CADHERIN MATERIALS AND METHODS

Abstract: DNA sequences encoding novel cadherins, designated cadherins-4 through -12, are disclosed along with methods and materials for the recombinant production of the same. Antibody substances specific for the novel cadherins and cadherin peptides are disclosed as useful for modulating the natural binding and/or regulatory activities of the cadherins.

Description: CADHERIN MATERIALS AND METHODS This application is a continuation-in-part of U. S . Patent Application Serial No. 07/872,643 filed on April 17, 1992. FIELD OF THE INVENTION The present invention relates, in general, to materials and methods relevant to cell-cell adhesion. More particularly, the invention relates to novel Ca + -dependent cell adhesion proteins, referred to as cadherins, and to polynucleotide sequences encoding the cadherins. The invention also relates to methods for inhibiting binding of the cadherins to their natural ligands/antiligands. BACKGROUND In vivo, cell-cell adhesion plays an important role in a wide range of events including morphogenesis and organ formation, leukocyte extravasion, tumor metastasis and invasion, and the formation of cell junctions. Additionally, cell-cell adhesion is crucial for the maintenance of tissue integrity, e.g., of the intestinal epithelial barrier, of the blood brain barrier and of cardiac muscle. Intercellular adhesion is mediated by specific cell adhesion molecules. Cell adhesion molecules have been classified into at least three -superfamilies including the immunoglobulin (Ig) superfamily, the integrin superfamily and the cadherin superfamily. All cell types that form solid tissues express some members of the cadherin superfamily suggesting that cadherins are involved in selective adhesion of most cell types. Cadherins have been generally described as glycosylated integral membrane proteins that have an N-terminal extracellular domain that determines binding specificity (the N-terminal 113 amino acids appear to be directly involved in binding), a hydrophobic membrane-spanning domain and a C-terminal cytoplasmic domain (highly conserved among the members of the superfamily) that interacts with the cytoskeleton through catenins and other cytoskeleton- associated proteins. Some cadherins lack a cytoplasmic domain, however, and appear to function in cell-cell adhesion by a different mechanism than cadherins that do have a cytoplasmic domain. The cytoplasmic domain is required for the binding function of the extracellular domain in cadherins that do have a cytoplasmic domain. Binding between members of the cadherin family expressed on different cells is mainly homophilic (i.e., a member of the cadherin family binds to cadherins of its own or a closely related subclass) and Ca 2+ -dependent. For recent reviews on cadherins, see Takeϊchi, Annu. Rev. Biochem. , 59: 237-252 (1990) and Takeichi, Science, 251, 1451-1455 (1991). The first cadherins to be described (E-cadherin in mouse epithelial cells, L-CAM in avian liver, uvomorulin in the mouse blastocyst, and CAM 120/80 in human epithelial cells) were identified by their involvment in Ca 2+ - dependent cell adhesion and by their unique immunological characteristics and tissue localization. With the later immunological identification of N-cadherin, which was found to have a different tissue distribution from E-cadherin, it became apparent that a new family of Ca 2+ -dependent cell-cell adhesion molecules had been discovered. The molecular cloning of the genes encoding mouse E- [see Nagafuchi et al, Nature, 329: 341-343 (1987)], chicken N- [Hatta et al, J. Cell Biol, 106: 873-881 (1988)], and mouse P-[Nose et al, EMBO J. 6: 3655-3661 (1987)] cadherins provided structural evidence that the cadherins comprised a family of cell adhesion molecules. Cloning of chicken L-CAM [Gallin et al , Proc. Natl Acad. Sci. USA, 84: 2808-2812 (1987)] and mouse uvomorulin [Ringwald et al, EMBO J., 6: 3647-3653 (1987)] revealed that they were identical to E-cadherin. Comparisons of the amino acid sequences of E-, N-, and P-cadherins showed a level of amino acid similarity of about 45 % -58 % among the three subclasses. Liaw et al, EMBO J., 9: 2701-2708 (1990) describes the use of PCR with degenerate olϊgonucleotides based on one conserved region of E-, N- and P-cadherins to isolate N- and P-cadherin from a bovine microvascular endothelial cell cDNA. The Liaw et al., supra, results implied that there were only E-, N-, and P-cadherins because no new cadherins were identified. Also in 1990, it was reported in Heimark et al , J. Cell Biol , 110: 1745-1756 (1990) that an antibody generated to bovine aortic endothelial cells recognized an intercellular junctional molecule designated V-cadherin which had a similar molecular weight to known cadherins and was able to inhibit Ca 2+ -dependent cell endothelial cell adhesion. The article did not disclose any sequence information for the protein recognized by the antibody. No further cadherin genes were described until the identification of eight of the novel cadherins claimed herein was reported in Suzuki et al , Cell Regulation, 2: 261-270 (1991). Subsequently, several other cadherins were described including chicken R-cadherin [Inuzuka et al , Neuron, 7: 69-79 (1991)], mouse M-cadherin [Donalies et al, Proc. Natl. Acad. Sci. USA, 88: 8024-8028 (1991)], chicken B-cadherin [Napolitano et al, J. Cell. Biol, 113: 893-905 (1991)], and T-cadherin [chicken in Ranscht et al, Neuron, 7: 391-402 (1991) and chicken and human in Patent Cooperation Treaty (PCT) International Publication No. WO 92/08731 published on May 29, 1992]. The determination of the tissue expression of the various cadherins reveals that each subclass of cadherins has a unique tissue distribution pattern. For example, E-cadherin is found in epithelial tissues while N-cadherin is found in nonepithelial tissues such as neural and muscle tissue. The unique expression pattern of the different cadherins is particularly significant when the role each subclass of cadherins may play in vivo in normal events (e.g. , the maintenance of the intestinal epithelial barrier) and in abnormal events (e.g., tumor metastatis or inflammation) is considered. Supression of cadherin function has been implicated in the progression of various cancers. See Shimoyama et al. , Cancer Res. , 52: 5770-5774 (1992). Different subclasses or combinations of subclasses of cadherins are likely to be responsible for different cell-cell adhesion events in which therapeutic detection and/or intervention may be desirable. Studies have also suggested that cadherins may have some regulatory activity in addition to adhesive activity. Matsunaga et al , Nature, 334, 62-64 (1988) reports that N- cadherin has neurite outgrowth promoting activity and Mahoney et al. , Cell, 67, 853-868 (1991) reports that the Drosophila fat tumor supressor gene, another member of the cadherin superfamily, appear to regulate cell growth. Expression of the cytoplasmic domain of N-cadherin without its extracellular domain has been shown in Kintner et al, Cell, 69: 229-236 (1992) to disrupt embryonic cell adhesion and in Fugimori et al, Mol Biol Cell, 4: Υ1-A1 (1993) to disrupt epithial cell adhesion. Thus, therapeutic intervention in the regulatory activities of cadherins expressed in specific tissues may also be desirable. There thus continues to exist a need in the art for the identification and characterization of additional cadherins participating in cell-cell adhesion and/or regulatory events. Moreover, to the extent that cadherins might form the basis for the development of therapeutic and diagnostic agents, it is essential that the genes encoding the proteins be cloned. Information about the DNA sequences and amino acid sequences encoding the cadherins would provide for the large scale production of the proteins and for the identification of the cells/tissues naturally producing the proteins, and would permit the preparation of antibody substances or other novel binding molecules specifically reactive with the cadherins that may be useful in modulating the natural ligand/antiligand binding reactions in which the cadherins are involved. SUMMARY OF THE INVENTION The present invention provides materials and methods that are relevant to cell-cell adhesion. In one of its aspects, the present invention provides purified and isolated polynucleotide sequences (e.g., DNA and RNA, both sense and antisense strands) encoding novel cadherins, cadherin-4 through -12. Preferred polynucleotide sequences of the invention include genomic and cDNA sequences " as well as wholly or partially synthesized DNA sequences, and biological replicas thereof (i.e., copies of purified and isolated DNA sequences made in vivo or in vitro using biological " reagents). Biologically active vectors comprising the polynucleotide sequences are also contemplated. The scientific value of the information contributed through the disclosures of the DNA and amino acid sequences of the present invention is manifest. For example, knowledge of the sequence of a cDNA encoding a cadherin makes possible the isolation by DNA/DNA hybridization of genomic DNA sequences that encode the protein and that specify cadherin-specific expression regulating sequences such as promoters, enhancers and the like. DNA/DNA hybridization procedures utilizing the DNA sequences of the present invention also allow the isolation of DNAs encoding heterologous species proteins homologous to the rat and human cadherins specifically illustrated herein. According to another aspect of the invention, host cells, especially eucaryotic and procaryotic cells, are stably transformed or transfected with the polynucleotide sequences of the invention in a manner allowing the expression of cadherin polypeptides in the cells. Host cells expressing cadherin polypeptide products, when grown in a suitable culture medium, are particularly useful for the large scale production of cadherin polypeptides, fragments and variants; thereby enabling the isolation of the desired polypeptide products from the cells or from the medium in which the cells are grown. The novel cadherin proteins, fragments and variants of the invention may be obtained as isolates from natural tissue sources, but are preferably produced by recombinant procedures involving the host cells of the invention. The products may be obtained in fully or partially glycosylated, partially or wholly de-glycosylated or non-glycosylated forms, depending on the host cell selected or recombinant production and/or post-isolation processing. Cadherin variants according to the invention may comprise polypeptide analogs wherein one or more of the specified (i.e. , naturally encoded) amino acids is deleted or replaced or wherein one or more nonspecified amino acids are added: (1) without loss, and preferably with enhancement, of one or more of the biological activities or immunological characteristics specific for a cadherin; or (2) with specific disablement of a particular ligand/antiligand binding function of a cadherin. Also contemplated by the present invention are antibody substances [e.g., monoclonal and polyclonal antibodies, chimeric and humanized antibodies, and antibody domains including Fab, Fab' and F(ab') 2 , single chain antibodies, and Fv or single variable domains] and other binding proteins or peptides specifically react with cadherins of the invention. Antibody substances can be developed using isolated natural, recombinant or synthetic cadherin polypeptide products or host cells expressing such products on their surfaces. The antibody substances may be utilized for purifying polypeptides of the invention, for determining the tissue expression of the polypeptides and as antagonists of the ligand/antiligand binding activities of the cadherins. Specifically illustrating antibody substances of the invention are the monoclonal antibodies produced by the hybridomas designated 30Q8A, 30Q4H, 45A5G, 30S2F and 45C6A which were all deposited with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852 on April 6, 1993 and were respectively assigned ATCC Deposit Nos. HB11316, HB11317, HB11318, HB11319 and HB11320. Also illustrating antibody substances of the invention is the monoclonal antibody produced by the hybridoma designated 30T11G which was deposited with the ATCC on April 8, 1993 and was assigned ATCC Deposit No. HB11324. The DNA and amino acid sequence information provided by the present invention makes possible the systematic analysis of the structure and function of the cadherins described herein and definition of those molecules with which the cadherins will interact on extracellular and intracellular levels. The idiotypes of anti-cadherin monoclonal antibodies of the invention are representative of such molecules and may mimic natural binding proteins (peptides and polypeptides) through which the intercellular and intracellular activities of cadherins are modulated. Alternately, they may represent new classes of modulators of cadherin activities. Anti-idiotypic antibodies, in turn, may represent new classes of biologically active cadherin equivalents. Methods for modulating cadherin activity may involve contacting a cadherin with an antibody (or antibody fragment), another polypeptide or peptide ligand (including peptides derived from cadherins or other proteins, or a novel peptide), or a small molecule ligand that specifically binds to a portion (extracellular or cytoplasmic) of the cadherin. Numerous aspects and advantages of the present invention will be apparent upon consideration of the following detailed description thereof, reference being made to the drawing wherein: FIGURE 1 is a bar graph illustrating the binding of polymorphomiclear neutrophils and T cells to fusion proteins comprising extracellular subdomains of cadherin-5. DETAILED DESCRIPTION The present invention is illustrated by the following examples wherein Example 1 describes the isolation of cDNA sequences encoding rat cadherins-4 through -11 and -13; Example 2 describes the isolation of cDNA sequences encoding the human homologs of rat cadherins-4, -5, -6, -8, -10, -11 and -13 and the isolation of a human cadherin not identified in rat, cadherin-12; Example 3 characterizes the relationship of cadherins of the invention to previously identified cadherins in terms of amino acid sequence and structure. The generation of polyclonal and monoclonal antibodies specific for cadherins of the invention is described in Example 4. Example 5 describes the construction of expression constructs comprising cadherin-4, -5 and -8 sequences, transfection of mammalian cells with the constructs and results of cell-cell adhesion assays performed with the transfected cells. Example 6 presents the results of assays for cadherin mRNA and protein expression in various mammalian tissues, cells and cell lines. The results of in vitro transendothelial migration assays involving cadherin-5 and assays of neutrophil and T-cell binding to cadherin-5 fusion protein are described in Example 7. Example 8 describes expression of cadherin-5 in the blood-brain barrier and Example 9 describes cadherin-5 peptides that are capable of increasing endothelim permeability. Example 10 describes the association of the cytoplasmic domain of cadherin-5 with plakoglobin. The disclosures of Suzuki et al, Cell Regulation, supra; Suzuki et άl., J. Cell Biol, 115, Abstract 72a (1991); Suzuki et al, Cell. Struc. Funct., 16, 605 (1991); and Tanihara et al, Invest. Ophthalmol Vis. Sci. , 32, 1013 (1991) are incorporated by reference herein for