ser Pro 725 730 735 Arg LeuSer Glu Glu Leu Tyr His Arg Cys Arg Leu Ser Asn Leu 740 745 750 GluGly Leu Gly Gly Arg Ala Gln Leu Ala Met Ala Leu Phe Glu 755 760 765Gln Glu Gln Ala Asn Ser Thr 770 340 1572 DNA Homo Sapien 340cggagtggtg cgccaacgtg agaggaaacc cgtgcgcggc tgcgctttcc 50tgtccccaag ccgttctaga cgcgggaaaa atgctttctg aaagcagctc 100ctttttgaag ggtgtgatgc ttggaagcat tttctgtgct ttgatcacta 150tgctaggaca cattaggatt ggtcatggaa atagaatgca ccaccatgag 200catcatcacc tacaagctcc taacaaagaa gatatcttga aaatttcaga 250ggatgagcgc atggagctca gtaagagctt tcgagtatac tgtattatcc 300ttgtaaaacc caaagatgtg agtctttggg ctgcagtaaa ggagacttgg 350accaaacact gtgacaaagc agagttcttc agttctgaaa atgttaaagt 400gtttgagtca attaatatgg acacaaatga catgtggtta atgatgagaa 450aagcttacaa atacgccttt gataagtata gagaccaata caactggttc 500ttccttgcac gccccactac gtttgctatc attgaaaacc taaagtattt 550tttgttaaaa aaggatccat cacagccttt ctatctaggc cacactataa 600aatctggaga ccttgaatat gtgggtatgg aaggaggaat tgtcttaagt 650gtagaatcaa tgaaaagact taacagcctt ctcaatatcc cagaaaagtg 700tcctgaacag ggagggatga tttggaagat atctgaagat aaacagctag 750cagtttgcct gaaatatgct ggagtatttg cagaaaatgc agaagatgct 800gatggaaaag atgtatttaa taccaaatct gttgggcttt ctattaaaga 850ggcaatgact tatcacccca accaggtagt agaaggctgt tgttcagata 900tggctgttac ttttaatgga ctgactccaa atcagatgca tgtgatgatg 950tatggggtat accgccttag ggcatttggg catattttca atgatgcatt 1000ggttttctta cctccaaatg gttctgacaa tgactgagaa gtggtagaaa 1050agcgtgaata tgatctttgt ataggacgtg tgttgtcatt atttgtagta 1100gtaactacat atccaataca gctgtatgtt tctttttctt ttctaatttg 1150gtggcactgg tataaccaca cattaaagtc agtagtacat ttttaaatga 1200gggtggtttt tttctttaaa acacatgaac attgtaaatg tgttggaaag 1250aagtgtttta agaataataa ttttgcaaat aaactattaa taaatattat 1300atgtgataaa ttctaaatta tgaacattag aaatctgtgg ggcacatatt 1350tttgctgatt ggttaaaaaa ttttaacagg tctttagcgt tctaagatat 1400gcaaatgata tctctagttg tgaatttgtg attaaagtaa aacttttagc 1450tgtgtgttcc ctttacttct aatactgatt tatgttctaa gcctccccaa 1500gttccaatgg atttgccttc tcaaaatgta caactaagca actaaagaaa 1550attaaagtga aagttgaaaa at 1572 341 318 PRT Homo Sapien 341 Met LeuSer Glu Ser Ser Ser Phe Leu Lys Gly Val Met Leu Gly 1 5 10 15 SerIle Phe Cys Ala Leu Ile Thr Met Leu Gly His Ile Arg Ile 20 25 30Gly His Gly Asn Arg Met His His His Glu His His His Leu Gln 35 4045 Ala Pro Asn Lys Glu Asp Ile Leu Lys Ile Ser Glu Asp Glu Arg 5055 60 Met Glu Leu Ser Lys Ser Phe Arg Val Tyr Cys Ile Ile Leu Val65 70 75 Lys Pro Lys Asp Val Ser Leu Trp Ala Ala Val Lys Glu ThrTrp 80 85 90 Thr Lys His Cys Asp Lys Ala Glu Phe Phe Ser Ser GluAsn Val 95 100 105 Lys Val Phe Glu Ser Ile Asn Met Asp Thr Asn AspMet Trp Leu 110 115 120 Met Met Arg Lys Ala Tyr Lys Tyr Ala Phe AspLys Tyr Arg Asp 125 130 135 Gln Tyr Asn Trp Phe Phe Leu Ala Arg ProThr Thr Phe Ala Ile 140 145 150 Ile Glu Asn Leu