purposes of illustrating the background of the invention. Example 1 Partial cDNA clones encoding nine novel cadherins were isolated from rat brain and retina by PCR. Eight of the novel rat cadherin cDNAs were isolated using degenerate PCR primers based on highly conserved regions of the cytoplasmic domain of known cadherins and one was isolated using degenerate PCR primers based on moderately conserved regions of the extracellular domain of known cadherins. A. Preparation of Rat cDNA Total RNAs were prepared from rat brain by the guanidium isothiocyanate/cesium chloride method described in Maniatis et al , pp. 196 in Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory (1982). Brain poly(A) + RNAs were then isolated using an Invitrogen (San Diego, CA) FastTrack kit. Rat retina poly (A) + RNA was purchased from Clonetech (Palo Alto, CA). cDNA was synthesized from the poly(A) + RNA of both rat brain and retina using a cDNA synthesis kit (Boehringer Mannheim Corporation, Indianopolis, IN). B. Design and Synthesis of PCR Primers Corresponding to Cadherin Cytoplasmic Domain A first pair of degenerate oligonucleotide primers, listed below in IUPAC nomenclature, was designed to correspond to highly conserved sequences in the cytoplasmic domain of mouse N-, E-, and P-cadherins. Underlined sequences at the end of each oligonucleotide indicate an EcøRl site added to the primers to facilitate cloning of the fragments generated by PCR. Degenerate Primer 1 TAPPYD (SEQ ID NO: 1) 5' GAATTCACNGCNCCNCCNTAYGA 3' (SEQ ID NO: 2) Degenerate Primer 2 FKKLAD (SEQ ID NO: 3) 3' AARTTYTTYRANCGNCTCTTAAG 5' (SEQ ID NO: 4) The degenerate oligonucleotides were synthesized using the Applied Biosystems model 380B DNA synthesizer (Foster City, CA). C. Design and Synthesis of PCR Primers Corresponding to Cadherin Extracellular Domain A second pair of degenerate oligonucleotide primers, listed below in IUPAC nomenclature, was designed to correspond to moderately conserved sequences in the third subdomain of the extracellular domain of mouse N-, E-, and P-cadherins. The extracellular domains of the mouse N-, E- and P-cadherins have been characterized as having five internal subdomains, some of which may be involved in cadherin interaction with Ca 2+ . Underlined sequences at the end of each oligonucleotide indicate an EcøRl site added to the primers to facilitate cloning of the fragments generated by PCR. Degenerate Primer 3 K(P/G)(L/I/V)D(F/Y)E (SEQ ID NO: 5) 5' GAATTCAARSSNNTNGAYTWYGA 3' (SEQ ID NO: 6) Degerenate Primer 4 (N D)E(A/P)PXF (SEQ ID NO: 7) 3' TRCTYSGNGGNNNNAARCTTAAG 5' (SEQ ID NO: 8) D. Cloning of cDNA Encoding Eight Novel Rat Cadherins PCR amplification reactions of rat brain and retina cDNA were carried out either with degenerate primers I and 2 or with degenerate primers 3 and 4 under conditions essentially the same as those described in Saiki et al, Science, 239, 487-491 (1988). Briefly, 100 ng of brain or retina first strand cDNA was used as template for amplification by Taq DNA polymerase (--nternational Bioltechnology, New Haven, CT) using 10 μg of each primer set per reaction. PCR reactions were initiated by adding 2 units of Taq DNA polymerase to the reaction solution, after which 35 PCR reaction cycles were carried out. Reaction cycles consisted of denaturation performed at 94° C for 1.5 minutes, oligonucleotide annealing at45°C for 2 minutes, and elongation at 72 °C for 3 minutes. The resulting PCR fragments were separated by agarose gel electrophoresis, and DNA bands of the expected size were extracted from the gel and digested with EcøRl. The fragments were then cloned into the M13 vector (Boehringer Mannheim Corp., Indianapolis, IN) and E. coli JM101 cells were transformed with the resulting constructs. Individual clones were then isolated and sequenced. Sequencing of the DNAs was carried out using a sequenase kit (United States Biochemicals, Cleveland, OH) and the resulting DNA and deduced amino acid sequences of the clones were compared to sequences of known cadherins using the Microgenϊe program (Beckman, Fullerton, CA). Ten representative cDNA clones encoding cadherins were identified from the PCR reaction based on degenerate primers 1 and 2. Two clones corresponded to rat N-, and E-cadherins, but eight clones encoded previously undescribed cadherins, and were designated cadherins-4 through -11. The DNA and deduced amino acid sequences of the eight rat cytoplasmic domain cDNA clones are respectively set out in SEQ ID NOs: 9 and 10 (cadherin-4), SEQ ID NOs: 11 and 12 (cadherin-5), SEQ ID NOs: 13 and 14 (cadherin-6), SEQ ID NOs: 15 and 16 (cadherin-7), SEQ ID NOs: 17 and 18 (cadherin-8), SEQ ID NOs: 19 and 20 (cadherin-9), SEQ ID NOs: 21 and 22 (cadherin-10) and SEQ ID NOs: 23 and 24 (cadherin- 11). An additional novel cadherin was identified from the PCR reaction based on degenerate primers 3 and 4, and it was designated cadherin-13. The DNA and deduced amino acid sequences of the rat cadherin-13 fragment are respectively set out in SEQ ID NOs: 25 and 26. The PCR reaction based on degenerate primers 3 and 4 also amplified sequences which were later determined to be fragments of the extracellular domains of rat cadherins-4, -5, -6, -8, -9, -10, -11 and -13. The DNA and amino acid sequences of these extracellular fragments are respectively set out in SEQ ID NOs: 27 and 28 (cadherin-4), SEQ ID NOs: 29 and 30 (cadherin-6), SEQ ID NOs: 31 and 32 (cadherin-8), SEQ ID NOs: 33 and 34 (cadherin-9), SEQ ID NOs: 35 and 36 (cadherin-10), SEQ ID NOs: 37 and 38 (cadherin-11), SEQ ID NOs: 39 and 40 (cadherin-13). Larger cadherin-8 and -10 cDNAs were isolated from a rat brain cDNA library made in Uni-ZAP vector (Stratagene, La Jolla, CA) using labelled cadherin-8 extracellular domain PCR fragment (SEQ ID NO: 17) or cadherin-10 extracellular domain fragment (SEQ ID NO: 21) as probes. Two types of cadherin-8 cDNA clones were isolated. The first type encodes a full length cadherin, but the second type encodes a truncated protein the sequence of which diverges from the first type of cadherin-8 clone near the N-terminus of the fifth extracellular subdomain (EC5). The truncated clone contains a short stretch of unique sequence in the N-terminus of EC5 but lacks the remainder of EC5, the transmembrane domain and the cytoplasmic domain. DNA and deduced amino acid sequences of the full length clone are respectively set out in SEQ ID NOs: 41 and 42 and the DNA and deducted amino acid sequences of the truncated cadherin-8 clone are set out in SEQ ID NOs: 43 and 44. The cadherin-10 cDNA clone that was isolated has an open reading frame which begins at a region corrsponding to the middle of the first extracellular domain (EC1) of previously identified cadherins. The DNA and deduced amino acid sequences of the cadherin-10 clone are set out in SEQ ID NOs: 45 and 46. Example 2 Full length cDNAs encoding human homologs of rat cadherins-4, - 8, -11 and -13 and partial cDNAs encoding human homologs of rat cadherins-6 and -10 were isolated from a human fetal brain cDNA library (λZapII vector, Stratagene). A full length cDNA encoding a human homolog of rat cadherin-5 was isolated from a human placental cDNA library (λgtl 1 vector, Dr. Millan, La Jolla Cancer Research Foundation, La Jolla, CA). Probes for screening the human fetal brain and placental cDNA libraries were amplified by PCR from human brain cDNA (Dr. Taketani, Kansain Medical University, Moriguchϊ, Osaka, Japan) using the primers described in Example 1B-C. Probes consisting of human cadherin-4, -5, -6, -8, -10 and -11 sequences were generated using degenerate primers 1 and 2 and probes consisting of human cadherin-13 sequence were generated using degenerate primers 3 and 4. Amplification of the human fetal brain cDNA with degenerate primers 3 and 4 also generated a PCR fragment encoding a cadherin not isolated from rat, designated cadherin-12. PCR fragments encoding human cadherins-4, -5, -6, -8, -10, -11, - 12 and -13 were labelled with 32 P and used to probe the human fetal brain and placental cDNA libraries according to the plaque hybridization method described in Ausubel et al., Eds., Current Protocols in Molecular Biology, Sections 6.1.1 to 6.1.4 and 6.2.1 to 6.2.3, John Wiley & Sons, New York (1987). Positives were plaque-purified and inserts were cut out using an in vivo excision method. The inserts were then subcloned into the M13 vector (Boehringer Mannheim) for sequencing. Inserts consisting of full length cDNAs encoding human homologs of rat cadherins-4, -8, -11, -12 (putative) and -13 and partial cDNAs encoding human homologs of rat cadherins-6 and -10 were identified in clones from the human fetal brain cDNA library and a full length cDNA encoding a human homolog of rat cadherin-5 was identified in a clone from the human placental cDNA library. The DNA and deduced amino acid sequences of the human homologs are respectively set out in SEQ ID NOs: 47 and 48 (cadherin-4), SEQ ID NOs: 49 and 50 (cadherin-5), SEQ ID NOs: 51 and 52 (cadherin-6), SEQ ID NOs: 53 and 54 (cadherin-8), SEQ ID NOs: 55 and 56 (cadherin-10), SEQ ID NOs: 57 and 58 (cadherin-11), SEQ ID NOs: 59 and 60 (cadherin- 12), and SEQ ID NOs: 61 and 62 (cadherin-13). Example 3 Comparison of the full-length sequences of the novel human cadherins described in Examples 1 and 2 with sequences of previously described cadherins and cadherin-related proteins provides support for the proposal that cadherins can be divided into at least three subgroups based on amino acid sequence identity and/or domain structure. Identity values for one possible alignment of the sequences of the extracellular domains of selected human cadherins are presented in Table 1 below. Based on such sequence alignments and on the fact that certain combinations of cadherin sequences seem to have conserved stretches of amino acids when aligned, one subgroup of cadherins may include E-cadherin, N- cadherin, P-cadherin and cadherin-4, while a second subgroup may include cadherin-5, cadherin-8, cadherin-11 and cadherin-12. Cadherins-6, -7, -9 and -10 may also be included with the second subgroup based on their partial amino acid - sequences disclosed herein. The amino acid sequence of cadherin-4 exhibits especially high amino acid sequence identity with that of R-cadherin (92%), indicating that cadherin-4 may be the human homolog of chicken R-cadherin. All cadherins in these two subgroups have a similar structure. Following an initiation codon, each has a signal sequence, prosequence, proteolytic cleavage site of precursor protein, an extracellular domain (which comprises five subdomains EC1-5), a transmembrane sequence and a cytoplasmic domain. For cadherin-5, these sequences/domains appear to correspond to about the following amino acid positions of SEQ ID NO: 50: 1-24 (signal sequence), 25-43 (prosequence), 44- ' 147 (EC1), 148-254 (EC2), 255-368 (EC3), 369-475 (EC4), 476-589 (EC5), 590- 616 (transmembrane sequence) and 617-780 (cytoplasmic domain). Cadherin-13, T-cadherin and V-cadherin may be representative of a third subgroup of cadherins. Cadherin-13 consists of a cadherin-like extracellular domain, but has no domains that would correspond to the typical transmembrane or cytoplasmic domains of other cadherins. Even though about 10% of the clones obtained by PCR using degenerate primers 3 and 4 were cadherin-13 clones, none of the clones included sequences corresponding to a cytoplasmic domain. An attempt to isolate a cDNA that contained this region by PCR using a primer corresponding to the most C-terminal region of cadherin-13 available and a mixed oligonucleotide primer corresponding to a well-conserved amino acid sequence of the cytoplasmic domain of cadherins failed to generate any product with the anticipated molecular weight. A similar protein, T-cadherin, has been identified in chicken which also lacks the typical cadherin cytoplasmic domain. The amino acid sequence identity between the two molecules is about 80%. Cadherin-13 may be the human homologue of chicken T-cadherin or may be a closely related molecule. Human cadherin-13 and avian T-cadherin may also both be closely related to V-cadherin. A 29-amino acid amino terminal sequence of bovine N-cadherin is similar to the start of the precursor region of cadherin-13 (93%) and T-cadherin (79%). N-cadherin is a 135 KD protein which appears to be restricted in tissue distribution to endothelium. In constrast, mature T-cadherin has a molecular weight of 95 KD and shows a wide tissue distribution. Both V- cadherin and T-cadherin are linked to the cell membrane through phosphoinositiol. Example 4 Polyclonal and/or monoclonal antibodies specific for cadherins of the invention were generated. A. Generation of Polyclonal Antibodies Bacterial fusion proteins consisting of maltose binding protein fused to portions of cadherin extracellular subdomains (either human cadherin-4, -5 or -11, or rat cadherin-8) were generated and subsequently used for the generation of polyclonal antibodies. A cDNA fragment coπesponding to a 40 KD portion of the extracellular domain of human cadherin-5 (nucleotides 535 to 1527 of SEQ ID NO: 49) was synthesized by PCR from the full-length human cadherin-5 cDNA described in Example 2. The fragment was subcloned into the multicloning site {EcόRl-Xbal) of the pMAL-RI plasmid vector [New England Biolabs Inc. (NEB), Beverly, MA]. The resulting construct encodes maltose binding protein fused to the extracellular domain of cadherin-5. Constructs encoding maltose binding protein fused to the three N-terminal subdomains of human cadherin-4, rat cadherin-8 and human cadherin- 11 were generated by similar methods. E. coli NM522 cells (Stratagene) were then transformed with one of the fusion protein constructs and grown in quantity. After disruption of E. coli cells, the individual fusion proteins were purified by affinity column chromatography using amylose resin (NEB) according to the instructions of the manufacturer. When subjected to SDS-PAGE, the purified fusion proteins each showed essentially one band of the expected size. A total of five hundred μg of a fusion protein in Freund's complete adjuvant was injected into rabbits at four subcutaneous sites. Subsequent injections were carried out at three week intervals using 100 μg of the fusion protein in Freund's incomplete adjuvant also at four subcutaneous sites. The resulting polyclonal sera generated from immunization of rabbits with cadherin-4, -5 or -8 fusion protein were collected and tested for specificity on L cells transfected with the appropriate cadherin sequence (see Example 5). Polyclonal serum generated from immunization of rabbits with cadherin-11 was also collected. Immunoblotting of various cell types showed that the The anti- cadherin-4 polyclonal serum reacts with protein of about 130 KD in L cells transfected with full length cadherin-4 cDNA and in rat brain. Cadherin-5- specific serum reacts with a protein of about 135 KD in L cells transfected with a full length cadherin-5 DNA and with a protein of about 135 KD in human umbilical vein endothelial cells (HUVEcs). The serum does not react with MDCK cells that expressed high levels of E-cadherin. In bovine aortic endothelial cells, the anti-cadherin-5 serum reacts with a protein of about 120 KD. Additionally, the anti-cadherin-5 serum reacts with a protein which has the same molecular weight in rat brain endothelial cells in culture. The cadherin-8 polyclonal antibody detected a strong band of about 90 KD and a weak band of about 130 KD in rat brain. B. Generation of Monoclonal Antibodies Specific for Human