Lys Tyr Phe Leu LeuLys Lys Asp Pro Ser Gln 155 160 165 Pro Phe Tyr Leu Gly His Thr IleLys Ser Gly Asp Leu Glu Tyr 170 175 180 Val Gly Met Glu Gly Gly IleVal Leu Ser Val Glu Ser Met Lys 185 190 195 Arg Leu Asn Ser Leu LeuAsn Ile Pro Glu Lys Cys Pro Glu Gln 200 205 210 Gly Gly Met Ile TrpLys Ile Ser Glu Asp Lys Gln Leu Ala Val 215 220 225 Cys Leu Lys TyrAla Gly Val Phe Ala Glu Asn Ala Glu Asp Ala 230 235 240 Asp Gly LysAsp Val Phe Asn Thr Lys Ser Val Gly Leu Ser Ile 245 250 255 Lys GluAla Met Thr Tyr His Pro Asn Gln Val Val Glu Gly Cys 260 265 270 CysSer Asp Met Ala Val Thr Phe Asn Gly Leu Thr Pro Asn Gln 275 280 285Met His Val Met Met Tyr Gly Val Tyr Arg Leu Arg Ala Phe Gly 290

295 300 His Ile Phe Asn Asp Ala Leu Val Phe Leu Pro Pro Asn Gly Ser305 310 315 Asp Asn Asp 342 23 DNA Artificial Sequence SyntheticOligonucleotide Probe 342 tccccaagcc gttctagacg cgg 23 343 18 DNAArtificial Sequence Synthetic Oligonucleotide Probe 343 ctggttcttccttgcacg 18 344 28 DNA Artificial Sequence SyntheticOligonucleotide Probe 344 gcccaaatgc cctaaggcgg tatacccc 28 345 50DNA Artificial Sequence Synthetic Oligonucleotide Probe 345gggtgtgatg cttggaagca ttttctgtgc tttgatcact atgctaggac 50 346 25DNA Artificial Sequence Synthetic Oligonucleotide Probe 346gggatgcagg tggtgtctca tgggg 25 347 18 DNA Artificial SequenceSynthetic Oligonucleotide Probe 347 ccctcatgta ccggctcc 18 348 48DNA Artificial Sequence Synthetic Oligonucleotide Probe 348ggattctaat acgactcact atagggctca gaaaagcgca acagagaa 48 349 47 DNAArtificial Sequence Synthetic Oligonucleotide Probe 349 ctatgaaattaaccctcact aaagggatgt cttccatgcc aaccttc 47 350 48 DNA ArtificialSequence Synthetic Oligonucleotide Probe 350 ggattctaat acgactcactatagggcggc gatgtccact ggggctac 48 351 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 351 ctatgaaatt aaccctcactaaagggacga ggaagatggg cggatggt 48 352 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 352 ggattctaat acgactcactatagggcacc cacgcgtccg gctgctt 47 353 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 353 ctatgaaatt aaccctcactaaagggacgg gggacaccac ggaccaga 48 354 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 354 ggattctaat acgactcactatagggcttg ctgcggtttt tgttcctg 48 355 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 355 ctatgaaatt aaccctcactaaagggagct gccgatccca ctggtatt 48 356 46 DNA Artificial SequenceSynthetic Oligonucleotide Probe 356 ggattctaat acgactcactatagggcgga tcctggccgg cctctg 46 357 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 357 ctatgaaatt aaccctcactaaagggagcc cgggcatggt ctcagtta 48 358 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 358 ggattctaat acgactcactatagggcggg aagatggcga ggaggag 47 359 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 359 ctatgaaatt aaccctcactaaagggacca aggccacaaa cggaaatc 48 360 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 360 ggattctaat acgactcactatagggctgt gctttcattc tgccagta 48 361 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 361 ctatgaaatt aaccctcactaaagggaggg tacaattaag gggtggat 48 362 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 362 ggattctaat acgactcactatagggcccg cctcgctcct gctcctg 47 363 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 363 ctatgaaatt aaccctcactaaagggagga ttgccgcgac cctcacag 48 364 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 364 ggattctaat acgactcactatagggcccc tcctgccttc cctgtcc 47 365 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 365 ctatgaaatt aaccctcactaaagggagtg gtggccgcga ttatctgc 48 366 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 366 ggattctaat acgactcactatagggcgca gcgatggcag cgatgagg 48 367 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 367 ctatgaaatt aaccctcactaaagggacag acggggcaga gggagtg 47 368 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 368 ggattctaat acgactcactatagggccag gaggcgtgag gagaaac 47 369 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 369 ctatgaaatt aaccctcactaaagggaaag acatgtcatc gggagtgg 48 370 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 370 ggattctaat acgactcactatagggccgg gtggaggtgg aacagaaa 48 371 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 371 ctatgaaatt aaccctcactaaagggacac agacagagcc ccatacgc 48 372 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 372 ggattctaat acgactcactatagggccag ggaaatccgg atgtctc 47 373 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 373 ctatgaaatt aaccctcactaaagggagta aggggatgcc accgagta 48 374 47 DNA Artificial SequenceSynthetic Oligonucleotide Probe 374 ggattctaat acgactcactatagggccag ctacccgcag gaggagg 47 375 48 DNA Artificial SequenceSynthetic Oligonucleotide Probe 375 ctatgaaatt aaccctcactaaagggatcc caggtgatga ggtccaga 48 376 997 DNA Homo Sapien 376cccacgcgtc cgatcttacc aacaaaacac tcctgaggag aaagaaagag 50agggagggag agaaaaagag agagagagaa acaaaaaacc aaagagagag 100aaaaaatgaa ttcatctaaa tcatctgaaa cacaatgcac agagagagga 150tgcttctctt cccaaatgtt cttatggact gttgctggga tccccatcct 200atttctcagt gcctgtttca tcaccagatg tgttgtgaca tttcgcatct 250ttcaaacctg tgatgagaaa aagtttcagc tacctgagaa tttcacagag 300ctctcctgct acaattatgg atcaggttca gtcaagaatt gttgtccatt 350gaactgggaa tattttcaat ccagctgcta cttcttttct actgacacca 400tttcctgggc gttaagttta aagaactgct cagccatggg ggctcacctg 450gtggttatca actcacagga ggagcaggaa ttcctttcct acaagaaacc 500taaaatgaga gagtttttta ttggactgtc agaccaggtt gtcgagggtc 550agtggcaatg ggtggacggc acacctttga caaagtctct gagcttctgg 600gatgtagggg agcccaacaa catagctacc ctggaggact gtgccaccat 650gagagactct tcaaacccaa ggcaaaattg gaatgatgta acctgtttcc 700tcaattattt tcggatttgt gaaatggtag gaataaatcc tttgaacaaa 750ggaaaatctc tttaagaaca gaaggcacaa