Cadherin-5 Monoclonal antibodies to cadherin-5 were prepared using bacterial fusion proteins containing subdomains of the extracellular domain of human cadherin-5 as immunogens. The fusion proteins prepared included maltose binding protein and the extracellular subdomains 1-2 (EC 1-2) or extracellular subdomains 2-4 (EC2-4) of cadherin-5 in the bacterial expression vector pMAL (NEB). The two fusion proteins were expressed in bacteria and purified on amylose-sepharose as described in foregoing section on generation of polyclonal antibodies. The purified fusion proteins were used separately to immunize mice at two subcutaneous sites (100 μg of fusion protein per mouse in Freund's complete adjuvant). The mice then were subcutaneously immunized with Freund's incomplete adjuvant. The spleen from each mouse was removed sterility and treated in the same manner. Briefly, a single-cell suspension was formed by grinding the spleen between the frosted ends of two glass microscope slides submerged in serum free RPMI 1640 supplemented with 2 mM L-glutamine, 1 mM sodium pyruvate, 100 units/ml penicillin and 100 mg/ml streptomycin (RPMI) (Gibco, Canada). The cell suspension was filtered through a sterile 70-mesh cell strainer, and washed twice by centrifuging at 200 g for 5 minutes and resuspending the pellet in 20 ml serum free RPMI. Thymocytes taken from 3 naive Balb/c mice were prepared in a similar manner. NS-1 myeloma cells, kept in log phase in RPMI with 11% fetal bovine serum (FBS) Cyclone Laboratories, Inc., Logan, UT) for three days prior to fusion, were centrifuged at 200 g for 5 minutes, and the pellet was washed twice as described for the mouse spleen cells. After washing, the spleen cells and myeloma cells were brought to a final volume of 10 ml in serum free RPMI, and 10 μl of that final volume was diluted 1: 100 in serum free RPMI. Twenty μl of each dilution was removed, mixed with 20 μl 0.4% trypan blue stain in 0.85% saline, loaded onto a hemacytometer and counted. Two x 10 8 spleen cells were combined with 4 x 10 7 NS-1 cells, centrifuged and the supernatant was aspirated. The cell pellets were dislodged by tapping the tubeand 2 ml of 37X PEG 1500 (50% in 75 mM Hepes, pH 8.0) (Boehringer Mannheim) was added with stirring over the course of 1 minute, followed by adding 14 ml of serum free RPMI over 7 minutes. An additional 16 ml RPMI was added and the cells were centrifuged at 200 g for 10 minutes. After discarding the supernatant, the pellet was resuspended in 200 ml RPMI containing 15% FBS, 100 mM sodium hypoxanthine, 0.4 mM aminopterin, 16 mM thymidine (HAT) (Gibco), 25 units/ml IL-6 (Boehringer Mannheim) and 1.5 x 10 6 thymocytes/ml (plating medium). The suspension was dispensed into ten 96-well flat bottom tissue culture plates at 200 ml/well. Cells in plates were fed on days 2, 4, and 6 days post-fusion by aspirating approximately 100 ml from each well with an 18 G needle, and adding 100 ml/well plating medium described above except containing 10 units/ml IL-6 and lacking thymocytes. Fusions 30 (from a mouse immunized with EC2-4) and 45 (from a mouse immunized with EC 1-2) were screened initially by antibody capture ELISA, testing for presence of mouse IgG. Secondary screening of fusions 30 and 45 consisted of assays using plates coated with a monolayer of fixed endothelial cells for ELISAs. HUVEcs, Lewis rat brain endothelial cells (LeBCE), and bovine aortic endothelial cells (BAE) were allowed to grow in 96- well flat bottom tissue culture microtiter plates until the bottom of well was completely covered with a monolayer of cells. Plates were washed twice with 100 μl/well of Ca 2+ /Mg 2+ free PBS (CMF-PBS) and aspirated completely. Cells were then fixed with 100 μl/well of 3% p-Formaldehyde, 1 % Sucrose in CMF- PBS at room temperature for 30 minutes. Cells were then permeablized with approximately 250 μl/well of CSK buffer (0.5% Triton 100, lOOmM NaCl, lOmM PIPES, 2mM MgCl) and incubated at room temperature for 30 minutes. Plates were blocked with 250 μl/well of 2% BSA in IX CMF-PBS (blocking solution) and incubated at 37 °C for 60 minutes. Blocking solution was aspirated and 50 to 100 μl/well of supernatant from fusion plates was added. Plates were incubated at room temperature for 60 minutes and then were washed one time with 250 μl/well of 0.5 % BSA in CMF-PBS (wash solution 1) and two times with 250 μl/well of CMF-PBS (wash solution 2). One hundred fifty μl of horseradish peroxidase conjugated goat anti-mouse IgG(fc) (Jackson ImmunoResearch, West Grove, PA) diluted 1:3500 in PBST was added and plates were incubated at room temperature for 60 minutes. Plates were washed as before and 150 μl substrate consisting of lmg/ml o-phenylene diamine (Sigma) and 0.1 ml/ml 30% H 2 O 2 in lOOmM Citrate, pH 4.5 was added. The color reaction was stopped after 30 minutes with the addition of 50 μl of 15 % H 2 SO 4 . A 490 was read on a plate reader (Dynatech). About 20 positive wells were identified for each fusion and were subsequently cloned. Hybridomas were screened in cloning steps in an ELISA assay by testing for reactivity of monoclonals to the cadherin-5 EC2-4 fusion protein and excluding maltose binding protein reactive monoclonals. Immulon 4 plates (Dynatech, Cambridge, MA) were coated at 4°C with 50 μl/well fusion protein diluted to 0.1 μg/well (for fusion protein) and to 0.2 μg/well (for maltose binding protein alone) in 50mM carbonate buffer, pH 9.6. Plates were washed 3 times with PBS, 0.05% Tween 20 (PBST) and 50 μl hybridoma culture supernatant was added. After incubation at 37 "C for 30 minutes, and washing as above, 50 μl of horseradish peroxidase conjugated goat anti-mouse IgG(fc) (Jackson ImmunoReseach, West Grove, PA) diluted 1:3500 in PBST was added. Plates were incubated at 37 °C for 30 minutes and washed 4 times with PBST. One hundred μl substrate consisting of 1 mg/ml o-phenylene diamine (Sigma Chemical Co., St. Louis, MO) and 0.1 μl 30% H 2 O 2 in 100 mM citrate, pH 4.5 was added. The color reaction was stopped after 5 minutes with the addition of 50 μl of 15% H 2 SO 4 . Absorbance at 490 nm was determined using a plate reader. The hybridomas designated 30Q8A (ATCC HB11316), 30Q4H (ATCC HB11317), 45A5G (HB11318), 30S2F (HB11319), 45C6A (HB11320), 30T11G (ATCC HB11324), 30M8G, 30O6E and 30R1A] were identified as reactive with endothelial cells and with the cadherin-5 EC2-4 fusion protein. The hybridomas were cloned twice by limiting dilution and grown in ascites. The monoclonal antibodies produced by the hybridomas were isotyped in an ELISA assay. The results of the assay are presented in Table 2 below. C. Subdomain Specificity of C5 Specific Monoclom-l Antibodies To determine if the hybridomas produced monoclonal antibodies reactive with unique epitopes of the extracellular domain of C5, the monoclonal antibodies were purified, biotinylated, and tested in a cross competition ELISA. Immulon IN 96-well plates were coated with either EC1-2 or EC2-4 cadherin-5 fusion protein at 0.2 μg/ml in 50 μl 50mM ΝaCO 3 , pH 9.6 overnight at 4°C. The wells were aspirated and washed three times with PBS/0.05% Tween 20. The plate was then blocked with 50 μl/well PBS , 2 % BSA (Sigma) for 30 minutes at 37° C. Monoclonal antibodies were purified from hybridoma supematants over a protein A-Sepharose column and the eluted antibody was dϊalyzed against 0.1M NaCO 3 pH 8.2. One mg/ml of antibody was reacted with 60 μl of a 1 mg/ml stock solution in DMSO of NHS-biotin (Pierce Chemical Co., Rockford, IL) for 1 hour at room temperature and the reaction was stopped by dialysis overnight at 4°C against CMF/PBS. The biotinylated antibodies in PBS/0.05% Tween 20 were then added as primary antibody (50 μl/well) to a plate coated with fusion protein and incubated for 30 minutes at 37° C. The plate was then aspirated and washed three times with PBS/0.05% Tween 20. Peroxidase-conjugated strepavidin in PBS/Tween was added 50 μl/well and incubated for 30 minutes at 37° C. The plate was aspirated and washed three times in PBS/0.05% Tween 20, and o-phenylenediamine in lOOmM citrate buffer and hydrogen peroxide was added at 100 μl/well. The plate was developed at room temperature for 5-15 minutes. The reaction was stopped with 50 μl/well 15% sulfuric acid and the plate was read on a plate reader. Results of the assay are presented in Table 2 below. To confirm subdomain specificity, the cadherin-5 fusion proteins ECl-2 and EC2-4 were run on SDS-PAGE (10%) and immunoblotted with the cadherin-5 specific monoclonal antibodies. Table 2 below set outs the domain specificity and isotype of the cadherin-5 specific monoclonal antibodies. Competition assays were carried out as described above for assays for binding to cadherin-5 EC2-4 fusion protein except that unlabelled primary cadherin-5 specific monoclonal antibodies (or mouse IgG) were added 30 minutes prior to addition of biotinylated cadherin-5 specific monoclonal antibodies. Monoclonal antibodies produced by the hybridomas 30M8G, 30O6E and 30RIA compete for a site that is near or identical to the binding site of the antibody produced by hybridoma 30Q4H. Example 5 Human cadherins-4 and -5 and rat cadherin -8 were expressed in mouse fibroblast L cells (ATCC CCL1.3) which do not normally express cadherins. A. Construction of Expression Vectors The cDNA sequences encoding human cadherins-4 and -5 which are described in Example 2 and the cDNA sequence encoding rat cadherin-8 which is described in Example 1 were subcloned into the multicloning site of expression vector pRC/RSV (Envitrogen). Cadherin-4 DNA sequences were isolated by an in vivo excision procedure from the λZapII clone (described in Example 2) containing the entire coding sequence of cadherin-4. Using a helper virus, the sequences were excised from λZapπ in the form of Bluescript plasmid. The plasmid was then cut with Hin ΩI and blunt-ended with T4 polymerase. The resulting DNA fragment was redigested with -5ζpel to generate a cadherin-4 cDNA fragment having a blunt end and a Spel sticky end. The fragment was purified by agarose gel electrophoresis and subcloned into the pRC/RSV expression vector that had been previously digested with Spel and Xbal (the Xbal end was blunt-ended with T4 polymerase). The λgtll clone containing the entire coding sequence of cadherin- 5 (described in Example 2) was cut with EcøRl and the resulting fragment containing the cadherin-5 sequences was purified by agarose gel electrophoresis. The purified fragment was then subcloned into the EcøRl site of the Bluescript plasmid. Cadherin-5 sequences were cut from the resulting construct with HincK and Xbal and subcloned into the Notl-Xbal site of the pRC/RS V vector. The full length cDNA encoding rat cadherin-8 was excised from the Uni-ZAP clone described in Example 1 by digestion with Kpnl, followed by blunt-ending and re-digestion with Spel. The cadherin-8 encoding fragment was purified by agarose gel electrophoresis and was subcloned into the pRC/RSV vector which had been digested with Xbal, blunt-ended and redigested with Spel. B. Transfection of L Cells Mouse fibroblast L cells were transfected with the human cadherin- 4 and -5 and rat cadherin-8 expression constructs by a Ca + phosphate precipitation method and stable transfectants were obtained by G418 selection. Cadherin-4 and -8 transfectant cells showed a morphology similar to that of parental L cells (fibroblastic), but cadherin-5 transfectant cells exhibited a flattened morphology. Neuro 2a cells (ATCC CCL131) were also transfected by a Ca 2+ phosphate precipitation procedure with the cadherin-4 and cadherin-8 expression constructs. Cadherin-4 transfectants showed epithelial structure, suggesting that cadherin-4 has activity in epithelial structure formation and may be involved in the neural tissue development. C. Northern and Western Blot Assays of Cadherin mRNA and Protein Expression in Transfected Cells Both cadherin-4, -5 and -8 transfectants showed mRNA of the expected size of 3.5 kb, 3.2 kb and 3 kb, respectively, in Northern blot analysis using the appropriate full length human cDNAs as a probe. (See Example 6A for a description of the Northern blot assay.) For Western blots, cadherin-4, -5 and -8 transfectants were washed with PBS and SDS-PAGE sample buffer was added directly to the cells. SDS-PAGE (Laemmli) was carried out and and gels were blotted electrophoretically onto PVDF membrane. The membranes were incubated in TBS containing 5% skim milk for 2 hours at room temperature and then were incubated with the appropriate polyclonal antibody in TBS containing 0.05 % Tween 20 for 1 hour at room temperature. After four washes (of 5 minutes each) with TBS containing 0.05% Tween 20, the membranes were incubated with alkaline phosphatase conjugated anti-rabbit IgG antibody (Promega Corp., Madison, WI) in TBS containing 0.05% Tween 20 for 1 hour at room temperature. The membranes were then washed again four times with TBS containing 0.05% Tween 20 at room temperature and developed by using Promega Western blue. Cadherin-4, -5 and -8 polyclonal antibodies each reacted with a band of about 130 KD. D. Calcium Protection from Trypsin Digestion Since cadherins have been shown to be protected from trypsin digestion by Ca 2+ , the effect of Ca 2+ on trypsin treatment (0.01 % soybean trypsin for 30 minutes at 37 °C) of human cadherin-4 and -5 and rat cadherin-8 expressed on the surface of transfected L cells was examined. Two mM Ca 2+ protected the cadherin-4 from the trypsin digestion, but cadherin-5 and cadherin-8 were digested easily even in the presence of 1-5 mM of Ca 2+ . E. Cell-Cell Adhesion Assay The cell-cell adhesion activity of the transfected cells was assayed by a re-aggregation assay as described in Yoshϊda-Noro et al , Devel Biol , 101, 19-27 (1984). Briefly, transfectants were grown to near confiuency and then dispersed into single cells with mild trypsin treatment (0.01% for 15 minutes) in the presence of 2mM Ca 2+ . After washing, the trypsinized cells were incubated in Hepes buffered saline (HBS) containing 2mM CaCl 2 , 1% BSA and 20 μg/ml deoxynuclease on a rotary shaker at 50 rpm for 30 to 60 minutes and then cell aggregation was monitored. Cadherin-4 transfectant cells aggregated within 30 minutes and formed relatively large aggregates, whereas cadherin-5 transfectant - cells did not aggregate under the same conditions. However, cadherin-5 transfectants gradually re-aggregated and formed relatively small aggregate after prolonged incubation (4-5 hours or more). Similarly, cadherin-8 transfectants did not show significant cell adhesion activity. Parental L cells did not show cell adhesion under the same conditions. The sensitivity of cadherin-5 and cadherin-8 to trypsin digestion may account for the reduced cell adhesion seen in the reaggregation assay because the transfected L cells are initially dispersed with trypsin in the assay. Example 6 The expression of mRNAs encoding cadherins of the invention was examined in rat brain, kidney, liver, lung and skin and in various human cells by Northern blot analysis. The expression of cadherin protein was also examined in endothelial cells and leukocytes by immunofluorescence or immunoblotting. A. Northern Blot Assays of Rat Tissue and Human Cells Poly(A) + RNA from rat brain, kidney, liver, lung and skin was prepared as described in Example 1 for rat brain. The RNA preparations were then electrophoresed in an 0.8% agarose gel under denaturing conditions and transfeπed onto a nitrocellulose filter. Northern blot analyses were carried out according to a method