ctcaaatgtg taaagaagga 800agagcaagaa catggccaca cccaccgccc cacacgagaa atttgtgcgc 850tgaacttcaa aggacttcat aagtatttgt tactctgata caaataaaaa 900taagtagttt taaatgttaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 950aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa 997 377 219 PRTHomo Sapien 377 Met Asn Ser Ser Lys Ser Ser Glu Thr Gln Cys Thr GluArg Gly 1 5 10 15 Cys Phe Ser Ser Gln Met Phe Leu Trp Thr Val AlaGly Ile Pro 20 25 30 Ile Leu Phe Leu Ser Ala Cys Phe Ile Thr ArgCys Val Val Thr 35 40 45 Phe Arg Ile Phe Gln Thr Cys Asp Glu LysLys Phe Gln Leu Pro 50 55 60 Glu Asn Phe Thr Glu Leu Ser Cys TyrAsn Tyr Gly Ser Gly Ser 65 70 75 Val Lys Asn Cys Cys Pro Leu AsnTrp Glu Tyr Phe Gln Ser Ser 80 85 90 Cys Tyr Phe Phe Ser Thr AspThr Ile Ser Trp Ala Leu Ser Leu 95 100 105 Lys Asn Cys Ser Ala MetGly Ala His Leu Val Val Ile Asn Ser 110 115 120 Gln Glu Glu Gln GluPhe Leu Ser Tyr Lys Lys Pro Lys Met Arg 125 130 135 Glu Phe Phe IleGly Leu Ser Asp Gln Val Val Glu Gly Gln Trp 140 145 150 Gln Trp ValAsp Gly Thr Pro Leu Thr Lys Ser Leu Ser Phe Trp 155 160 165 Asp ValGly Glu Pro Asn Asn Ile Ala Thr Leu Glu Asp Cys Ala 170 175 180 ThrMet Arg Asp Ser Ser Asn Pro Arg Gln Asn Trp Asn Asp Val 185 190 195Thr Cys Phe Leu Asn Tyr Phe Arg Ile Cys Glu Met Val Gly Ile 200 205210 Asn Pro Leu Asn Lys Gly Lys Ser Leu 215 378 21 DNA ArtificialSequence Synthetic Oligonucleotide Probe 378 ttcagcttct gggatgtaggg 21 379 24 DNA Artificial Sequence Synthetic Oligonucleotide Probe379 tattcctacc atttcacaaa tccg 24 380 49 DNA Artificial SequenceSynthetic oligonucleotide probe 380 ggaggactgt gccaccatgagagactcttc aaacccaagg caaaattgg 49 381 26 DNA Artificial SequenceSynthetic oligonucleotide probe 381 gcagattttg aggacagcca cctcca 26382 18 DNA Artificial Sequence Synthetic oligonucleotide probe 382ggccttgcag acaaccgt 18 383 21 DNA Artificial Sequence Syntheticoligonucleotide probe 383 cagactgagg gagatccgag a 21 384 20 DNAArtificial Sequence Synthetic oligonucleotide probe 384 cagctgcccttccccaacca 20 385 18 DNA Artificial Sequence Syntheticoligonucleotide probe 385 catcaagcgc ctctacca 18 386 21 DNAArtificial Sequence Synthetic oligonucleotide probe 386 cacaaactcgaactgcttct g 21 387 18 DNA Artificial Sequence Syntheticoligonucleotide probe 387 gggccatcac agctccct 18 388 22 DNAArtificial Sequence Synthetic oligonucleotide probe 388 gggatgtggtgaacacagaa ca 22 389 22 DNA Artificial Sequence Syntheticoligonucleotide probe 389 tgccagctgc atgctgccag tt 22 390 20 DNAArtificial Sequence Synthetic oligonucleotide probe 390 cagaaggatgtcccgtggaa 20 391 17 DNA Artificial Sequence Syntheticoligonucleotide probe 391 gccgctgtcc actgcag 17 392 21 DNAArtificial Sequence Synthetic oligonucleotide probe 392 gacggcatcctcagggccac a 21 393 20 DNA Artificial Sequence Syntheticoligonucleotide probe 393 