described in Thomas, Proc. Natl. Acad. Sci. USA, 77, 5201-5202 (1980). Filters were hybridized with rat cadherin PCR fragments (described in Example 1) labeled with 32 P, including fragments coπesponding to cadherins-4 through -11. The final hybridization wash was in 0.2X standard saline citrate containing 0.1 % sodium dodecyl sulfate at 65 °C for 10 minutes. Cadherin-4 and cadherin-8 through -10 mRNAs were detected only in rat brain. The cadherin-8 PCR fragment hybridized to a major band of about 3.5 kb and a minor band of about 4.5 kb in rat brain. The mRNAs detected may be alternative splicing products and may coπespond to the truncated and full length cadherin-8 clones described in Example 1. Cadherin-6 and -7 probes gave weak signals on rat brain mRNA even after prolonged exposure. Cadherins-5, -6 and -11 mRNAs were detected in rat brain and other rat tissues including cadherin-5 mRNA in lung and kidney, cadherin-6 mRNA in kidney, and cadherin- 11 mRNA in liver. The expression of cadherin-8 and -11 in cultured human SK-N-SH neuroblastoma cells (ATCC HTB11), U251MG glioma cells and Y79 retinoblastoma cells (ATCC HTB18) was also assayed by Northern blot. Human cDNAs encoding cadherins-8 and -11 (described in Example 2) were labelled with 32 P and used as probes of poly(A) + RNA prepared from the cells using an Invitrogen FastTrack kit. The Northern blot procedure detected cadherin-8 RNA in the neuroblastoma and retinoblastoma cell lines, while cadherin-11 RNA was detected only in neuroblastoma cells. These results indicate that at least some of the cadherins of the invention are expressed in neurons and glial cells and/or their precursor cells. Cadherin-5 RNA was detected by Northern blot assay of HUVECs (Clonetics), but was not detected in A431 human epidermoid carcinoma cells (ATCC CRL1555) or IMR90 human fibroblast cells (ATCC CCL186). B. Immunoflourescence of Endothelial Cells and Immunoblotting of Leukocytes Cultured endothelial cells isolated from bovine aorta, bovine brain microvasculature and human umbilical vein were subjected to immunofluorescence microscopy using anti-C5 polyclonal antibodies. Cadherin-5 protein at the cell junctions which was in close association with the peripheral actin microfilaments was labelled. In contrast, when freshly isolated leukocytes (human PMN, lymphocytes and monocytes) or the monocyte-like cell line U937 were analyzed for the expression of cadherin-5 by immunoblotting using polyclonal antibodies and a monoclonal antibody (30O6E) to cadherin-5, no cadherin-5 was detected. Furthermore, using a pan-cadherin antibody [Geiger et al, J. Cell Science, 97: 607-614 (1990)] specific for the cytoplasmic tail, no other cadherins were detected in these cell populations. Example 7 Three in vitro transendothelial migration assays were utilized to show that cadherin-5 may participate in the movement of leukocytes across the intercellular junctions of endothelium. A. Transmigration Assays The migration of leukocytes (either human polymorphonuclear neutrophils or rat T cells) was followed for specific periods of time (15 minutes for PMNs and 2 hours for T cells). Immunofluorescent labeling of leukocytes using antibodies to specific cellular markers was used distinguish between leukocytes and endothelium. The polyclonal antibodies described in Example 4 were used to measure changes in the distribution of cadherin-5. An antibody (Novocastra Laboratories Ltd., United Kingdom) to PE-CAM1 (CD31) which is an intercellular junction molecule in endothelium was used as a control. The role of cadherin-5 in the transmigration of polymorphonuclear neutrophils (PMNs) across HUVEcs was analyzed. The system utilized, which is described in Furie et al, J. Immunol , 143: 3309-3317 (1989), has been characterized with regard to electrical resistance of the endothelium and the adhesion molecules used in transmigration. HUVEcs were isolated in the absence of growth factor and cultured on human amniotic connective tissue in a two- chamber system. PMN migration on ILljS-treated HUVEcs has previously been shown to involve E-selectin and /5 2 integrins (CD11/CD18). See Furie et al, J. Immunol, 148: 2395-2484 (1992). In the first assay, transmigration of PMNs was followed as an 11 minute time course on HUVEcs pretreated for four hours with ILljS (1.5 U/ml) (Collaborative Research Inc., Beford, MA). Prior to addition of neutrophils, antibodies to cadherin-5 heavily labelled the cell junctions of the HUVEcs in a continuous pattern. Pretreatment of the endothelial monolayer with ILlβ had no effect on the distribution of cadherin-5 in the HUVEc monolayer compared to a control untreated culture. In the second assay, chemotaxis of PMNs across HUVEcs was stimulated by leukotriene B 4 (LTB 4 ) (Sigma) which was placed in the bottom chamber at 10 "7 M while neutrophils were added to the upper chamber. Chemotaxis of PMNs to LTB 4 across the endothelial monolayer was previously shown to be blocked by antibodies to CDlla, CDl lb and ICAM-1. [See Furie etal, Blood, 78: 2089-2097 (1991)] In both assays, PMNs were identified with anti-CD45 antibody (Becton Dickinson, San Jose, CA). In both assays during the 11-minute time course, the majority of the PMNs that adhered also transmigrated. Addition of neutrophils caused a rapid redistribution and regional loss of cadherin-5 even at the earliest time point (3 minutes). CD31 was also lost at sites of disruption of the monolayer, but in general appeared to be more stable during the transmigration process. The loss of cadherin-5 is probably the result of proteases released from the neutrophils during transmigration. i a third assay, CD4 antigen activated rat T cells were utilized instead of PMNs (for a two-hour time course). Rat brain microvascular endothelium was grown on Transwell 5 micron polycarbonate membranes (Costar, Cambridge, MA). T cells were identified using an anti-CD4 antibody (Serotec, Indianapolis, IN). In this assay, the loss of cadherin-5 immunolabeling did not occur during transendothelial migration even though 10% of the T cells had crossed the endothelium after two hours. These results demonstrate differential effects of PMN versus T cells on intercellular junctions during tranendothelial migration . Analysis by confocal microscopy suggests that CD4 antigen-activated T cells and PMNs have a ligand that is able to interact with cadherin-5 on the endothelium during transmigration. Photomicrographs from confocal analysis show that during leukocyte transendothelial migration leukocytes can be found spanning the intercellular junction. The leukocyte separates the cell junction and cadherin-5 remains on adjacent cells even though the endothelial cells are not in contact. B. Adhesion of PMNs and T Cells to Cadherin-5 To quantitate the binding of PMNs and activated T-cells to cadherin-5, a cell-substrate adhesion assay was developed. This assay utilized plate-bound fusion proteins containing various extracellular subdomains of cadherin-5 (ECl-2 or EC2-4, see Example 4) and measured the binding of dye- labelled leukocytes to cadherin-5 protein using a cytofluor 2300 (Millipore, Bedford, MA). The purified fusion proteins were absorbed to styrene plates and the binding of dye-labeled leukocytes to the fusion proteins was compared to binding to maltose binding protein and heat denatured bovine serum albumin (BSA) which was used to block nonspecific binding. The fusion proteins were dissolved in PBS containing Ca 2+ and Mg 2+ , diluted into coating buffer and incubated overnight at 4°C. The plates were blocked with heat denatured BSA and then incubated with calcien (Molecular Probes, Eugene, OR)-labelled cells for 1 hour at 37 °C. Results of the assay are presented in FIGURE 1 wherein the relative fluorescence values reported are the mean value of three samples. PMNs bound to fusion proteins comprising the EC2-4 of cadherin- 5, but preferentially bound to fusion proteins comprisng ECl-2. These results are consistent with presence of cadherin subdomain 2 sequences in both fusion proteins. CD4 antigen activated T cells bound EC2-4 fusion protein. All these results, which indicate that PMNs interact with a more terminal or exposed subdomain of cadherin-5, are consistent with the rate that these cell types cross the endothelium, PMNs transmigrate in a few minutes and T cells require 30-60 minutes. The binding of U937 cells could be blocked in a dose dependent manner by polyclonal antisera made to the cadherin-5 EC2-4 subdomains. The results presented in the foregoing paragraph in combination with the results presented in Example 6B that leukocytes do not express cadherins suggests that the counter ligand to which cadherin-5 binds on leukocytes is a distantly related cadherin or is not a cadherin. Cadherin binding has previously been thought to be homotypic. Example 8 Expression of cadherin-5 in the blood-brain barrier in the endothelium of the cerebral cortex was assayed by Western blot and immunocytochemistry. A SDS lysate was prepared by boiling bovine or macaque capillaries in SDS sample buffer for 2 minutes and then drawing the extract through a 25 G syringe needle. The extract was centrifuged in a microfuge for 15 minutes at 4°C. Protein concentration in the supernatant was determined by the BCA method (Pierce) using bovine serum albumin as a standard. Samples of the supernatent (75μg) were separated by SDS-PAGE (Laemmli) and electrophoretically transfeπed to nitrocellulose. The nitrocellulose was blocked with 5% milk and 10% FBS in Tris-buffered saline, pH 8.0, containing 0.05% Tween 20. Cadherin-5 specific monoclonal antibodies (30Q4H and 45C6A) were added. After washing to remove unbound antibody, the filters were incubated with alkaline phosphatase-conjugated anti-mouse IgG (Promega, Madison, WI). Reactive bands were visualized by addition of NBT/BCIP (Sigma, St. Louis, MO). Expression of cadherin-5 was detected in the freshly isolated bovine and macaque capillaries. The Western blot results were confirmed by immunocytochemistry using the cadherin-5 antibodies 30Q4H and 45C6A. Macaque cerebral cortex was incubated in 15% sucrose in PBS for 30 minutes at 4°C and embedded in OCT compound (Tissue-Tek, Elkhart, IN) in cryomolds and quickly frozen. Six micron sections were cut and placed on glass slides. The slides were washed with PBS and fixed in 3% p-formaldehyde for 5 minutes. To permeabilϊze the tissue sections the slides were immersed in -20 X acetone for 10 minutes and air dried. The sections were blocked with 2% goat serum and 1% BSA in PBS for 30 minutes and then incubated with the primary antisera for 1 hour at room temperature. The sections were rinsed 3 times in PBS containing 0.1% BSA and incubated with biotinylated anti-rabbit or anti-mouse IgG (Vector Laboratories, Burlingame, CA) in 1% BSA in PBS for 30 minutes. After rinsing 3 times, strepavidin-conjugated with horseradish peroxidase (Vector Laboratories) was added for 30 minutes and washed 3 times. Immunolabeling was detected by reaction with diaminobenzoic acid in the presence of NiCl 2 . The monoclonal antibody 45C6A only appeared to label larger vessels and the monoclonal antibody 30Q4H labeled both large and microvessels. The cell junctions of cerebral capillaries were labelled with the anti-cadherin-5 antibodies in a localized site. These results and the results presented in Example 7 suggest cadherin-5 is involved in maintenance of the blood-brain barrier and that cadherin- 5 peptides or cadherin-5 specific monoclonal antibodies may be able to open the blood-brain barrier. Example 9 Patent Cooperation Treaty (PCT) International Publication No. WO 91/04745 discusses fragments of cell adhesion molecules and antibodies to cell adhesion molecules which are purported to disrupt microvascular and endothelial cell tight junctions. Three cadherin-5 peptides coπesponding to the cell binding domain [HAV region, Blaschuk et al, Devel Biol, 139: 227-229 (1990)], the calcium binding region Al and the calcium binding region Bl of E-cadherin [Ringwald et al, EMBO J., 6: 3647-3653 (1987)] were tested for the ability to affect the permeability of brain endothelium. The peptides utilized had the following sequences: Peptide 1 (Amino acids 114 to 128 of SEQ ID NO: 50) LTAVIVDKDTGENLE, Peptide 2 (Amino acids 132 to 145 of SEQ ID NO: 50) SFTIKVHDVNDNWP, and Peptide 3 (Amino acids 168 to 178 of SEQ ID NO: 50) SVTAVDADDPT, respectively. Permeability was measured using a two-chamber culture system (Costar). Rat brain microvascular endothelium was grown on 12 mm Transwell filters with 3 micron pores (Costar) in the culture system. When the monolayer s were confluent, two weeks after plating, 3 H-inulin (201 mCi/g) (New England Nuclear, Boston, MA) was added to the upper chamber. Cadherin-5 peptide at 100 μg/ml was added to both the upper and lower chambers. Radioactivity appearing in the bottom chamber was measured at 15 minute intervals over a two hour time course carried out at 37 °C and was compared to the radioactivity appearing in the bottom chamber of cultures where no peptide was added or where no endothelial cells were present. Both peptides 1 and 3 increased endothelium permeability in comparison to control cultures. The increase in permeability obtained with peptide 3 was 2.5-fold and the increase with peptide 1 was 1.5-fold over the controls. Peptide 2 had no effect on permeability. Example 10 The functional properties of cadherins involve not only specific intercellular interactions, but also involve intracellular interactions with the cytoskeleton. Immunoprecipitation experiments utilizing the cadherin-5-specific rabbit polyclonal antibodies and the monoclonal antibody 30Q8A (see Example 4) were performed to determine with which proteins cadherin-5 interacts on an intracellular level. Endothelial cells were metabolically labeled overnight with 50 μCi/ml of [ 35 S]-methionine and were then extracted with 0.5% Triton X-100 in lOmM HEPES pH 7.4, 0.15M NaCl, 2mM EDTA, 2mM EGTA, ImM phenanthroline and protease inhibitors. The inhibitors included ImM PMSF, 10 μg/ml aprotinin, leupeptin, pepstatin A, antipain, soybean trypsin inhibitor, 100 μg/ml chymostatin and TPCK, 40 μg/ml of TPCK and bestatin, 50 μg/ml of benzamidine, ImM o-vanidate and 20mM NaF. After 20 minutes on ice, the cells were scraped and centrifuged in a microfuge for 30 minutes at 4°C. The supernatant was precleared and either polyclonal anti-cadherin-5 or normal rabbit serum was added and incubated overnight at 4°C. Protein A-sepharose (Pharmacia, Piscataway, NJ) was added for 2 hours at 4°C and centrifuged. A first low stringency wash with lOmM HEPES pH 7.4, 0.15M NaCl, 2mM EDTA and 2mM EGTA containing 1 % Triton X-100, 0.5% DOC and 0.2% SDS was performed. A second high stringency wash was performed with the same buffer containing 2% SDS. A final wash was then performed with Tris-buffered saline, and the samples were boiled and analyzed on SDS/PAGE (7%). Three bands with molecular weights of 104 KD, 95 KD, and 82 KD were identified as associated with cadherin-5. Three intracellular proteins, termed catenins, have previously been identified by their ability to bind to the cytoplasmic domain of E-cadherin. These proteins have been designated a, β, and catenins and have molecular weights of 102 KD, 88 KD and 80 KD, respectively [Ozawa et al , EMBO J. 8: 1711- 1717 (1989)]. The association of catenins with E-cadherin seem to be required for E-cadherin function because deletion of the cytoplasmic domain of E-cadherin results in loss of cell adhesion function and catenin binding. The molecular