atgtcctcca tgcccacgcg 20 394 20 DNAArtificial Sequence Synthetic oligonucleotide probe 394 gagtgcgacatcgagagctt 20 395 18 DNA Artificial Sequence Syntheticoligonucleotide probe 395 ccgcagcctc agtgatga 18 396 21 DNAArtificial Sequence Synthetic oligonucleotide probe 396 gaagagcacagctgcagatc c 21 397 22 DNA Artificial Sequence Syntheticoligonucleotide probe 397 gaggtgtcct ggctttggta gt 22 398 20 DNAArtificial Sequence Synthetic oligonucleotide probe 398 cctctggcgcccccactcaa 20 399 18 DNA Artificial Sequence Syntheticoligonucleotide probe 399 ccaggagagc tggcgatg 18 400 23 DNAArtificial Sequence Synthetic oligonucleotide probe 400 gcaaattcagggctcactag aga 23 401 29 DNA Artificial Sequence Syntheticoligonucleotide probe 401 cacagagcat ttgtccatca gcagttcag 29 402 22DNA Artificial Sequence Synthetic oligonucleotide probe 402ggcagagact tccagtcact ga 22 403 22 DNA Artificial SequenceSynthetic oligonucleotide probe 403 gccaagggtg gtgttagata gg 22 40424 DNA Artificial Sequence Synthetic oligonucleotide probe 404caggccccct tgatctgtac ccca 24 405 23 DNA Artificial SequenceSynthetic oligonucleotide probe 405 gggacgtgct tctacaagaa cag 23406 26 DNA Artificial Sequence Synthetic oligonucleotide probe 406caggcttaca atgttatgat cagaca 26 407 31 DNA Artificial SequenceSynthetic oligonucleotide probe 407 tattcagagt tttccattggcagtgccagt t 31 408 21 DNA Artificial Sequence Syntheticoligonucleotide probe 408 tctacatcag cctctctgcg c 21 409 23 DNAArtificial Sequence Synthetic oligonucleotide probe 409 cgatcttctccacccaggag cgg 23 410 18 DNA Artificial Sequence Syntheticoligonucleotide probe 410 gccaggcctc acattcgt 18 411 23 DNAArtificial Sequence Synthetic oligonucleotide probe 411 ctccctgaatggcagcctga gca 23 412 24 DNA Artificial Sequence Syntheticoligonucleotide probe 412 aggtgtttat taagggccta cgct 24 413 19 DNAArtificial Sequence Synthetic oligonucleotide probe 413 cagagcagagggtgccttg 19 414 21 DNA Artificial Sequence Syntheticoligonucleotide probe 414 tggcggagtc ccctcttggc t 21 415 22 DNAArtificial Sequence Synthetic oligonucleotide probe 415 ccctgtttccctatgcatca ct 22 416 21 DNA Artificial Sequence Syntheticoligonucleotide probe 416 tcaacccctg accctttcct a 21 417 24 DNAArtificial Sequence Synthetic oligonucleotide probe 417 ggcaggggacaagccatctc tcct 24 418 20 DNA Artificial Sequence Syntheticoligonucleotide probe 418 gggactgaac tgccagcttc 20 419 22 DNAArtificial Sequence Synthetic oligonucleotide probe 419 gggccctaacctcattacct tt 22 420 23 DNA Artificial Sequence Syntheticoligonucleotide probe 420 tgtctgcctc agccccagga agg 23 421 21 DNAArtificial Sequence Synthetic oligonucleotide probe 421 tctgtccaccatcttgcctt g 21 422 3554 DNA Homo Sapien 422 gggactacaa gccgcgccgcgctgccgctg gcccctcagc aaccctcgac 50 atggcgctga ggcggccaccgcgactccgg ctctgcgctc ggctgcctga 100 cttcttcctg ctgctgcttttcaggggctg cctgataggg gctgtaaatc 150 tcaaatccag caatcgaaccccagtggtac aggaatttga aagtgtggaa 200 ctgtcttgca tcattacggattcgcagaca agtgacccca ggatcgagtg 250 gaagaaaatt caagatgaacaaaccacata tgtgtttttt gacaacaaaa 300 ttcagggaga cttggcgggtcgtgcagaaa tactggggaa gacatccctg 350 aagatctgga atgtgacacggagagactca gccctttatc gctgtgaggt 400 cgttgctcga aatgaccgcaaggaaattga tgagattgtg atcgagttaa 450 ctgtgcaagt gaagccagtgacccctgtct gtagagtgcc gaaggctgta 500 ccagtaggca agatggcaacactgcactgc caggagagtg agggccaccc 550 ccggcctcac tacagctggtatcgcaatga tgtaccactg cccacggatt 600 ccagagccaa tcccagatttcgcaattctt ctttccactt aaactctgaa 650 acaggcactt tggtgttcactgctgttcac aaggacgact ctgggcagta 700 ctactgcatt gcttccaatgacgcaggctc agccaggtgt gaggagcagg 750 agatggaagt ctatgacctgaacattggcg gaattattgg gggggttctg 800 gttgtccttg ctgtactggccctgatcacg ttgggcatct gctgtgcata 850 cagacgtggc tacttcatcaacaataaaca ggatggagaa agttacaaga 900 acccagggaa accagatggagttaactaca tccgcactga cgaggagggc 950 gacttcagac acaagtcatcgtttgtgatc tgagacccgc ggtgtggctg 1000 agagcgcaca gagcgcacgtgcacatacct ctgctagaaa ctcctgtcaa 1050 ggcagcgaga gctgatgcactcggacagag ctagacactc attcagaagc 1100 ttttcgtttt ggccaaagttgaccactact cttcttactc taacaagcca 1150 catgaataga agaattttcctcaagatgga cccggtaaat ataaccacaa 1200 ggaagcgaaa ctgggtgcgttcactgagtt gggttcctaa tctgtttctg 1250 gcctgattcc cgcatgagtattagggtgat cttaaagagt ttgctcacgt 1300 aaacgcccgt gctgggccctgtgaagccag catgttcacc actggtcgtt 1350 cagcagccac gacagcaccatgtgagatgg cgaggtggct ggacagcacc 1400 agcagcgcat cccggcgggaacccagaaaa ggcttcttac acagcagcct 1450 tacttcatcg gcccacagacaccaccgcag tttcttctta aaggctctgc 1500 tgatcggtgt tgcagtgtccattgtggaga agctttttgg atcagcattt 1550 tgtaaaaaca accaaaatcaggaaggtaaa ttggttgctg gaagagggat 1600 cttgcctgag gaaccctgcttgtccaacag ggtgtcagga tttaaggaaa 1650 accttcgtct taggctaagtctgaaatggt actgaaatat gcttttctat 1700 gggtcttgtt tattttataaaattttacat ctaaattttt gctaaggatg 1750 tattttgatt attgaaaagaaaatttctat ttaaactgta aatatattgt 1800 catacaatgt taaataacctatttttttaa aaaagttcaa cttaaggtag 1850 aagttccaag ctactagtgttaaattggaa aatatcaata attaagagta 1900 ttttacccaa ggaatcctctcatggaagtt tactgtgatg ttccttttct 1950 cacacaagtt ttagcctttttcacaaggga actcatactg tctacacatc 2000 agaccatagt tgcttaggaaacctttaaaa attccagtta agcaatgttg 2050 aaatcagttt gcatctcttcaaaagaaacc tctcaggtta gctttgaact 2100 gcctcttcct gagatgactaggacagtctg tacccagagg ccacccagaa 2150 gccctcagat gtacatacacagatgccagt cagctcctgg ggttgcgcca 2200 ggcgcccccg ctctagctcactgttgcctc gctgtctgcc aggaggccct 2250 gccatccttg ggccctggcagtggctgtgt cccagtgagc tttactcacg 2300 tggcccttgc ttcatccagcacagctctca ggtgggcact gcagggacac 2350 tggtgtcttc catgtagcgtcccagctttg ggctcctgta