cloning of α-catenin has shown it to be a vinculin-like protein [Nagafuki et al , Cell, 65: 849-857 (1991); Heπenkenecht et al, Proc. Natl Acad. Sci. USA, 88: 9156-9160 (1991)]. The amino acid sequence of the Xenopus j8-catenin [McCrea et al, Science, 254: 1359-1361 (1991)] exhibits 63% similarity to the human protein plakoglobin [Franke e al, Proc. Na . Acad. Sci. USA, 86: 4027-4031 (1989)]. Plakoglobin has been localized to both the cytoplasmic region of desmosome and adherens junctions in epithelial cells. The desmonsomal component desmoglein I interacts with plakoglobin and is a member of the cadherin superfamily [Koch et al, Eur. J. Cell. Biol, 53: 1-12 (1990) J. Plakoglobin has a molecular weight of 82 KD and may be the -catenin [Peifer et al, J. Cell Biol, 118: 681-691 (1992)]. Even though endothelial cells lack desmosome, they have been shown to contain plakoglobin-associated with intercellular junctions [Franke et al, Biol of the Cell, 59: 205-218 (1987)]. Other cytoskeletal elements associated with cadherins are ankyrin and fodrin [Nelson et al, J. Cell Biol, 110: 349-357 (1990)]. To identify whether plakoglobin was one of the proteins complexed to cadherin-5, an unlabeled lysate of bovine aortic endothelial cells was made and immunoprecϊpitation was carried out as described above using anti-cadherin-5 antibody. The unlabelled immunoprecipitates were separated by SDS/PAGE and then electrophoretically transferred to nitrocellulose. The membrane was blocked with 5% milk in Tris-buffered saline, pH 8.0, containing 0.05% Tween 20 (TBST) and then was incubated with the murine monoclonal antibody PG5.1 (IBI Research Products, Cambridge, MA) to plakoglobin in blocking solution (1:20) for 1 hour at room temperature. The membrane was washed with TBST and then incubated with goat anti-mouse IgG conjugated to alkaline phosphatase. An 82 KD protein was identified using NBT/BCIP under both low and high stringency wash conditions. These results demonstrate that plakoglobin is tightly associated with the cytoplasmic domain of cadherin-5 in endothelium. Immunofluorescence studies of regenerated endothelium show that cadherin-5 and plakoglobin are localized to the cell junctions and are coordinately regulated. The interation of cadherin-5 with plakoglobin may be a target for modulation of cadherin-5 activity. While the present invention has been described in terms of preferred embodiments, it is understood that variations and improvements will occur to those skilled in the art. Thus, only such limitations as appear in the appended claims should be placed on the scope of the invention. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Suzuki, Shintaro (ii) TITLE OF INVENTION: CADHERIN MATERIALS AND METHODS (iii) NUMBER OF SEQUENCES: 62 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Marshall, O'Toole, Gerstein, Murray & Borun (B) STREETϊ 6300 Sears Tower, 233 S. Wacker Drive (C) CITY: Chicago (D) STATE: Illinois (E) COUNTRY: USA (F) ZIP: 60606 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPEr Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patenfcln Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: US 07/872,643 CB) FILING DATE: 17 APR 1992 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Noland, Greta E. (B) REGISTRATION NUMBER: 35,302 (C) REFERENCE/DOCKET NUMBER: 31340 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 0312) 474-6300 (B) TELEFAX: (312) 474-0448 (C) TELEX: 25-3856 (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: Thr Ala Pro Pro Tyr Asp 1 5 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICSJ (A) LENGTH: 23 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: GAATTCACNG CNCCNCCNTA YGA 23 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Phe Lys Lys Leu Ala Asp 1 5 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 23 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: GAATTCTCNG CNARYTTYTT RAA 23 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 2 (D) OTHER INFORMATION: /note= "The amino acid at this position is a proline or a glycine." (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 3 (D) OTHER INFORMATION: /note= "The amino acid at this . position is a leucine, an isoleucine or a valine." (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 5 (D) OTHER INFORMATION: /note= "The amino acid at this position is a phenylalanine or a tyrosine." (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: Lys Xaa Xaa Asp Xaa Glu 1 5 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 23 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: GAATTCAARS SNNTNGAYTW YGA 23 (2) INFORMATION FOR SEQ ID NO:7t (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPEt amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Modified-site (B) LOCATION: 1 (D) OTHER INFORMATION: /note= "The amino acid at this position is an asparagine or an aεpartic acid." (ix) FEATUREr (A) NAME/KEY: Modified-site (B) LOCATION: 3 (D) OTHER INFORMATION: /note= "The amino acid at this position is an alanine or a proline. " (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: Xaa Glu Xaa Pro Xaa Phe 1 5 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 23 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOG i linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: GAATTCRAAN NNNGGNGSYT CRT 23 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 117 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: TCCCTGCTGG TCTTCGACTA CGAAGGCAGC GGTTCTACTG CAGGCTCTGT CAGCTCCCTG 60 AACTCCTCCA GCTCCGGGGA TCAAGATTAC GACTACTTGA ATGACTGGGG GCCCCGG 117 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 39 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: Ser Leu Leu Val Phe Asp Tyr Glu Gly Ser Gly Ser Thr Ala Gly Ser 1 5 10 15 Val Ser Ser Leu Asn Ser Ser Ser Ser Gly Asp Gin Asp Tyr Asp Tyr 20 25 30 Leu Asn Asp Trp Gly Pro Arg 35 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 120 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: ACACTGCACA TCTACGGCTA CGAGGGCACA GAGTCCATCG CAGAGTCCCT CAGCTCCCTG 60 AGCACCAATT CCTCCGACTC TGACATCGAC TATGACTTCC TCAATGACTG GGGACCCAGG 120 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Thr Leu His lie Tyr Gly Tyr Glu Gly Thr Glu Ser lie Ala Glu Ser 1 5 10 15 Leu Ser Ser Leu Ser Thr Asn Ser Ser Asp Ser Asp lie Asp Tyr Asp 20 25 30 Phe Leu Asn Asp Trp Gly Pro Arg 35 40 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 120 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13r TCCTTGGCCA CCTATGCCTA CGAAGGAACT GGCTCGGTGG CCGACTCCCT GAGCTCACTA 60 GAATCAGTGA CCACAGATGG AGACCAAGAT TATGACTATT TGAGTG CTG GGGCCCTCGA 120 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: Ser Leu Ala Thr Tyr Ala Tyr Glu Gly Thr Gly Ser Val Ala Asp Ser 1 5 10 15 Leu Ser Ser Leu Glu Ser Val Thr Thr Asp Gly Asp Gin Asp Tyr Asp 20 25 30 Tyr Leu Ser Asp Trp Gly Pro Arg 35 40 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 120 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: TCGCTTCAGA CTTATGCATT TGAAGGAAAT GGCTCAGTAG CTGAATCTCT CAGTTCTTTA 60 GATTCTAACA GCTCGAACTC TGATCAGAAT TATGACTACC TTAGTGACTG GGGTCCTCTC 120 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: Ser Leu Gin Thr Tyr Ala Phe Glu Gly Asn Gly Ser Val Ala Glu Ser 1 5 10 15 Leu Ser Ser Leu Asp Ser Asn Ser Ser Asn Ser Asp Gin Asn Tyr Asp 20 25 30 Tyr Leu Ser Asp Trp Gly Pro Arg 35 40 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 120 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: TCCATTCAGA TTTATGGCTA TGAAGGCCGA GGGTCTGTGG CTGGCTCTCT CAGCTCGTTG 60 GAGTCCACCA CATCAGACTC AGACCAGAAT TTTGACTACC TCAGTGACTG GGGTCCCCGC 120 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: Ser lie Gin lie Tyr Gly Tyr Glu Gly Arg Gly Ser Val Ala Gly Ser 1 5 10 15 Leu Ser Ser Leu Glu Ser Thr Thr Ser Asp Ser Asp Gin Asn Phe Asp 20 25 30 Tyr Leu Ser Asp Trp Gly Pro Arg 35 40 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 120 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: TCCTTGGCCA CTTACGCCTA TGAAGGGAAT GATTCTGTAG CCAATTCTCT CAGCTCCTTA 60 GAATCTCTCA CAGCTGATTG TACCCAGGAT TATGACTACC TTAGTGACTG GGGGCCACGC 120 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: Ser Leu Ala Thr Tyr Ala Tyr Glu Gly Asn Asp Ser Val Ala Asn Ser 1 5 10 15 Leu Ser Ser Leu Glu Ser Leu Thr Ala Asp Cys Asn Gin Asp Tyr Asp 20 25 30 Tyr Leu Ser Asp Trp Gly Pro Arg 35 40 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 120 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA ( i) SEQUENCE DESCRIPTION: SEQ ID NO:21: TCGCTGGCTA CCTATGCCTA TGAAGGAAAC GACTCTGTTG CTGAATCTCT GAGCTCCTTA 60 GAATCAGGTA CCACTGAAGG AGACCAAAAC TACGATTACC TTCGAGAATG GGGGCCTCGG " 120 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: Ser Leu Ala Thr Tyr Ala Tyr Glu Gly Asn Asp Ser Val Ala Glu Ser 1 5 10 15 Leu Ser Ser Leu Glu Ser Gly Thr Thr Glu Gly Asp Gin Asn Tyr Asp 20 25 30 Tyr Leu Arg Glu Trp Gly Pro Arg 35 40 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 120 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: TCCATCCAAA TCTATGGTTA TGAGGGCAGG GGTTCCGTGG CTGGGTCCCT GAGCTCCTTG 60 GAGTCTGCCA CCACAGATTC GGACCTGGAC TACGACTATC TACAGAACTG GGGACCTCGG 120 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 40 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: Ser lie Gin lie Tyr Gly Tyr Glu Gly Arg Gly Ser Val Ala Gly Ser 1 5 10 15 Leu Ser Ser Leu Glu Ser Ala Thr Thr Asp Ser Asp Leu Asp Tyr Asp 20 25 30 Tyr Leu Gin Asn Trp Gly Pro Arg 35 40 (2) INFORMATION FOR SEQ ID NO:25: (1) SEQUENCE CHARACTERISTICS: (A) LENGTH: 150 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: AAGCGGTTTG ATTACGAGAT CTCTGCCTTT CACACCCTGC TGATCAAAGT GGAGAATGAG 60 GACCCATTGG TACCCGACGT CTCCTATGGC CCCAGCTCCA CGGCCACTGT CCACATCACG 120 GTCTTGGATG TCAACGAGGG ACCAGTCTTC 150 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTHt 50 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: Lys Arg Phe Asp Tyr Glu lie Ser Ala Phe His Thr Leu Leu lie Lys 1 5 10 15 Val Glu Asn Glu Asp Pro Leu Val Pro Asp Val Ser Tyr Gly Pro Ser 20 25 30 Ser Thr Ala Thr Val His lie Thr Val Leu Asp Val Asn Glu Gly Pro 35 40 45 Val Phe 50 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 150 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA Cxi) SEQUENCE DESCRIPTION: SEQ ID NO:27: AAGGGTATGG ATTATGAGCT GAACCGTGCC TCCATGCTGA CCATAATGGT GTCCAACCAG 60 GCGCCCCTGG CCAGCGGGAT CCAGATGTCC TTCCAGTCCA CAGTGGGGGT AACCATCTCT 120 GTCACCGATG TCAACGAAGC CCCCTACTTC 150 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: Lys Gly Met Asp Tyr Glu Leu Asn Arg Ala Ser Met Leu Thr lie Met 1 5 10 15 Val Ser Asn Gin Ala Pro Leu Ala Ser Gly lie Gin Met Ser Phe Gin 20 25 30 Ser Thr Val Gly Val Thr He Ser Val Thr Asp Val Asn Glu Ala Pro 35 40 45 Tyr Phe 50 (2) INFORMATION FOR SEQ ID NO:29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 153 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: AAACGACTGG ATTTTGAACT CATCCAGCAG TACACGTTCC ACATCGAGGC CACAGACCCC 60 ACTATCAGAC TCGGATACCT GAGCAGCACT GCGGGCAAAA ACAAAGCCAA GATCATCATC 120 AATGTCCTAG ATGTGGATGA GCCCCCTGTT TTC 153 (2) INFORMATION FOR SEQ ID NO:30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: Lys Arg Leu Asp Phe Glu Leu He Gin Gin Tyr Thr Phe His He Glu • 1 • 5 . 10 15 Ala Thr Asp Pro Thr He Arg Leu Gly Tyr Leu Ser Ser Thr Ala Gly 20 25 30 Lys Asn Lys Ala Lys He He He Asn Val Leu Asp Val Asp Glu Pro 35 40 45 Pro Val Phe 50 (2) INFORMATION FOR SEQ ID NO:31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH.. 153 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: AAGGGTTTGG ATTTTGAAAA GAAGAAAGTG TATACCCTTA AAGTGGAAGC CTCCAATCCT 60 TATGTTGAGC CACGATTTCT CTACTTGGGG CCTTTCAAAG ATTCAGCCAC GGTTAGAATT 120 GTGGTGGAGG ATGTAGATGA ACCTCCTGCC TTC 153 (2) INFORMATION FOR SEQ ID NO:32: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32t Lys Gly Leu Asp Phe Glu Lys Lys Lys Val Tyr Thr Leu Lys Val Glu 1 5 10 15 Ala Ser Asn Pro Tyr Val Glu Pro Arg Phe Leu Tyr Leu Gly Pro Phe 20 25 30 Lys Asp Ser Ala Thr Val Arg He Val Val Glu Asp Val Asp Glu Pro 35 40 45 Pro Ala Phe 50 (2) INFORMATION FOR SEQ ID NO:33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 153 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: - - AAGCCTCTGG ACTTTGAGAC CAAAAAATCC TATACTCTGA AGGTGGAGGC AGCCAATATC 60 CACATCGACC CACGTTTCAG TGGCAGGGGA CCCTTTAAAG ATACAGCAAC AGTCAAAATT 120 GTTGTAGAGG ATGCTGATGA GCCTCCGGTC TTC 153 (2) INFORMATION FOR SEQ ID NO:34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: Asp Ala Leu Asp Phe Glu Thr Lys Lys Ser Tyr Thr Leu Lys Val Glu 1 5 10 15 Ala Ala Asn He His He Asp Pro Arg Phe Ser Gly Arg Gly Pro Phe 20 25 30 Lys Asp Thr Ala Thr Val Lys He Val Val Glu Asp Ala Asp Glu Pro 35 40 45 Pro Val Phe 50 (2) INFORMATION FOR SEQ ID NO:35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 152 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: AAGGGGGTGG ACTATGAAGC CAAAACAAGT TATACCCTGC GCATAGAAGC TGCAAATCGA 60 GATGCTGATC CCCGGTTTCT GAGCTTGGGT CCATTCAGTG ACACAACAAC AGTTAAGATA 120 ATTGTGGAAG ACGTGGATGA ACCCCCGTACT C 152 (2) INFORMATION FOR SEQ ID NO:36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: Lys Gly Val Asp Tyr Glu Ala Lys Thr Ser Tyr Thr Leu Arg He Glu 1 5 10 15 . . Ala Ala Asn Arg Asp Ala Asp Pro Arg Phe Leu Ser Leu Gly Pro Phe 20 25 30 Ser Asp Thr Thr Thr Val Lys He He Val Glu Asp Val Asp Glu Pro 35 40 45 Pro Tyr Ser 50 (2) INFORMATION FOR SEQ ID NO:37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 153 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: AAGCCACTTG ACTATGAGAA CCGAAGACTA TATACACTGA AGGTGGAGGC AGAAAATACC 60 CATGTGGATC CACGTTTTTA CTATTTAGGG CCATTCAAAG ATACAACAAT TGTAAAAATC 120 TCCATAGAAG ACGTGGATGA GCCACCCCCC TTT 153 (2) INFORMATION FOR SEQ ID NO:38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: Lys Pro Leu Asp Tyr Glu Asn Arg Arg Leu Tyr Thr Leu Lys Val Glu 1 5 10 15 Ala Glu Asn Thr His Val Asp Pro Arg Phe Tyr Tyr Leu Gly Pro Phe 20 25 30 Lys Asp Thr Thr He Val Lys He Ser He Glu Asp Val Asp Glu Pro 35 40 45 Pro Pro Phe 50 (2) INFORMATION FOR SEQ ID NO:39: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 153 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA " (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: AGGGGTGTGG ATTATGAAAC CAAAAGAGCA TATAGCTTGA AGGTAGAGGC GGCCAATGTA 60 CACATTGATC CGAAGTTCAT CAGCAATGGA CCTTTCAAGG ACACAGTGAC TGTCAAGATT 120 GCAGTAGAAG ATGCCAATGA GCCCCCTCCC TTC 153 (2) INFORMATION FOR SEQ ID NO:40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: Arg Gly Val Asp Tyr Glu Thr Lys Arg Ala Tyr Ser Leu Lys Val Glu 1 5 10 15 Ala Ala Asn Val His He Asp Pro Lys Phe He Ser Asn Gly Pro Phe 20 25 30 Lys Asp Thr Val Thr Val Lys He Ala Val Glu Asp Ala Asn Glu Pro 35 40 45 Pro Pro Phe 50 (2) INFORMATION FOR SEQ ID NO:41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3136 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: GGCACGAGCG CAAGCCGGGG AGCGCTCGGC CCAGAATTAG TGGATGGATT TGGAATCTCC 60 CTGCCTCCTC CAAGCTCCGC CACTGCCACT TTAGGCAGAG ACCTGAGCGT CAACACGCGA 120 GCCGTACTTT TAGGCTGCGG ACACTGAGCC CAGCGCGCCA GCTTCGCATC TCCGCACCAG 180 GCTCCACAGC TCGGAGAGGC ATGAACGCGA TCCGGAGGAG ACTACCCTGC GCGCGGGGAT 240 CCGTGGACAT TAGCCGCTCT CGGGAACTGA CCCCCAGCTC CTTCAGCCAT TTATGAATCC 300 AGAGGCTTGA GATTTTTTTC CGCATCCCGG AGCCCGACCT GAGAAATTTC AATGAAAAGG 360 AAAGTCAATG GATCGTGGTC TTGGAAAAGC TGCTTAGACA TGTCTGTTTC CCGGCTCTCT 420 GAACCCGTGG CAGAGCTGTA AGTAAGCGCT TCACAGTGCG TGATGAATTG GATGGCTTCG 480 GACCCGAGGC AAAAAAAATA ATTGTCTCAT TTTCGTGCTG ATTTGCTTAA CTGGTGGGAC 540 CATGCCAGAA AGGCTAGCTG AGACGCTTTT GGACCTCTGG ACTCCATTAA TAATATTATG 600 GATTACTCTT CCCTCTTTTG TGTACATGGC TCCGATGAAT CAGGCTCACG TTTTAACTAC 660 TGGATCCCCT TTGGAACTAA GCAGGCAGAG TGAAGAAATG CGGATTTTGA ACCGCTCCAA 720 AAGAGGTTGG GTTTGGAATC AAATGTTTGT TCTGGAAGAA TTTTCTGGAC CTGAACCGAT 780 TCTCGTTGGC CGGTTACACA CAGATCTGGA TCCTGGGAGC AAAAAAATCA AGTATATCCT 840 ATCGGGTGAT GGAGCCGGCA CAATCTTTCA AATAAACGAT ATAACTGGAG ACATCCATGC 900 TATCAAAAGA CTTGACCGAG AGGAAAAGGC TGAGTATACG TTAACAGCTC AGGCAGTGGA 960 CTGGGAGACA AACAAACCTC TCGAGCCTCC TTCTGAATTT ATTATTAAGG TTCAAGACAT 1020 CAACGACAAT GCCCCCGAGT TTCTCAATGG ACCTTACCAT GCTACTGTTC CAGAGATGTC 1080 CATCTTGGGT ACATCTGTCA CTAATGTAAC GGCCACTGAT GCTGACGATC CAGTTTATGG 1140 AAACAGTGCA AAGTTGGTTT ACAGTATCTT GGAGGGACAG CCGTATTTTT CCATTGAGCC 1200 TGAAACAGCT ATTATAAAAA CTGCCCTTCC TAACATGGAC AGAGAGGCCA AGGAGGAATA 1260 CCTGGTTGTA. ATTCAAGCCA AAGATATGGG TGGGCATTCC GGTGGTCTGT CTGGAACCAC 1320 GACACTCACA GTGACGCTTA CCGATGTGAA TGACAATCCT CCAAAATTTG CTCAAAGTTT 1380 GTATCACTTC TCAGTACCAG AAGATGTGGT CCTTGGCACT GCAATAGGAA GGGTTAAAGC 1440 CAATGACCAG GATATTGGTG AAAATGCACA ATCTTCCTAT GACATCATTG ATGGAGATGG 1500 GACAGCACTA TTTGAAATCA CTTCTGATGC CCAGGCACAG GATGGTGTTA TAAGACTAAG 1560 AAAGCCTCTG GACTTTGAGA CCAAAAAATC CTATACTCTG AAGGTGGAGG CAGCCAATAT 1620 CCACATCGAC CCACGTTTCA GTGGCAGGGG ACCCTTTAAA GATACAGCAA CAGTCAAAAT 1680 TGTTGTAGAG GATGCTGATG AGCCTCCGGT CTTCTCTTCA CCGACTTACC TCCTTGAAGT 1740 TCATGAAAAT GCTGCCTTGA ACTCTGTGAT TGGCCAAGTG ACAGCTCGTG ACCCTGATAT 1800 CACTTCCAGC CCAATAAGGT TTTCCATTGA CCGCCACACT GACTTGGAGA GACAGTTCAA 1860 CATCAATGCA GATGATGGGA AGATAACACT GGCGACCCCA CTGGACAGAG AACTAAGTGT 1920 GTGGCACAAC ATCTCCATCA TTGCTACTGA GATCAGGAAC CACAGTCAGA TATCGCGAGT 1980 GCCTGTTGCT ATTAAAGTGC TGGATGTCAA TGACAACGCC CCTGAATTCG CGTCCGAATA 2040 TGAGGCATTT TTATGTGAAA ATGGAAAACC CGGCCAAGTC ATTCAAACAG TAAGCGCCAT 2100 GGACAAAGAC GATCCCAAAA ATGGACATTT TTTCTTGTAC AGTCTTCTTC CAGAAATGGT 2160 CAACAACCCA AATTTCACCA TCAAGAAAAA CGAAGATAAT TCCCTGAGCA TTCTGGCAAA 2220 ACATAATGGA TTCAACCGCC AGAAGCAAGA AGTCTACCTT CTGCCTATCG TGATCAGTGA 2280 CAGTGGGAAC CCCCCTCTGA GTAGCACCAG TACCCTGACC ATCCGCGTCT GTGGCTGTAG 2340 CAATGACGGC GTGGTTCAGT CGTGCAATGT CGAAGCTTAT GTCCTTCCTA TTGGGCTCAG 2400 TATGGGCGCG TTAATTGCTA TATTAGCCTG CATCATTTTG CTGCTCGTCA TTGTGGTTCT 2460 GTTCGTTACC CTGAGGCGGC ATAAAAATGA ACCACTAATA ATCAAAGATG ATGAAGACGT 2520 TCGAGAAAAC ATCATTCGCT ACGACGACGA AGGAGGCGGG GAGGAGGACA CAGAGGCTTT 2580 TGACATTGCA ACTTTGCAAA ACCCAGATGG AATTAATGGA TTTTTACCCC GTAAGGATAT 2640 TAAACCAGAT TTGCAGTTTA TGCCAAGGCA AGGGCTTGCT CCAGTTCCAA ATGGTGTTGA 2700 TGTCGATGAA TTTATAAATG TAAGGCTTCA TGAGGCAGAT AATGACCCCA CGGCCCCACC 2760 ATATGACTCC ATTCAGATTT ATGGCTATGA AGGCCGAGGG TCTGTGGCTG GCTCTCTCAG 2820 CTCGTTGGAG TCCACCACAT CAGACTCAGA CCAGAATTTT GACTACCTCA GTGACTGGGG 2880 TCCCCGCTTT AAGAGACTGG GCGAACTCTA CTCTGTTGGT GAAAGTGACA AAGAAACTTG 2940 ACAGTGGATT ACATAAATAA TCAATGGAAC TGAGCATTCT GTAATATTCT AGGGTCACTC 3000 CCCTTAGATG CAACAAATGT GGCTATTTGT TTTAGAGGCA AGTTTAGCAC CAATCATCTA 3060 TAAACTCAAC CACATTTTAA TGTTGAACCA AAAAAAATAA TAAAAAATAA AAAGTATATG 3120 TTAGGAGGTG AAAAAA 3136 (2) INFORMATION FOR SEQ ID NO:42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 799 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: Met Pro Glu Arg Leu Ala Glu Thr Leu Leu Asp Leu Trp Thr Pro Leu 1 5 10 15 He He Leu Trp He Thr Leu Pro Ser Phe Val Tyr Met Ala Pro Met 20 25 30 Asn Gin Ala His Val Leu Thr Thr Gly Ser Pro Leu Glu Leu Ser Arg 35 40 45 Gin Ser Glu Glu Met Arg He Leu Asn Arg Ser Lys Arg Gly Trp Val 50 55 60 Trp Asn Gin Met Phe Val Leu Glu Glu Phe Ser Gly Pro Glu Pro He 65 70 75 80 Leu Val Gly Arg Leu His Thr Asp Leu Asp Pro Gly Ser Lys Lys He 85 90 95 Lys Tyr He Leu Ser Gly Asp Gly Ala Gly Thr He Phe Gin He Asn 100 105 110 Asp He Thr Gly Asp He His Ala He Lys Arg Leu Asp Arg Glu Glu 115 120 125 Lys Ala Glu Tyr Thr Leu Thr Ala Gin Ala Val Asp Trp Glu Thr Asn 130 135 140 Lys Pro Leu Glu Pro Pro Ser Glu Phe He He Lys Val Gin Asp He 145 150 155 160 Asn Asp Asn Ala Pro Glu Phe Leu Asn Gly Pro Tyr His Ala Thr Val 165 170 175 Pro Glu Met Ser He Leu Gly Thr Ser Val Thr Asn Val Thr Ala Thr 180 185 190 Asp Ala Asp Asp Pro Val Tyr Gly Asn Ser Ala Lys Leu Val Tyr Ser 195 200 205 He Leu Glu Gly Gin Pro Tyr Phe Ser He Glu Pro Glu Thr Ala He 210 215 220 He Lys Thr Ala Leu Pro Asn Met Asp Arg Glu Ala Lys Glu Glu Tyr 225 230 235 240 Leu Val Val He Gin Ala Lys Asp Met Gly Gly His Ser Gly Gly Leu 245 250 255 Ser Gly Thr Thr Thr Leu Thr Val Thr Leu Thr Asp Val Asn Asp Asn 260 265 270 Pro Pro Lys Phe Ala Gin Ser Leu Tyr His Phe Ser Val Pro Glu Asp 275 280 285 Val Val Leu Gly Thr Ala He Gly Arg Val Lys Ala Asn Asp Gin Asp 290 295 300 He Gly Glu Asn Ala Gin Ser Ser Tyr Asp He He Asp Gly Asp Gly 305 310 315 320 Thr Ala Leu Phe Glu He Thr Ser Asp Ala Gin Ala Gin Asp Gly Val 325 330 335 He Arg Leu Arg Lys Pro Leu Asp Phe Glu Thr Lys Lys Ser Tyr Thr 340 345 350 Leu Lys Val Glu Ala Ala Asn He His He Asp Pro Arg Phe Ser Gly 355 360 365 Arg Gly Pro Phe Lys Asp Thr Ala Thr Val Lys He Val Val Glu Asp 370 375 380 Ala Asp Glu Pro Pro Val Phe Ser Ser Pro Thr Tyr Leu Leu Glu Val 385 390 395 400 His Glu Asn Ala Ala Leu Asn Ser Val He Gly Gin Val Thr Ala Arg 405 410 415 Asp Pro Asp He Thr Ser Ser Pro He Arg Phe Ser He Asp Arg His 420 425 430 Thr Asp Leu Glu Arg Gin Phe Asn He Asn Ala Asp Asp Gly Lys He 435 440 445 Thr Leu Ala Thr Pro Leu Asp Arg Glu Leu Ser Val Trp His Asn He 450 455 460 Ser He He Ala Thr Glu He Arg Asn His Ser Gin He Ser Arg Val 465 470 475 480 Pro Val Ala He Lys Val Leu Asp Val Asn Asp Asn Ala Pro Glu Phe 485 490 495 Ala Ser Glu Tyr-Glu Ala Phe Leu Cys Glu Asn Gly Lys Pro Gly Gin 500 505 510 Val He Gin Thr Val Ser Ala Met Asp Lys Asp Asp Pro Lys Asn Gly 515 520 525 His Phe Phe Leu Tyr Ser Leu Leu Pro Glu Met Val Asn Asn Pro Asn 530 535 540 Phe Thr He Lys Lys Asn Glu Asp Asn Ser Leu Ser He Leu Ala Lys 545 550 555 560 His Asn Gly Phe Asn Arg Gin Lys Gin Glu Val Tyr Leu Leu Pro He 565 570 575 Val He Ser Asp Ser Gly Asn Pro Pro Leu Ser Ser Thr Ser Thr Leu 580 585 590 Thr He Arg Val Cys Gly Cys Ser Asn Asp Gly Val Val Gin Ser Cys 595 600 605 Asn Val Glu Ala Tyr Val Leu Pro He Gly Leu Ser Met Gly Ala Leu 610 615 620 He Ala He Leu Ala Cys He He Leu Leu Leu Val He Val Val Leu 625 630 635 640 Phe Val Thr Leu Arg Arg His Lys Asn Glu Pro Leu He He Lys Asp 645 650 655 Asp Glu Asp Val Arg Glu Asn He He Arg Tyr Asp Asp Glu Gly Gly 660 665 670 Gly Glu Glu Asp Thr Glu Ala Phe Asp He Ala Thr Leu Gin Asn Pro 675 680 685 Asp Gly He Asn Gly Phe Leu Pro Arg Lys Asp He Lys Pro Asp Leu 690 695 700 Gin Phe Met Pro Arg Gin Gly Leu Ala Pro Val Pro Asn Gly Val Asp 705 710 715 720 Val Asp Glu Phe He Asn Val Arg Leu His Glu Ala Asp Asn Asp Pro 725 730 735 Thr Ala Pro Pro Tyr Asp Ser He Gin He Tyr Gly Tyr Glu Gly Arg 740 745 750 Gly Ser Val Ala Gly Ser Leu Ser Ser Leu Glu Ser Thr Thr Ser Asp 755 760 765 Ser Asp Gin Asn Phe Asp Tyr Leu Ser Asp Trp Gly Pro Arg Phe Lys 770 775 780 Arg Leu Gly Glu Leu Tyr Ser Val Gly Glu Ser Asp Lys Glu Thr 785 790 795 (2) INFORMATION FOR SEQ ID NO:43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3043 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: 1inear (ii) MOLECULE TYPE: CDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: GGCACGAGCG CAAGCCGGGG AGCGCTCGGC CCAGAATTAG TGGATGGATT TGGAATCTCC 60 CTGCCTCCTC CAAGCTCCGC CACTGCCACT TTAGGCAGAG ACCTGAGCGT CAACACGCGA 120 GCCGTACTTT TAGGCTGCGG ACACTGAGCC CAGCGCGCCA GCTTCGCATC TCCGCACCAG 180 GCTCCACAGC TCGGAGAGGC ATGAACGCGA TCCGGAGGAG ACTACCCTGC GCGCGGGGAT 240 CCGTGGACAT TAGCCGCTCT CGGGAACTGA CCCCCAGCTC CTTCAGCC T TTATGAATCC 300 AGAGGCTTGA GATTTTTTTC CGCATCCCGG AGCCCGACCT GAGAAATTTC AATGAAAAGG 360 AAAGTCAATG GATCGTGGTC TTGGAAAAGC TGCTTAGACA TGTCTGTTTC CCGGCTCTCT 420 GAACCCGTGG CAGAGCTGTA AGTAAGCGCT TCACAGTGCG TGATGAATTG GATGGCTTCG 480 GACCCGAGGC AAAAAAAATA ATTGTCTCAT TTTCGTGCTG ATTTGCTTAA CTGGTGGGAC 540 CATGCCAGAA AGGCTAGCTG AGACGCTTTT GGACCTCTGG ACTCCATTAA TAATATTATG 600 GATTACTCTT CCCTCTTTTG TGTACATGGC TCCGATGAAT CAGGCTCACG TTTTAACTAC 660 TGGATCCCCT TTGGAACTAA GCAGGCAGAG TGAAGAAATG CGGATTTTGA ACCGCTCCAA 720 AAGAGGTTGG GTTTGGAATC AAATGTTTGT TCTGGAAGAA TTTTCTGGAC CTGAACCGAT 780 TCTCGTTGGC CGGTTACACA CAGATCTGGA TCCTGGGAGC AAAAAAATCA AGTATATCCT 840 ATCGGGTGAT GGAGCCGGCA CAATCTTTCA AATAAACGAT ATAACTGGAG ACATCCATGC 900 TATCAAAAGA CTTGACCGAG AGGAAAAGGC TGAGTATACG TTAACAGCTC AGGCAGTGGA 960 CTGGGAGACA AACAAACCTC TCGAGCCTCC TTCTGAATTT ATTATTAAGG TTCAAGACAT 1020 CAACGACAAT GCCCCCGAGT TTCTCAATGG ACCTTACCAT GCTACTGTTC CAGAGATGTC 1080 CATCTTGGGT ACATCTGTCA CTAATGTAAC GGCCACTGAT GCTGACGATC CAGTTTATGG 1140 AAACAGTGCA AAGTTGGTTT ACAGTATCTT GGAGGGACAG CCGTATTTTT CCATTGAGCC 1200 TGAAACAGCT ATTATAAAAA CTGCCCTTCC TAACATGGAC AGAGAGGCCA AGGAGGAATA 1260 CCTGGTTGTA ATTCAAGCCA AAGATATGGG TGGGCATTCC GGTGGTCTGT CTGGAACCAC 1320 GACACTCACA GTGACGCTTA CCGATGTGAA TGACAATCCT CCAAAATTTG CTCAAAGTTT 1380 GTATCACTTC TCAGTACCAG AAGATGTGGT CCTTGGCACT GCAATAGGAA GGGTTAAAGC 1440 CAATGACCAG GATATTGGTG AAAATGCACA ATCTTCCTAT GACATCATTG- TGGAGATGG 1500 GACAGCACTA TTTGAAATCA CTTCTGATGC CCAGGCACAG GATGGTGTTA TAAGACTAAG 1560 AAAGCCTCTG GACTTTGAGA CCAAAAAATC CTATACTCTG AAGGTGGAGG CAGCCAATAT 1620 CCACATCGAC CCACGTTTCA GTGGCAGGGG ACCCTTTAAA GATACAGCAA CAGTCAAAAT 1680 TGTTGTAGAG GATGCTGATG AGCCTCCGGT CTTCTCTTCA CCGACTTACC TCCTTGAAGT 1740 TCATGAAAAT GCTGCCTTGA ACTCTGTGAT TGGCCAAGTG ACAGCTCGTG ACCCTGATAT 1800 CACTTCCAGC CCAATAAGGT TTTCCATTGA CCGCCACACT GACTTGGAGA GACAGTTCAA 1860 CATCAATGCA GATGATGGGA AGATAACACT GGCGACCCCA CTGGACAGAG AACTAAGTGT 1920 GTGGCACAAC ATCTCCATCA TTGCTACTGA GATCAGGAAC CACAGTCAGA TATCGCGAGT 1980 GCCTGTTGCT ATTAAAGTGC TGGATGTCAA TGACAACGCC CCTGAATTCG CGTCCGAATA 2040 TGAGGCATTT TTATGTGAAA ATGGAAAACC CGGCCAAGTA AATATCTCCA TGTTGTTAAT 2100 ACTGAATATG TTTGTATACA ACTGTTTCCT AGTTAATTAA CCTGCATTAC TTCCTGATTT 2160 TGCATTGGTT GGATTTACAA AGTCACAGGC AGGAAACTCC TCCAAGCGGT AACAGAAGGG 2220 AATATTTGTC TTTCTCAGAT GTTAATTCTC TTCTAACTTA GGAACCAATT GGCTCAGAAA 2280 GTGTGATGAT CTGCTCTGCT CTGACCCCAG CCAAATCACT GTCTTAAAAT ACATCACATA 2340 TGGGTGATGG CTGGGGACAG TCTTACAGTG CAGAAGGTTG AAATCGCCAT CAATTGGCAA 2400 GAATCTAAAG AATAGCTCAT GGGAAGCATG CATTTTTGTT TTATGTTGAA AAGAAGATTA 2460 ATGCACAAAT GTGGAATGCA AAAAAACACA GTAGTTTATA GAAAGCTCTA TGTAGTGGTA 2520 CTTATGTCTG TACACATATT TGCAAGTTTA GTAAACATAA TGTAGACATC AAATTGTTAG 2580 ATATGCCCCT AAGGCATTTC AATATGTAGA GGTAAGACTC CTAAGGCATA GATGGGGATA 2640 ATGAAGACAA AAATAAAGGG CAGAAAAATG TATAAAATAG AACAGACAGA AATACACTAA 2700 AGATCTAAAG ATAGAAGCAG GAAAGAGGGG AGGGAGGGAG GGAGACAGGG CTGGAAGAAG 2760 ATAGGGTGGG AGGGAGGGAA GGAGAGTCAA GGCTCAGGGT GTGGGGGGGA AGGTAAAATG 2820 CAAAACAAAA TCTACAGAAA CCACTATACT CTGAATGTCA AAATGCAACT AACCTATGTA 2880 AAATCACCCA ACCACATGTG TAATAGATTT ATTTTAACGA GGTGCCGGAG TACTGTATGT 2940 TTAAGAAATT TATCATTTTT CAACTTCCTA ATTTATTTCT GGATGGTGAC ATTTTAATTT 3000 AAATAAACAG CAGCTGACAG CATGAAAAAA AAAAAAAAAA AAA 3043 (2) INFORMATION FOR SEQ ID NO:44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 532 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: Met Pro Glu Arg Leu Ala Glu Thr Leu Leu Asp Leu Trp Thr Pro Leu 1 5 10 15 He He Leu Trp He Thr Leu Pro Ser Phe Val Tyr Met Ala Pro Met 20 25 30 Asn Gin Ala His Val Leu Thr Thr Gly Ser Pro Leu Glu Leu Ser Arg 35 40 45 Gin Ser Glu Glu Met Arg He Leu Asn Arg Ser Lys Arg Gly Trp Val 50 55 60 Trp Asn Gin Met Phe Val Leu Glu Glu Phe Ser Gly Pro Glu Pro He 65 70 75 80 Leu Val Gly Arg Leu His Thr Asp Leu Asp Pro Gly Ser Lys Lys He 85 90 95 Lys Tyr He Leu Ser Gly Asp Gly Ala Gly Thr He Phe Gin He Asn 100 105 110 Asp He Thr Gly Asp He His Ala He Lys Arg Leu Asp Arg Glu Glu 115 120 125 Lys Ala Glu Tyr Thr Leu Thr Ala Gin Ala Val Asp Trp Glu Thr Asn 130 135 140 Lys Pro Leu Glu Pro Pro Ser Glu Phe He He Lys Val Gin Asp He 145 150 155 160 Asn Asp Asn Ala Pro Glu Phe Leu Asn Gly Pro Tyr His Ala Thr Val 165 170 175 Pro Glu Met Ser He Leu Gly Thr Ser Val Thr Asn Val Thr Ala Thr 180 185 190 Asp Ala Asp Asp Pro Val Tyr Gly Asn Ser Ala Lys Leu Val Tyr Ser 195 200 205 He Leu Glu Gly Gin Pro Tyr Phe Ser He Glu Pro Glu Thr Ala He 210 215 220 He Lys Thr Ala Leu Pro Asn Met Asp Arg Glu Ala Lys Glu Glu Tyr 225 230 235 240 Leu Val Val He Gin Ala Lys Asp Met Gly Gly His Ser Gly Gly Leu 245 250 255 Ser Gly Thr Thr Thr Leu Thr Val Thr Leu Thr Asp Val Asn Asp Asn 260 265 270 Pro Pro Lys Phe Ala Gin Ser Leu Tyr His Phe Ser Val Pro Glu Asp 275 280 285 Val Val Leu Gly Thr Ala He Gly Arg Val Lys Ala Asn Asp Gin Asp 290 295 300 He Gly Glu Asn Ala Gin Ser Ser Tyr Asp He He Asp Gly Asp Gly 305 310 315 320 Thr Ala Leu Phe Glu He Thr Ser Asp Ala Gin Ala Gin Asp Gly Val 325 330 335 He Arg Leu Arg Lys Pro Leu Asp Phe Glu Thr Lys Lys Ser Tyr Thr 340 345 350 Leu Lys Val Glu Ala Ala Asn He His He Asp Pro Arc- Phe Ser Gly 355 360 365 Arg Gly Pro Phe Lys Asp Thr Ala Thr Val Lys He Val Val Glu Asp 370 375 380 Ala Asp Glu Pro Pro Val Phe Ser Ser Pro Thr Tyr Leu Leu Glu Val 385 390 395 400 His Glu Asn Ala Ala Leu Asn Ser Val He Gly Gin Val Thr Ala Arg 405 410 415 Asp Pro Asp He Thr Ser Ser Pro He Arg Phe Ser He Asp Arg His 420 425 430 Thr Asp Leu Glu Arg Gin Phe Asn He Asn Ala Asp Asp Gly Lys He 435 440 445 Thr Leu Ala Thr Pro Leu Asp Arg Glu Leu Ser Val Trp His Asn He 450 455 460 Ser He He Ala Thr Glu He Arg Asn His Ser Gin He Ser Arg Val 465 470 475 480 Pro Val Ala He Lys Val Leu Asp Val Asn Asp Asn Ala Pro Glu Phe 485 490 495 Ala Ser Glu Tyr Glu Ala Phe Leu Cys Glu Asn Gly Lys Pro Gly Gin 500 505 510 Val Asn He Ser Met Leu Leu He Leu Asn Met Phe Val Tyr Asn Cys 515 520 525 Phe Leu Val Asn 530 (2) INFORMATION FOR SEQ ID NO:45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2490 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA ( i) SEQUENCE DESCRIPTION: SEQ ID NO:45: GGCACGAGGG CCAGTTGAGC CAGAGTCAGA ATTTGTGATC AAAATTCACG ATATCAACGA 60 CAATGAGCCT ACATTCCCAG AAGAAATTTA TACAGCCAGC GTTCCTGAAA TGTCTGTTGT 120 AGGTACTTCT GTGGTGCAAG TCACAGCTAC AGATGCCGAT GACCCTTCAT ATGGAAACAG 180 CGCCAGAGTC ATTTACAGCA TACTTCAAGG GCAGCCTTAT TTCTCTGTGG AACCAGAAAC 240 AGGTATCATA AGGACAGCTC TACCAAACAT GAACAGAGAG AACAAGGAAC AGTACCAGGT 300 GGTTATTCAA GCCAAGGACA TGGGCGGTCA GATGGGGGGT CTGTCTGGAA CCACCACAGT 360 GAACATCACT CTCACAGATG TCAACGACAA TCCTCCTCGC TTCCCCCAAA ACACCATCCA 420 TCTGCGAGTT CTTGAATCCT CTCCAGTTGG CACAGCTGTG GGAAGTGTAA AAGCCACCGA 480 TGCTGACACG GGGAAAAATG CCGAAGTGGA TTACCGCATT ATTGATGGAG ATGGCACAGA 540 TATGTTTGAC ATTATAACTG AGAAGGACAC ACAGGAAGGC ATCATCACTG TGAAAAAGCC 600 ACTTGACTAT GAGAACCGAA GACTATATAC TCTGAAGGTG GAGGCAGAAA ATACCCATGT 660 GGATCCACGT TTTTACTATT TAGGGCCATT CAAAGATACA ACAATTGTAA AAATCTCCAT 720 AGAAGACGTG GATGAGCCTC CAGTTTTCAG TCGATCCTCC TATCTGTTTG AGGTTCATGA 780 GGATATTGAA GTGGGCACAA TCATCGGTAC TGTAATGGCA AGAGACCCAG ATTCTACTTC 840 CAGTCCCATC AGATTTACTT TAGATCGCCA TACTGATCTT GACAGGATCT TTAACATTCA 900 TTCTGGAAAC GGATCACTTT ATACATCAAA GCCACTTGAT CGTGAACTAT CTCAATGGCA 960 CAACCTTACC GTCATAGCTG CCGAGATCAA TAATCCTAAA GAAACAACTC GTGTGTCTGT 1020 TTTTGTGAGG ATTTTGGATG TTAATGACAA CGCTCCACAA TTTGCTGTGT TTTATGACAC 1080 ATTTGTATGT GAAAATGCCA GACCAGGACA GCTGATACAG ACAATAAGTG CAGTTGACAA 1140 AGATGACCCC TTAGGTGGAC AGAAGTTCTT CTTCAGTTTG GCTGCTGTGA ATCCTAACTT 1200 CACAGTGCAA GACAATGAAG ACAACACTGC CAGAATTTTA ACCAGAAAGA ATGGCTTCAA 1260 CCGTCATGAA ATAAGCACCT ACCTACTGCC GGTAGTGATA TCTGATAATG ACTACCCCAT 1320 TCAGAGCAGC ACTGGCACCC TGACGATCCG TGTTTGCGCC TGTGACAGCC AGGGCAACAT 1380 GCAGTCCTGC AGTGCCGAAG CCCTGCTCCT TCCTGCTGGC CTCAGCACTG GCGCCTTGAT 1440 CGCCATTCTT CTCTGCATCA TCATTCTGCT GGTTATAGTA GTCCTCTTTG CAGCCCTGAA 1500 AAGGCAACGG AAGAAAGAGC CTCTGATTTT ATCCAAAGAA GACATCAGAG ACAACATTGT 1560 GAGCTATAAC GACGAAGGTG GCGGAGAGGA GGACACCCAA CCCTTTGAT TTGGAACCCT 1620 GAGGAATCCT GCAGCTATCG AGGAGAAAAA GCTGCGGCGA GATATCATTC CTGAAACGTT 1680 ATTTATACCG CGGCGGACTC CTACGGCCCC GGATAACACG GATGTCCGGG ATTTCATTAA 1740 TGAGCGCCTC AAAGAGCACG ACTTGGACCC CACTGCGCCT CCCTACGACT CGCTGGCTAC 1800 CTATGCCTAT GAAGGAAACG ACTCTGTTGC TGAATCTCTG AGCTCCTTAG AATCAGGTAC 1860 CACTGAAGGA GACCAAAACT ACGATTACCT TCGAGAATGG GGGCCTCGGT TTAATAAACT 1920 AGCAGAAATG TACGGTGGTG GTGAGAGCGA CAAAGACGCT