acagacctct 2400 ttttggttat ggatggctca caaaataggg cccccaatgctatttttttt 2450 ttttaagttt gtttaattat ttgttaagat tgtctaaggccaaaggcaat 2500 tgcgaaatca agtctgtcaa gtacaataac atttttaaaagaaaatggat 2550 cccactgttc ctctttgcca cagagaaagc acccagacgccacaggctct 2600 gtcgcatttc aaaacaaacc atgatggagt ggcggccagtccagcctttt 2650 aaagaacgtc aggtggagca gccaggtgaa aggcctggcggggaggaaag 2700 tgaaacgcct gaatcaaaag cagttttcta attttgactttaaatttttc 2750 atccgccgga gacactgctc ccatttgtgg ggggacattagcaacatcac 2800 tcagaagcct gtgttcttca agagcaggtg ttctcagcctcacatgccct 2850 gccgtgctgg actcaggact gaagtgctgt aaagcaaggagctgctgaga 2900 aggagcactc cactgtgtgc ctggagaatg gctctcactactcaccttgt 2950 ctttcagctt ccagtgtctt gggtttttta tactttgacagctttttttt 3000 aattgcatac atgagactgt gttgactttt tttagttatgtgaaacactt 3050 tgccgcaggc cgcctggcag aggcaggaaa tgctccagcagtggctcagt 3100 gctccctggt gtctgctgca tggcatcctg gatgcttagcatgcaagttc 3150 cctccatcat tgccaccttg gtagagaggg atggctccccaccctcagcg 3200 ttggggattc acgctccagc ctccttcttg gttgtcatagtgatagggta 3250 gccttattgc cccctcttct tataccctaa aaccttctacactagtgcca 3300 tgggaaccag gtctgaaaaa gtagagagaa gtgaaagtagagtctgggaa 3350 gtagctgcct ataactgaga ctagacggaa aaggaatactcgtgtatttt 3400 aagatatgaa tgtgactcaa gactcgaggc cgatacgaggctgtgattct 3450 gcctttggat ggatgttgct gtacacagat gctacagacttgtactaaca 3500 caccgtaatt tggcatttgt ttaacctcat ttataaaagcttcaaaaaaa 3550 ccca 3554 423 310 PRT Homo Sapien 423 Met Ala LeuArg Arg Pro Pro Arg Leu Arg Leu Cys Ala Arg Leu 1 5 10 15 Pro AspPhe Phe Leu Leu Leu Leu Phe Arg Gly Cys Leu Ile Gly 20 25 30 AlaVal Asn Leu Lys Ser Ser Asn Arg Thr Pro Val Val Gln Glu 35 40 45Phe Glu Ser Val Glu Leu Ser Cys Ile Ile Thr Asp Ser Gln Thr 50 5560 Ser Asp Pro Arg Ile Glu Trp Lys Lys Ile Gln Asp Glu Gln Thr 6570 75 Thr Tyr Val Phe Phe Asp Asn Lys Ile Gln Gly Asp Leu Ala Gly80 85 90 Arg Ala Glu Ile Leu Gly Lys Thr Ser Leu Lys Ile Trp AsnVal 95 100 105 Thr Arg Arg Asp Ser Ala Leu Tyr Arg Cys Glu Val ValAla Arg 110 115 120 Asn Asp Arg Lys Glu Ile Asp Glu Ile Val Ile GluLeu Thr Val 125 130 135 Gln Val Lys Pro Val Thr Pro Val Cys Arg ValPro Lys Ala Val 140 145 150 Pro Val Gly Lys Met Ala Thr Leu His CysGln Glu Ser Glu Gly 155 160 165 His Pro Arg Pro His Tyr Ser Trp TyrArg Asn Asp Val Pro Leu 170 175 180 Pro Thr Asp Ser Arg Ala Asn ProArg Phe Arg Asn Ser Ser Phe 185 190 195 His Leu Asn Ser Glu Thr GlyThr Leu Val Phe Thr Ala Val His 200 205 210 Lys Asp Asp Ser Gly GlnTyr Tyr Cys Ile Ala Ser Asn Asp Ala 215 220 225 Gly Ser Ala Arg CysGlu Glu Gln Glu Met Glu Val Tyr Asp Leu 230 235 240 Asn Ile Gly GlyIle Ile Gly Gly Val Leu Val Val Leu Ala Val 245 250 255 Leu Ala LeuIle Thr Leu Gly Ile Cys Cys Ala Tyr Arg Arg Gly 260 265 270 Tyr PheIle Asn Asn Lys Gln Asp Gly Glu Ser Tyr Lys Asn Pro 275 280 285 GlyLys Pro Asp Gly Val Asn Tyr Ile Arg Thr Asp Glu Glu Gly 290 295 300Asp Phe Arg His Lys Ser Ser Phe Val Ile 305 310

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