TAGCCTGGCC CCTGAGCTCT 1980 GTTCAACGAG ATACGTAACT TTGCAGACAT TGTCTCCACT TCACAATATT TGATATTCAG 2040 GAGAAAAAAT TCCTGCCACT CAGCACAAGT TTCCCACCTA TTTCTTAATT TGTTCATTAA 2100 TTATATTAAT TCCTTCCTGT AGAATGTCTC ATGGGATATA TACGACATTT TATTTAATCA 2160 CTTCCAAGAG CCAAAGCTAT GGAAATTCAA TGTTGCCCAT CTTAGTAAAT AAAAGAAACC 2220 CGAGCAGGAT AGTTCTCCCT TAAGCAACCT CACGAACAAG TCGCTTCTGT TAGATACACG 2280 TCTTGCCCTT GCAAATGAAG CTTTGAAAAG ACGAAGAAAA CATTTAAGAT GTATCCTGTT 2340 CTGTACATTA AGTTTAAAAA AAAAAGTCCA TGTGGTGTTA GTAGGTGTGA TATGCAGCCT 2400 GGTATACGAG CATTCGTGCA ATTTCATTTC ATCAAATTCT ATCTGCTAAT GTTTTATATT 2460 TATATTTTTG TATTTATTTT TTAAAAAAAA 2490 (2) INFORMATION FOR SEQ ID NO:46: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 653 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: Ala Arg Gly Pro Val Glu Pro Glu Ser Glu Phe Val He Lys He His 1 5 10 15 Asp He Asn Asp Asn Glu Pro Thr Phe Pro Glu Glu He Tyr Thr Ala 20 25 30 Ser Val Pro Glu Met Ser Val Val Gly Thr Ser Val Val Gin Val Thr 35 40 45 Ala Thr Asp Ala Asp Asp Pro Ser Tyr Gly Asn Ser Ala Arg Val He 50 55 60 Tyr Ser He Leu Gin Gly Gin Pro Tyr Phe Ser Val Glu Pro Glu Thr 65 70 75 80 Gly He He Arg Thr Ala Leu Pro Asn Met Asn Arg Glu Asn Lys Glu 85 90 95 Gl-n Tyr Gin Val Val He Gin Ala Lys Asp Met Gly Gly Gin Met Gly 100 105 110 Gly Leu Ser Gly Thr Thr Thr Val Asn He Thr Leu Thr Asp Val Asn 115 120 125 Asp Asn Pro Pro Arg Phe Pro Gin Asn Thr He His Leu Arg Val Leu 130 135 140 Glu Ser Ser Pro Val Gly Thr Ala Val Gly Ser Val Lys Ala Thr Asp 145 150 155 160 Ala Asp Thr Gly Lys Asn Ala Glu Val Asp Tyr Arg He He Asp Gly 165 170 175 Asp Gly Thr Asp Met Phe Asp He He Thr Glu Lys Asp Thr Gin Glu 180 185 190 Gly He He Thr Val Lys Lys Pro Leu Asp Tyr Glu Asn Arg Arg Leu 195 200 205 Tyr Thr Leu Lys Val Glu Ala Glu Asn Thr His Val Asp Pro Arg Phe 210 215 220 Tyr Tyr Leu Gly Pro Phe Lys Asp Thr Thr He Val Lys He Ser He 225 230 235 240 Glu Asp Val Asp Glu Pro Pro Val Phe Ser Arg Ser Ser Tyr Leu Phe 245 250 255 Glu Val His Glu Asp He Glu Val Gly Thr He He Gly Thr Val Met 260 265 270 Ala Arg Asp Pro Asp Ser Thr Ser Ser Pro He Arg Phe Thr Leu Asp 275 280 285 Arg His Thr Asp Leu Asp Arg He Phe Asn He His Ser Gly Asn Gly 290 295 300 Ser Leu Tyr Thr Ser Lys Pro Leu Asp Arg Glu Leu Ser Gin Trp His 305 310 315 320 Asn Leu Thr Val He Ala Ala Glu He Asn Asn Pro Lys Glu Thr Thr 325 330 335 Arg Val Ser Val Phe Val Arg He Leu Asp Val Asn Asp Asn Ala Pro 340 345 350 Gin Phe Ala Val Phe Tyr Asp Thr Phe Val Cys Glu Asn Ala Arg Pro 355 360 365 Gly Gin Leu He Gin Thr He Ser Ala Val Asp Lys Asp Asp Pro Leu 370 375 380 Gly Gly Gin Lys Phe Phe Phe Ser Leu Ala Ala Val Asn Pro Asn Phe 385 390 395 400 Thr Val Gin Asp Asn Glu Asp Asn Thr Ala Arg He Leu Thr Arg Lys 405 410 415 Asn Gly Phe Asn Arg His Glu He Ser Thr Tyr Leu Leu Pro Val Val 420 425 430 He Ser Asp Asn Asp Tyr Pro He Gin Ser Ser Thr Gly Thr Leu Thr 435 440 445 He Arg Val Cys Ala Cys Asp Ser Gin Gly Asn Met Gin Ser Cys Ser 450 455 460 Ala Glu Ala Leu Leu Leu Pro Ala Gly Leu Ser Thr Gly Ala Leu He 465 470 475 480 Ala He Leu Leu Cys He He He Leu Leu Val He Val Val Leu Phe 485 490 495 Ala Ala Leu Lys Arg Gin Arg Lys Lys Glu Pro Leu lie Leu Ser Lys 500 505 510 Glu Asp He Arg Asp Asn He Val Ser Tyr Asn Asp Glu Gly Gly Gly 515 520 525 Glu Glu Asp Thr Gin Pro Phe Asp He Gly Thr Leu Arg Asn Pro Ala 530 535 540 Ala He Glu Glu Lys Lys Leu Arg Arg Asp He He Pro Glu Thr Leu 545 550 555 560 Phe He Pro Arg Arg Thr Pro Thr Ala Pro Asp Asn Thr Asp Val Arg 565 570 575 Asp Phe He Asn Glu Arg Leu Lys Glu His Asp Leu Asp Pro Thr Ala 580 585 590 Pro Pro Tyr Asp Ser Leu Ala Thr Tyr Ala Tyr Glu Gly Asn Asp Ser 595 600 605 Val Ala Glu Ser Leu Ser Ser Leu Glu Ser Gly Thr Thr Glu Gly Asp 610 615 620 Gin Asn Tyr Asp Tyr Leu Arg Glu Trp Gly Pro Arg Phe Asn Lys Leu 625 630 635 640 Ala Glu Met Tyr Gly Gly Gly Glu Ser Asp Lys Asp Ala 645 650 (2) INFORMATION FOR SEQ ID NO:47: ( ) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3048 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY- linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: CGCCGGCGGG GAAGATGACC GCGGGCGCCG GCGTGCTCCT TCTGCTGCTC TCGCTCTCCG 60 GCGCGCTCCG GGCCCATAAT GAGGATCTTA CAACTAGAGA GACCTGCAAG GCTGGGTTCT 120 CTGAAGATGA TTACACGGCA TTAATCTCCC AAAATATTCT AGAAGGGGAA AAGCTACTTC 180 AAGTCAAGTT CAGCAGCTGT GTGGGGACCA AGGGGACACA ATATGAGACC AACAGCATGG 240 ACTTCAAAGT TGGGGCAGAT GGGACAGTCT TCGCCACCCG GGAGCTGCAG GTCCCCTCCG 300 AGCAGGTGGC GTTCACGGTG ACTGCATGGG ACAGCCAGAC AGCAGAGAAA TGGGACGCCG 360 TGGTGCGGTT GCTGGTGGCC CAGACCTCGT CCCCGCACTC TGGACACAAG CCGCAGAAAG 420 GAAAGAAGGT CGTGGCTCTG GACCCCTCTC CGCCTCCGAA GGACACCCTG CTGCCGTGGC 480 CCCAGCACCA GAACGCCAAC GGGCTGAGGC GGCGCAAACG GGACTGGGTC ATCCCACCCA 540 TCAACGTGCC CGAGAACTCG CGCGGGCCCT TCCCGCAGCA GCTCGTGAGG ATCCGGTCCG 600 ACAAAGACAA TGACATCCCC ATCCGGTACA GCATCACGGG AGTGGGTGCC GACCAGCCCC 660 CCATGGAGGT CTTCAGCATT AACTCCATGT CCGGCCGGAT GTACGTCACA AGGCCCATGG 720 ACCGGGAGGA GCACGCCTCT TACCACCTCC GAGCCCACGC AGGTGGAGAA CCCCATCGAC CTGTACATCT ACGTCATCGA AGTTCATCAA CCAGGTCTAC AACTGCTCCG TGGACGAGGG TGATGACCAT CACGGCCAAC GATGCTGACG ACAGCACCAC ACCGGATCGT GACCCAGACC CCACAGAGCC CGTCCCAGAA AGACTGGAGA TATCGTCACA GTGGCGGCTG GCTGGGACCG CAGTCATCGT TCAGGCCACA GATATGGAAG GAAATCTCAA CCACAGCCAT CATCACGGTG ACAGATGTGA ATGACAACCC CGTTTGCAGG GGAGGTCCCC GAAAACAGCG TGGAGACCGT TGGACCGAGA TCAGCCCCAC TCTCCAAACT GGAATGCCGT ATCCATCCGG GCACTTCAGC GTCCGCACAG ACCCCGTAAC TGGTGAAGGC AGTCGACTAC GAGCTCAACA GAGCTTTCAT ACCAGGCGCC CCTGGCCAGC GGAATCCAGA TGTCCTTCCA TCTCCATCAT GGACATCAAC GAGGCTCCCT ACTTCCCCTC TGGAGGAGGG CGTGCCCCCC GGCACCGTGC TGACCACGTT GGTTCATGCA GCAGGCTGTG AGATACTCAA AGCTGTCAGA TCAATGCCAC CAACGGCCAG ATCACCACGG TGGCAGTGCT CCAAAAACAA CGTCTACGAG GCCACCTTCC TGGCAGCTGA GCGGCACCGG GACCCTCCAG ATCTATCTCA TTGACATCAA TGCCCAAGGA GGCGCAGATC TGCGAGAGGC CCAACCTGAA CCGACGCTGA CGTGCACCCC AACATCGGCC CCTACGTCTT CGGCCGTGCG GAAGAACTGG ACCATCACCC GCCTGAACGG TGCGCATCCT GTACCTGGAG GCCGGGATGT ATGACGTCCC GAAACCCTCC CCTGTCCAAC ACGTCCATCA TCAAAGTCAA ACGGGGACTG CACCACCATT GGCGCAGTGG CAGCGGCTGG TGGCCATCCT CATCTGCATC CTCATCCTGC TGACCATGGT TGAAGCGGCG AGAGAAGGAG CGCCACACGA AGCAGCTGCT TCCGCGAAAA GATCCTCAAG TATGACGAGG AAGGCGGTGG ACCTCAGCCA GCTGCAGCAG CCGGAAGCCA TGGGGCACGT TGCGTCGCGT GGATGAGCGG CCGGTGGGCC CTGAGCCCCA TGCCGCACCC AGGCGACATC GGTGACTTCA TCAATGAGGG ACCCCACGGC ACCCCCCTAT GACTCCCTGC TGGTCTTCGA CCGCAGGCTC CGTCAGCTCC CTGAACTCAT CCAGTTCCGG TCAACGACTG GGGCCCCAGA TTCAAGAAGC TGGCGGACAT ATTGACTGAC CTCGCATCTT CGGACCGAAG TGAGAGCCGT GCTCGGACGC CGGAGGAGCA 2820 GGACTGAGCA GAGGCGGCCG GTCTTCCCGA CTCCCTGCGG CTGTGTCCTT AGTGCTGTTA 2880 GGAGGCCCCC CAATCCCCAC GTTGAGCTGT CTAGCATGAG CACCCACCCC CACAGCGCCC 2940 TGCACCCGGC CGCTGCCCAG CACCGCGCTG GCTGGCACTG AAGGACAGCA AGAGGCACTC 3000 TGTCTTCACT TGAATTTCCT AGAACAGAAG CACTGTTTTT AAAAAAAG 3048 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 916 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: Met Thr Ala Gly Ala Gly Val Leu Leu Leu Leu Leu Ser Leu Ser Gly 1 5 10 15 Ala Leu Arg Ala His Asn Glu Asp Leu Thr Thr Arg Glu Thr Cys Lys 20 25 30 Ala Gly Phe Ser Glu Asp Asp Tyr Thr Ala Leu He Ser Gin Asn He 35 40 45 Leu Glu Gly Glu Lys Leu Leu Gin Val Lys Phe Ser Ser Cys Val Gly 50 55 60 Thr Lys Gly Thr Gin Tyr Glu Thr Asn Ser Met Asp Phe Leu Val Gly 55 70 75 80 Ala Asp Gly Thr Val Phe Ala Thr Arg Glu Leu Gin Val Pro Ser Glu 85 90 95 Gin Val Ala Phe Thr Val Thr Ala Trp Asp Ser Gin Thr Ala Glu Lys 100 105 110 Trp Asp Ala Val Val Arg Leu Leu Val Ala Gin Thr Ser Ser Pro His 115 120 125 Ser Gly His Lys Pro Gin Lys Gly Lys Lys Val Val Ala Leu Asp Pro 130 135 140 Ser Pro Pro Pro Lys Asp Thr Leu Leu Pro Trp Pro Gin His Gin Asn 145 150 155 160 Ala Asn Gly Leu Arg Arg Arg Lys Arg Asp Trp Val He Pro Pro He 165 170 175 Asn Val Pro Glu Asn Ser Arg Gly Pro Phe Pro Gin Gin Leu Val Arg 180 185 190 He ' Arg Ser .Asp Lys Asp Asn Asp He Pro He Arg Tyr Ser He Thr 195 200 205 Gly Val Gly Ala Asp Gin Pro Pro Met Glu Val Phe Ser He Asn Ser 210 215 220 Met Ser Gly Arg Met Tyr Val Thr Arg Pro Met Asp Arg Glu Glu His 225 230 235 240 Ala Ser Tyr His Leu Arg Ala His Ala Val Asp Met Asn Gly Asn Lys 245 250 255 Val Glu Asn Pro He Asp Leu Tyr He Tyr Val He Asp Met Asn Asp 260 265 270 Asn His Pro Glu Phe He Asn Gin Val Tyr Asn Cys Ser Val Asp Glu 275 280 285 Gly Ser Lys Pro Gly Thr Tyr Val Met Thr He Thr Ala Asn Asp Ala 290 295 300 Asp Asp Ser Thr Thr Ala Asn Gly Met Val Arg Tyr Arg He Val Thr 305 310 315 320 Gin Thr Pro Gin Ser Pro Ser Gin Asn Met Phe Thr He Asn Ser Glu 325 330 335 Thr Gly Asp He Val Thr Val Ala Ala Gly Trp Asp Arg Glu Lys Val 340 345 350 Gin Gin Tyr Thr Val He Val Gin Ala Thr Asp Met Glu Gly Asn Leu 355 360 365 Asn Tyr Gly Leu Ser Asn Thr Ala Thr Ala He He Thr Val Thr Asp 370 375 380 Val Asn Asp Asn Pro Ser Glu Phe Thr Ala Ser Thr Phe Ala Gly Glu 385 390 395 400 Val Pro Glu Asn Ser Val Glu Thr Val Val Ala Asn Leu Thr Val Met 405 410 415 Asp Arg Asp Gin Pro His Ser Pro Asn Trp Asn Ala Val Tyr Arg He 420 425 430 He Ser Gly Asp Pro Ser Gly His Phe Ser Val Arg Thr Asp Pro Val 435 440 445 Thr Asn Glu Gly Met Val Thr Val Val Lys Ala Val Asp Tyr Glu Leu 450 455 460 Asn Arg Ala Phe Met Leu Thr Val Met Val Ser Asn Gin Ala Pro Leu 465 470 475 480 Ala Ser Gly He Gin Met Ser Phe Gin Ser Thr Ala Gly Val Thr He 485 490 495 Ser He Met Asp He Asn Glu Ala Pro Tyr Phe Pro Ser Asn His Lys 500 505 510 Leu He Arg Leu Glu Glu Gly Val Pro Pro Gly Thr Val Leu Thr Thr 515 520 525 Phe Ser Ala Val Asp Pro Asp Arg Phe Met Gin Gin Ala Val Arg Tyr 530 535 540 Ser Lys Leu Ser Asp Pro Ala Ser Trp Leu His He Asn Ala Thr Asn 545 550 555 560 Gly Gin lie Thr Thr Val Ala " Val Leu Asp Arg Glu Ser Leu Tyr Thr 565 570 575 Lys Asn Asn Val Tyr Glu Ala Thr Phe Leu Ala Ala Asp Asn Gly He 580 585 590 Pro Pro Ala Ser Gly Thr Gly Thr Leu Gin He Tyr Leu He Asp He 595 600 605 Asn Asp Asn Ala Pro Glu Leu Leu Pro Lys Glu Ala Gin He Cys Glu 610 615 620 Arg Pro Asn Leu Asn Ala He Asn He Thr Ala Ala Asp Ala Asp Val 625 630 635 640 His Pro Asn He Gly Pro Tyr Val Phe Glu Leu Pro Phe Val Pro Ala 645 650 655 Ala Val Arg Lys Asn Trp Thr He Thr Arg Leu Asn Gly Asp Tyr Ala 660 665 670 Gin Leu Ser Leu Arg He Leu Tyr Leu Glu Ala Gly Met Tyr Asp Val 675 680 685 Pro He He Val Thr Asp Ser Gly Asn Pro Pro Leu Ser Asn Thr Ser 690 695 700 He He Lys Val Lys Val Cys Pro Cys Asp Asp Asn Gly Asp Cys Thr 705 710 715 720 Thr He Gly Ala Val Ala Ala Ala Gly Leu Gly Thr Gly Ala He Val 725 730 735 Ala He Leu He Cys He Leu He Leu Leu Thr Met Val Leu Leu Phe 740 745 750 Val Met Trp Met Lys Arg Arg Glu Lys Glu Arg His Thr Lys Gin Leu 755 760 765 Leu He Asp Pro Glu Asp Asp Val Arg Glu Lys He Leu Lys Tyr Asp 770 775 780 Glu Glu Gly Gly Gly Glu Glu Asp Gin Asp Tyr Asp Leu Ser Gin Leu 785 790 795 800 Gin Gin Pro Glu Ala Met Gly His Val Pro Ser Lys Ala Pro Gly Val 805 810 815 Arg Arg Val Asp Glu Arg Pro Val Gly Pro Glu Pro Gin Tyr Pro He 820 825 830 Arg Pro Met Val Pro His Pro Gly Asp He Gly Asp Phe He Asn Glu 835 840 845 Gly Leu Arg Ala Ala Asp Asn Asp Pro Thr Ala Pro Pro Tyr Asp Ser 850 855 860 Leu Leu Val Phe Asp Tyr Glu Gly Ser Gly Ser Thr Ala Gly Ser Val 865 870 875 880 Ser Ser Leu Asn Ser Ser Ser Ser Gly Asp Gin Asp Tyr Asp Tyr Leu 885 890 895 Asn Asp Trp Gly Pro Arg Phe Lys Lys Leu Ala Asp Met Tyr Gly Gly 900 905 910 Gly Glu Glu Asp 915 (2) INFORMATION FOR SEQ ID NO:49: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3164 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: CTCCACTCAC GCTCAGCCCT GGACGGACAG GCAGTCCAAC CCCACAGGCA CGATCTGTTC CTCCTGGGAA GATGCAGAGG TCGGGCGCCT GCCTGGGCCT GCTGGCAGTG GCAGCAGTGG GCCCAACGGG ACACCCACAG CCTGCTGCCC ACCCACCGGC TGGAACCAGA TGCACATTGA TGAAGAGAAA AACACCTCAC ATCAAGTCAA GCGTGAGTCG CAAGAATGCC AAGTACCTGC AAGGTCTTCC GGGTCGATGC AGAGACAGGA GACGTGTTCG GAGAATATCT CAGAGTACCA CCTCACTGCT GTCATTGTGG CTGGAGACTC CTTCCAGCTT CACCATCAAA GTTCATGACG TTCACGCATC GGTTGTTCAA TGCGTCCGTG CCTGAGTCGT ATCTCTGTGA CAGCAGTGGA TGCAGACGAC CCCACTGTGG TACCAAATCC TGAAGGGGAA AGAGTATTTT GCCATCGATA ATAACGAAAA GCTTGGACCG AGAGAAGCAG GCCAGGTATG GATGCCCAGG GCCTCCGGGG GGACTCGGGC ACGGCCACCG ATCAATGACA ACTTCCCCTT CTTCACCCAG ACCAAGTACA ACCCGTGTGG GCACCTCTGT GGGCTCTCTG TTTGTTGAGG CGGATGACCA AGTACAGCAT CTTGCGGGGC GACTACCAGG AACCCCGCCC ACAACGAGGG CATCATCAAG CCCATGAAGC CAGCAATACA GCTTCATAGT CGAGGCCACA GACCCCACCA CCTCCCGCGG GAAACAGAGC CCAGGTCATT ATCAACATCA ATTTTCCAGC AGCCTTTCTA CCACTTCCAG CTGAAGGAAA GGCACAGTGC TGGCCATGGA CCCTGATGCG GCTAGGCATA AGGACCAGTG ACAAGGGCCA GTTCTTCCGA GTCACAAAAA AAAGAACTGG ACAGAGAAGT CTACCCCTGG TATAACCTGA GATTCCACTG GAACCCCCAC AGGAAAAGAA TCCATTGTGC GATGAGAATG ACAATGCCCC GGAGTTTGCC AAGCCCTACC GCTGTCCATG GCCAGCTGGT CCTGCAGATC TCCGCAATAG AACGTGAAGT TCAAATTCAT CTTGAATACT GAGAACAACT TTACCCTCAC GATAACACGG CCAACATCAC AGTCAAGTAT GGGCAGTTTG ACCGGGAGCA CACTTCCTAC CCGTGGTCAT CTCAGACAAT GGGATGCCAA GTCGCACGGG CTGACCGTGG CCGTGTGCAA GTGCAACGAG CAGGGCGAGT TCACCTTCTG GCCGCCCAGG TGGGCGTGAG CATCCAGGCA GTGGTAGCCA TCTTACTCTG ATCACAGTGA TCACCCTGCT CATCTTCCTG CGGCGGCGGC TCCGGAAGCA CACGGCAAGA GCGTGCCGGA GATCCACGAG CAGCTGGTCA CCTACGACGA GGCGAGATGG ACACCACCAG CTACGATGTG TCGGTGCTCA ACTCGGTGCG GCCAAGCCCC CGCGGCCCGC GCTGGACGCC CGGCCTTCCC TCTATGCGCA CCACCGAGGC ACGCGCCTGG GGCACACGGA GGGCCCGGGG AGATGGCAGC GTGAAGAAGG ACGAGGCGGA CCACGACGGC GACGGCCCCC CCTACGACAC TACGGCTACG AGGGCTCCGA GTCCATAGCC GAGTCCCTCA GCTCCCTGGG TCCGACTCTG ACGTGGATTA CGACTTCCTT AACGACTGGG GACCCAGGTT GCTGAGCTGT ACGGCTCGGA CCCCCGGGAG GAGCTGCTGT ATTAGGCGGC CTGGGCCTGG GGACCCAAAC CCCCTGCAGC CCAGGCCAGT CAGACTCCAG CTCCAAAAAT GGCAGTGACT CCCCAGCCCA GCACCCCTTC CTCGTGGGTC CATCAGCCTT GGGATAGCAA ACTCCAGGTT CCTGAAATAT CCAGGAATAT TGACTATTCT CAAATGCTGG CAAATCCAGG CTGGTGTTCT GTCTGGGCTC ATAACCCTGT CACCCACAGA CCGCCGTCTA ACTCAAAGAC TTCCTCTGGC TGCAAAGCAA AACAGACTGT GTTTAACTGC TGCAGGGTCT TTTTCTAGGG CCCTGGTAAG GCTGGTGAGG TCCTGGTGCC TATCTGCCTG GAGGCAAAGG TTGACTTGTG GGGCAGGATT CTCTGCAGCC CATTCCCAAG GGAGACTGAC TCTCTCGGGA GCCCTAGCCC TGCTCCAACT CCATACTCCA CTCCAAGTGC CCCAACCCCT CTCCAGGCCT GTCAAGAGGG AGGAAGGGGC CCCATGGCAG TGGGTCCTGA AGTGACCTCA CTGGCCTGCC ATGCCAGTAA CTGTGCTGTA AACCACATTC AGGGAAATGG CTTATTAAAC TTTGAAGCAA CTGT (2) INFORMATION FOR SEQ ID NO:50: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 780 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50ϊ Met Met Leu Leu Ala Thr Ser Gly Ala Cys Leu Gly Leu Leu Ala Val 1 5 10 15 Ala Ala Val Ala Ala Ala Gly Ala Asn Pro Ala Gin Arg Asp Thr His 20 25 30 Ser Leu Leu Pro Thr His Arg Arg Gin Lys Arg Asp Trp He Trp Asn 35 40 45 Gin Met His He Asp Glu Glu Lys Asn Thr Ser Leu Pro His His Val 50 55 60 Gly Lys He Lys Ser Ser Val Ser Arg Lys Asn Ala Lys Tyr Leu Leu 65 70 75 80 Lys Gly Glu Tyr Val Gly Lys Val Phe Arg Val Asp Ala Glu Thr Gly 85 90 95 Asp Val Phe Ala He Glu Arg Leu Asp Arg Glu Asn He Ser Glu Tyr 100 105 110 His Leu Thr Ala Val He Val Asp Lys Asp Thr Gly Glu Asn Leu Glu 115 120 125 Thr Pro Ser Ser Phe Thr He Lys Val His Asp Val Asn Asp Asn Trp 130 135 140 Pro Val Phe Thr His Arg Leu Phe Asn Ala Ser Val Pro Glu Ser Ser 145 150 155 160 Ala Val Gly Thr Ser Val He Ser Val Thr Ala Val Asp Ala Asp Asp 165 170 175 Pro Thr Val Gly Asp His Ala Ser Val Met Tyr Gin He Leu Lys Gly 180 185 190 Lys Glu Tyr Phe Ala He Asp Asn Ser Gly Arg He He Thr He Thr 195 200 205 Lys Ser Leu Asp Arg Glu Lys Gin Ala Arg Tyr Glu He Val Val Glu 210 215 220 Ala Arg Asp Ala Gin Gly Leu Arg Gly Asp Ser Gly Thr Ala Thr Val 225 230 235 240 Leu Val Thr Leu Gin Asp He Asn Asp Asn Phe Pro Phe Phe Thr Gin 245 250 255 Thr Lys Tyr Thr Phe Val Val Pro Glu Asp Thr Arg Val Gly Thr Ser 260 265 270 Val Gly Ser Leu Phe Val Glu Asp Pro Asp Glu Pro Gin Asn Arg Met 275 280 285 Thr Lys Tyr Ser He Leu Arg Gly Asp Tyr Gin Asp Ala Phe Thr He 290 295 300 Glu Thr Asn Pro Ala His Asn Glu Gly He He Lys Pro Met Lys Pro 305 310 315 320 Leu Asp Tyr Glu Tyr He Gin Gin Tyr Ser Phe He Val Glu Ala Thr 325 330 335 Asp Pro Thr He Asp- Leu Arg Tyr Met Ser Pro Pro Ala Gly Asn Arg 340 345 350 Ala Gin Val He He Asn He Thr Asp Val Asp Glu Pro Pro He Phe 355 360 365 Gln Gin Pro Phe Tyr His Phe Gin Leu Lys Glu Asn Gin Lys Lys Pro 370 375 380 Leu He Gly Thr Val Leu Ala Met Asp Pro Asp Ala Ala Arg His Ser 385 390 395 400 He Gly Tyr Ser He Arg Arg Thr Ser Asp Lys Gly Gin Phe Phe Arg 405 410 415 Val Thr Lys Lys Gly Asp He Tyr Asn Glu Lys Glu Leu Asp Arg Glu 420 425 430 Val Tyr Pro Trp Tyr Asn Leu Thr Val Glu Ala Lys Glu Leu Asp Ser 435 440 445 Thr Gly Thr Pro Thr Gly Lys Glu Ser He Val Gin Val His He Glu 450 455 460 Val Leu Asp Glu Asn Asp Asn Ala Pro Glu Phe Ala Lys Pro Tyr Gin 465 470 475 480 Pro Lys Val Cys Glu Asn Ala Val His Gly Gin Leu Val Leu Gin He 485 490 495 Ser Ala He Asp Lys Asp He Thr Pro Arg Asn Val Lys Phe Lys Phe 500 505 510 He Leu Asn Thr Glu Asn Asn Phe Thr Leu Thr Asp Asn His Asp Asn 515 520 525 Thr Ala Asn He Thr Val Lys Tyr Gly Gin Phe Asp Arg Glu His Thr 530 535 540 Lys Val His Phe Leu Pro Val Val He Ser Asp Asn Gly Met Pro Ser 545 " 550 555 560 Arg Thr Gly Thr Ser Thr Leu Thr Val Ala Val Cys Lys Cys Asn Glu 565 570 575 Gin Gly Glu Phe Thr Phe Cys Glu Asp Met Ala Ala Gin Val Gly Val 580 585 590 Ser He Gin Ala Val Val Ala He Leu Leu Cys He Leu Thr He Thr 595 600 605 Val He Thr Leu Leu He Phe Leu Arg Arg Arg Leu Arg Leu Gin Ala 610 615 620 Arg Ala His Gly Lys Ser Val Pro Glu He His Glu Gin Leu Val Thr 625 630 635 640 Tyr Asp Glu Glu Gly Gly Gly Glu Met Asp Thr Thr Ser Tyr Asp Val 645 650 655 Ser Val Leu Asn Ser Val Arg Arg Gly Gly Ala Lys Pro Pro Arg Pro 660 665 670 Ala Leu Asp Ala Arg Pro Ser Leu Tyr Ala Gin Val Gin Lys Pro Pro 675 680 685 Arg His Ala Pro Gly Ala His Gly Gly Pro Gly Glu Met Ala Ala Met 690 695 700 He Glu Val Lys Lys Asp Glu Ala Asp His Asp Gly Asp Gly Pro Pro 705 710 715 720 Tyr Asp Thr Leu His He Tyr Gly Tyr Glu Gly Ser Glu Ser He Ala 725 730 735 Glu Ser Leu Ser Ser Leu Gly Thr Asp Ser Ser Asp Ser Asp Val Asp 740 745 750 Tyr Asp Phe Leu Asn Asp Trp Gly Pro Arg Phe Lys Met Leu Ala Glu 755 760 765 Leu Tyr Gly Ser Asp Pro Arg Glu Glu Leu Leu Tyr 770 775 780 (2) INFORMATION FOR SEQ ID NO:51: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1369 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: TGTAGATGAG CCACCTGTCT TCAGCAAACT GGCCTACATC TTACAAATAA GAGAAGATGC 60 TCAGATAAAC ACCACAATAG GCTCCGTCAC AGCCCAAGAT CCAGATGCTG CCAGGAATCC 120 TGTCAAGTAC TCTATAGATC GACACACAGA TATGGACAGA ATATTCAACA TTGATTCTGG 180 AAATGGTTCG ATTTTTACAT CGAAACTTCT TGACCGAGAA ACACTGCTAT GGCACAACAT 240 TACAGTGATA GCAACAGAGA TCAATAATCC AAAGCAAAGT AGTCGAGTAC CTCTATATAT 300 TAAAGTTCTA GATGTCAATG ACAACGCCCC AGAATTTGCT GAGTTCTATG AAACTTTTGT 360 CTGTGAAAAA GCAAAGGCAG ATCAGTTGAT TCAGACCTTG CATGCTGTTA GCAAGGATGA 420 CCCTTATAGT GGGCACCAAT TTTCGTTTTC CTTGGCCCCT GAAGCAGCCA GTGGCTCAAA 480 CTTTACCATT CAAGACAACA AAGACAACAC GGCGGGAATC TTAACTCGGA AAAATGGCTA 540 TAATAGACAC GAGATGAGCA CCTATCTCTT GCCTGTGGTC ATTTCAGACA ACGACTACCC 600 AGTTCAAAGC AGCACTGGGA CAGTGACTGT CCGGGTCTGT GCATGTGACC ACCACGGGAA 660 CATGCAATCC TGCCATGCGG AGGCGCTCAT CCACCCCACG GGACTGAGCA CGGGGGCTCT 720 GGTTGCCATC CTTCTGTGCA TCGTGATCCT ACTAGTGACA GTGGTGCTGT TTGCAGCTCT 780 GAGGCGGCAG CGAAAAAAAG AGCCTTTGAT CATTTCCAAA GAGGACATCA GAGATAACAT 840 TGTCAGTTAC AACGACGAAG GTGGTGGAGA GGAGGACACC CAGGCTTTTG ATATCGGCAC 900 CCTGAGGAAT CCTGAAGCCA TAGAGGACAA CAAATTACGA AGGGACATTG TGCCCGAAGC 960 CCTTTTCCTA CCCCGACGGA CTCCAACAGC TCGCGACAAC ACCGATGTCA GAGATTTCAT 1020 TAACCAAAGG TTAAAGGAAA ATGACACGGA CCCCACTGCC CCGCCATACG ACTCCCTGGC 1080 CACTTACGCC TATGAAGGCA CTGGCTCCGT GGCGGATTCC CTGAGCTCGC TGGAGTCAGT 1140 GACCACGGAT GCAGATCAAG ACTATGATTA CCTTTAGTGA CTGGGACCTC GATTCAAAAA 1200 GCTTGCAGAT ATGTATGGAG GAGTGGACAG TGACAAAGAC TCCTAATCTG TTGCCTTTTT 1260 CATTTTCCAA TACGACACTG AAATATGTGA AGTGGCTATT TCTTTATATT TATCCACTAC 1320 TCCGTGAAGG CTTCTCTGTT CTACCCGTTC CAAAAGCCAA TGGCTGCAG 1369 (2) INFORMATION FOR SEQ ID NO:52: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 414 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: Val Asp Glu Pro Pro Val Phe Ser Lys Leu Ala Tyr He Leu Gin He 1 5 10 15 Arg Glu Asp Ala Gin He Asn Thr Thr He Gly Ser Val Thr Ala Gin 20 25 30 Asp Pro Asp Ala Ala Arg Asn Pro Val Lys Tyr Ser He Lys Arg His 35 40 45 Thr Asp Met Asp Arg He Phe Asn He Asp Ser Gly Asn Gly Ser He 50 55 60 Phe Thr Ser Lys Leu Leu Lys Arg Glu Thr Leu Leu Trp His Asn He 65 70 75 80 Thr Val He Ala Thr Glu He Asn Asn Pro Lys Gin Ser Ser Arg Val 85 90 95 Pro Leu Tyr He Lys Val Leu Asp Val Asn Asp Asn Ala Pro Glu Phe 100 105 110 Ala Glu Phe Tyr Glu Thr Phe Val Cys Glu Lys Ala Lys Ala Asp Gin 115 120 125 Leu He Gin Thr Leu His Ala Val Asp Lys Asp Asp Pro Tyr Ser Gly - 130 135 140 His Gin Phe Ser Phe Ser Leu Ala Pro Glu Ala Ala Ser Gly Ser Asn 145 150 155 160 Phe Thr He Gin Asp Asn Lys Asp Asn Thr Ala Gly He Leu Thr Arg 165 170 175 Lys Asn Gly Tyr Asn Arg His Glu Met Ser Thr Tyr Leu Leu Pro Val 180 185 190 Val He Ser Asp Asn Asp Tyr Pro Val Gin Ser Ser Thr Gly Thr Val 195 200 205 Thr Val Arg Val Cys Ala Cys Asp His His Gly Asn Met Gin Ser Cys 210 215 220 His Ala Glu Ala Leu He His Pro Thr Gly Leu Ser Thr Gly Ala Leu 225 230 235 240 - Val Ala He Leu Leu Cys He Val He Leu Leu Val Thr Val Val Leu 245 250 255 Phe Ala Ala Leu Arg Arg Gin Arg Lys Lys Glu Pro Leu He He Ser 260 265 270 Lys Glu Asp He Arg Asp Asn He Val Ser Tyr Asn Asp Glu Gly Gly 275 280 285 Gly Glu Glu Asp Thr Gin Ala Phe Asp He Gly Thr Leu Arg Asn Pro 290 295 300 Glu Ala He Glu Asp Asn Lys Leu Arg Arg Asp He Val Pro Glu Ala 305 310 315 320 Leu Phe Leu Pro Arg Arg Thr Pro Thr Ala Arg Asp Asn Thr Asp Val 325 330 335 Arg Asp Phe He Asn Gin Arg Leu Lys Glu Asn Asp Thr Asp Pro Thr 340 345 350 Ala Pro Pro Tyr Asp Ser Leu Ala Thr Tyr Ala Tyr Glu Gly Thr Gly 355 360 365 Ser Val Ala Asp Ser Leu Ser Ser Leu Glu Ser Val Thr Thr Asp Ala 370 375 380 Asp Gin Asp Tyr Asp Tyr Leu Ser Asp Trp Gly Pro Arg Phe Lys Lys 385 390 395 400 Leu Ala Asp Met Tyr Gly Gly Val Asp Ser Asp Lys Asp Ser 405 410 (2) INFORMATION FOR SEQ ID NO:53: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2550 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) .TOPOLOGY: 1inear (ii) MOLECULE TYPE: cDNA ( i) SEQUENCE DESCRIPTION: SEQ ID NO:53: CAGGAAATGC TCTTGGATCT CTGGACTCCA TTAATAATAT TATGGATTAC TCTTCCCCCT 60 TGCATTTACA TGGCTCCGAT GAATCAGTCT CAAGTTTTAA TGAGTGGATC CCCTTTGGAA 120 CTAAACAGTC TGGGTGAAGA ACAGCGAATT TTGAACCGCT CCAAAAGAGG CTGGGTTTGG 180 AATCAAATGT TTGTCCTGGA AGAGTTTTCT GGACCTGAAC CGATTCTTGT TGGCCGGCTA 240 CACACAGACC TGGATCCTGG GAGCAAAAAA ATCAAGTATA TCCTATCAGG TGATGGAGCT 300 GGGACCATAT TTCAAATAAA TGATGTAACT GGAGATATCC ATGCTATAAA AAGACTTGAC 360 CGGGAGGAAA AGGCTGAGTA TACCCTAACA GCTCAAGCAG TGGACTGGGA GACAAGCAAA 420 CCTCTGGAGC CTCCTTCTGA ATTTATTATT AAAGTTCAAG ACATCAATGA CAATGCACCA 480 GAGTTTCTTA ATGGACCCTA TCATGCTACT GTGCCAGAAA TGTCCATTTT GGGTACATCT 540 GTCACTAACG TCACTGCGAC CGACGCTGAT GACCCAGTTT ATGGAAACAG TGCAAAGTTG 600 GTTTATAGTA TATTGGAAGG GCAGCCTTAT TTTTCCATTG AGCCTGAAAC AGCTATTATA 660 AAAACTGCCC TTCCCAACAT GGACAGAGAA GCCAAGGAGG AGTACCTGGT TGTTATCCAA 720 GCCAAAGATA TGGGTGGACA CTCTGGTGGC CTGTCTGGGA CCACGACACT TACAGTGACT 780 CTTACTGATG TTAATGACAA TCCTCCAAAA TTTGCACAGA GCCTGTATCA CTTCTCAGTA 840 CCGGAAGATG TGGTTCTTGG CACTGCAATA GGAAGGGTGA AGGCCAATGA TCAGGATATT 900 GGTGAAAATG CACAGTCATC ATATGATATC ATCGATGGAG ATGGAACAGC ACTTTTTGAA 960 ATCACTTCTG ATGCCCAGGC CCAGGATGGC ATTATAAGGC TAAGAAAACC TCTGGACTTT 1020 GAGACCAAAA AATCCTATAC GCTAAAGGAT GAGGCAGCCA ATGTCCATAT TGACCCACGC 1080 TTCAGTGGCA GGGGGCCCTT TAAAGACACG GCGACAGTCA AAATCGTGGT TGAAGATGCT 1140 GATGAGCCTC CGGTCTTCTC TTCACCGACT TACCTACTTG AAGTTCATGA AAATGCTGCT 1200 CTAAACTCCG TGATTGGGCA AGTGACTGCT CGTGACCCTG ATATCACTTC CAGTCCTATA 1260 AGGTTTTCCA TCGACCGGCA CACTGACCTG GAGAGGCAGT TCAACATTAA TGCAGACGAT 1320 GGGAAGATAA CGCTGGCAAC ACCACTTGAC AGAGAATTAA GTGTATGGCA CAACATAACA 1380 ATCATTGCTA CTGAAATTAG GAACCACAGT CAGATATCAC GAGTACCTGT TGCTATTAAA 1440 GTGCTGGATG TCAATGACAA CGCCCCTGAA TTCGCATCCG AATATGAGGC ATTTTTATGT 1500 GAAAATGGAA AACCCGGCCA AGTCATTCAA ACTGTTAGCG CCATGGACAA AGATGATCCC 1560 AAAAACGGAC ATTATTTCTT ATACAGTCTC CTTCCAGAAA TGGTCAACAA TCCGAATTTC 1620 ACCATCAAGA AAAATGAAGA TAATTCCCTC AGTATTTTGG CAAAGCATAA TGGATTCAAC 1680 CGCCAGAAGC AAGAAGTCTA TCTTTTACCA ATCATAATCA GTGATAGTGG AAATCCTCCA 1740 CTGAGCAGCA CTAGCACCTT GACAATCAGG GTCTGTGGCT GCAGCAATGA CGGTGTCGTC 1800 CAGTCTTGCA ATGTCGAAGC TTATGTCCTT CCAATTGGAC TCAGTATGGG " CGCCTTAATT 1860 GCCATATTAG CATGCATCAT TTTGCTGTTA GTCATCGTGG TGCTGTTTGT AACTCTACGG 1920 CGGCATCAAA AAAATGAACC ATTAATTATC AAAGATGATG AAGACGTTCG AGAAAACATC 1980 ATTCGCTACG ATGATGAAGG AGGAGGGGAG GAGGACACAG AGGCTTTTGA CATTGCAACT 2040 TTACAAAATC CAGATGGAAT TAATGGATTT TTACCCCGTA AGGATATTAA ACCAGATTTG 2100 CAGTTTATGC CAAGGCAAGG GCTTGCTCCA GTTCCAAATG GTGTTGATGT CGATGAATTT 2160 ATAAATGTAA GGCTGCATGA GGCAGATAAT GATCCCACAG CCCCGCCATA TGACTCCATT 2220 CAAATATATG GCTATGAAGG CCGAGGGTCA GTGGCTGGCT CCCTCAGCTC CTTGGAGTCC 2280 ACCACATCAG ACTCAGACCA GAATTTTGAC TACCTCAGTG ACTGGGGTCC CCGCTTTAAG 2340 AGACTGGGCG AACTCTACTC TGTTGGTGAA AGTGACAAAG AAACTTGACA GTGGATTATA 2400 AATAAATCAC TGGAACTGAG CATTCTGTAA TATTCTAGGG TCACTCCCCT TAGATACAAC 2460 CAATGTGGCT ATTTGTTTAG AGGCAAGTTT AGCACCAGTC ATCTATAACT CAACCACATT 2520 TAATGTTGAC AAAAAGATAA TAAATAAAAA 2550 (2) INFORMATION FOR SEQ ID NO:54: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 793 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: Met Leu Leu Asp Leu Trp Thr Pro Leu He He Leu Trp He Thr Leu 1 5 10 15 Pro Pro Cys He Tyr Met Ala Pro Met Asn Gin Ser Gin Val Leu Met 20 25 30 Ser Gly Ser Pro Leu Gin Leu Asn Ser Leu Gly Glu Glu Gin Arg He 35 40 45 Leu Asn Arg Ser Lys Arg Gly Trp Val Trp Asn Gin Met Phe Val Leu 50 55 60 Glu Glu Phe Ser Gly Pro Glu Pro He Leu Val Gly Arg Leu His Thr 65 70 75 80 Asp Leu Asp Pro Gly Ser Lys Lys He Lys Tyr He Leu Ser Gly Asp 85 90 95 Gly Ala Gly Thr He Phe Gin He Asn Asp Val Thr Gly Asp He His 100 105 110 Ala He Lys Arg Leu Asp Arg Glu Glu Lys Ala Glu Tyr Thr Leu Thr 115 120 125 Ala Gin Ala Val Asp Trp Glu Thr Ser Lys Pro Leu Glu Pro Pro Ser 130 135 140 Glu Phe He He Lys Val Gin Asp He Asn Asp Asn Ala Pro Glu Phe 145 150 155 160 Leu Asn Gly Pro Tyr His Ala Thr Val Pro Glu Met Ser He Leu Gly 165 170 175 ' Thr Ser Val Thr Asn Val Thr Ala Thr Asp Ala Asp Asp Pro Val Tyr 180 185 190 Gly Asn Ser Ala Lys Leu Val Tyr Ser He Leu Glu Gly Gin Pro Tyr 195 200 205 Phe Ser He Glu Pro Glu Thr Ala He He Lys Thr Ala Leu Pro Asn 210 215 220 Met Asp Arg Glu Ala Lys Glu Glu Tyr Leu Val Val He Gin Ala Lys 225 230 235 240 Asp Met Gly Gly His Ser Gly Gly Leu Ser Gly Thr Thr Thr Leu Thr 245 250 255 Val Thr Leu Thr Asp Val Asn Asp Asn Pro Pro Lys Phe Ala Gin Ser 260 265 270 Leu Tyr His Phe Ser Val Pro Glu Asp Val Val Leu Gly Thr Ala He 275 280 285 Gly Arg Val Lys Ala Asn Asp Gin Asp He Gly Glu Asn Ala Gin Ser 290 295 300 Ser Tyr Asp He He Asp Gly Asp Gly Thr Ala Leu Phe Glu He Thr 305 310 315 320 Ser Asp Ala Gin Ala Gin Asp Gly He He Arg Leu Arg Lys Pro Leu 325 330 335 Asp Phe Glu Thr Lys Lys Ser Tyr Thr Leu Lys Asp Glu Ala Ala Asn 340 345 350 Val His He Asp Pro Arg Phe Ser Gly Arg Gly Pro Phe Lys Asp Thr 355 360 365 Ala Thr Val Lys He Val Val Glu Asp Ala Asp Glu Pro Pro Val Phe 370 375 380 Ser Ser Pro Thr Tyr Leu Leu Glu Val His Glu Asn Ala Ala Leu Asn 385 390 395 400 Ser Val He Gly Gin Val Thr Ala Arg Asp Pro Asp He Thr Ser Ser 405 410 415 Pro He Arg Phe Ser He Asp Arg His Thr Asp Leu Glu Arg Gin Phe 420 425 430 Asn He Asn Ala Asp Asp Gly Lys He Thr Leu Ala Thr Pro Leu Asp 435 440 445 Arg Glu Leu Ser Val Trp His Asn He Thr He He Ala Thr Glu He 450 455 460 Arg Asn His Ser Gin He Ser Arg Val Pro Val Ala He Lys Val Leu 465 470 475 480 Asp Val Asn Asp Asn Ala Pro Glu Phe Ala Ser Glu Tyr Glu Ala Phe 485 490 495 Leu Cys Glu Asn Gly Lys Pro Gly Gin Val He Gin Thr Val Ser Ala 500 505 510 Met Asp Lys Asp Asp Pro Lys Asn Gly His Tyr Phe Leu Tyr Ser Leu 515 520 525 Leu Pro Glu Met Val Asn Asn Pro Asn Phe Thr He Lys Lys Asn Glu 530 535 540 Asp Asn Ser Leu Ser He Leu Ala Lys His Asn Gly Phe Asn Arg Gin 545 550 555 560 Lys Gin Glu Val Tyr Leu Leu Pro He He He Ser Asp Ser Gly Asn 565 570 575 Pro Pro Leu Ser Ser Thr Ser Thr Leu Thr He Arg Val Cys Gly Cys 580 585 590 Ser Asn Asp Gly Val Val Gin Ser Cys Asn Val Glu Ala Tyr Val Leu 595 600 605 Pro He Gly Leu Ser Met Gly Ala Leu He Ala He Leu Ala Cys He 610 615 620 He Leu Leu Leu Val He Val Val Leu Phe Val Thr Leu Arg Arg His 625 630 635 640 Gin Lys Asn ' Glu Pro Leu He He Lys Asp-Asp Glu Asp Val Arg Glu 645 650 655 Asn He He Arg Tyr Asp Asp Glu Gly Gly Gly Glu Glu Asp Thr Glu 660 665 670 Ala Phe Asp He Ala Thr Leu Gin Asn Pro Asp Gly He Asn Gly Phe 675 680 685 Leu Pro Arg Lys Asp He Lys Pro Asp Leu Gin Phe Met Pro Arg Gin 690 695 700 Gly Leu Ala Pro Val Pro Asn Gly Val Asp Val Asp Glu Phe He Asn 705 710 715 720 Val Arg Leu His Glu Ala Asp Asn Asp Pro Thr Ala Pro Pro Tyr Asp 725 730 735 Ser He Gin He Tyr Gly Tyr Glu Gly Arg Gly Ser Val Ala Gly Ser 740 745 750 Leu Ser Ser Leu Glu Ser Thr Thr Ser Asp Ser Asp Gin Asn Phe Asp 755 760 765 Tyr Leu Ser Asp Trp Gly Pro Arg Phe Lys Arg Leu Gly Glu Leu Tyr 770 775 780 Ser Val Gly Glu Ser Asp Lys Glu Thr 785 790 (2) INFORMATION FOR SEQ ID NO:55: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 730 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 2..730 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: G AAT TCG AGC TCG GTA CCC GGG GAT CCT CTA GAG TCG ACC TGC AGT 46 Asn Ser Ser Ser Val Pro Gly Asp Pro Leu Glu Ser Thr Cys Ser 1 5 10 15 GCT GAA GCC CTG CTC CTC CCT GCC GGC CTC AGC ACT GGG GCC TTG ATC 94 Ala Glu Ala Leu Leu Leu Pro Ala Gly Leu Ser Thr Gly Ala Leu He 20 25 30 GCC ATC CTC CTC TGC ATC ATC ATT CTA CTG GTT ATA GTA GTA CTG TTT 142 Ala He Leu Leu Cys He He He Leu Leu Val He Val Val Leu Phe 35 40 45 GCA GCT CTG AAA AGA CAG CGA AAA AAA GAG CCT CTG ATC TTG TCA AAA 190 Ala Ala Leu Lys Arg Gin Arg Lys Lys Glu Pro Leu He Leu Ser Lys 50 55 60 GAA GAT ATC AGA GAC AAC ATT GTG AGC TAT AAC GAT GAG GGT GGT GGA 238 Glu Asp He Arg Asp Asn lie Val Ser Tyr Asn Asp Glu Gly Gly Gly ■ 65 " 70 75 GAG GAG GAC ACC CAG GCC TTT GAT ATC GGC ACC CTG AGG AAT CCT GCA 286 Glu Glu Asp Thr Gin Ala Phe Asp He Gly Thr Leu Arg Asn Pro Ala 80 85 90 95 GCC ATT GAG GAA AAA AAG CTC CGG CGA GAT ATT ATT CCA GAA ACG TTA 334 Ala He Glu Glu Lys Lys Leu Arg Arg Asp He He Pro Glu Thr Leu 100 105 110 TTT ATT CCT CGG AGG ACT CCT ACA GCT CCA GAT AAC ACG GAC GTC CGG 382 Phe He Pro Arg Arg Thr Pro Thr Ala Pro Asp Asn Thr Asp Val Arg 115 120 125 GAT TTC ATT AAT GAA AGG CTA AAA GAG CAT GAT CTT GAC CCC ACC GCA 430 Asp Phe He Asn Glu Arg Leu Lys Glu His Asp Leu Asp Pro Thr Ala 130 135 140 CCC CCC TAC GAC TCA CTT GCA ACC TAT GCC TAT GAA GGA AAT GAT TCC 478 Pro Pro Tyr Asp Ser Leu Ala Thr Tyr Ala Tyr Glu Gly Asn Asp Ser 145 150 155 ATT GCT GAA TCT CTG AGT TCA TTA GAA TCA GGT ACT ACT GAA GGA GAC 526 He Ala Glu Ser Leu Ser Ser Leu Glu Ser Gly Thr Thr Glu Gly Asp 160 165 170 175 CAA AAC TAC GAT TAC CTC CGA GAA TGG GGC CCT CGG TTT AAT AAG CTA 574 Gin Asn Tyr Asp Tyr Leu Arg Glu Trp Gly Pro Arg Phe Asn Lys Leu 180 185 190 GCA GAA ATG TAT GGT GGT GGG GAA AGT GAC AAA GAC TCT TAA CGT AGG 622 Ala Glu Met Tyr Gly Gly Gly Glu Ser Asp Lys Asp Ser * Arg Arg 195 200 205 ATA TAT GTT CTG TTC AAA CAA GAG AAA GTA ACT CTA CCC ATG CTG TCT 670 He Tyr Val Leu Phe Lys Gin Glu Lys Val Thr Leu Pre Met Leu Ser 210 215 220 CCA CTT CAC AAT ATT TGA TAT TCA GGA GCA TTT CCT GCA GTC AGC ACA 718 Pro Leu His Asn He * Tyr Ser Gly Ala Phe Pro Ala Val Ser Thr 225 230 235 ATT TTT TTC TCA 730 He Phe Phe Ser 240 (2) INFORMATION FOR SEQ ID NOr56: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 241 amino acids (B) TYPE: amino acid (D) TOPOLOGYΪ linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: Asn Ser Ser Ser Val Pro Gly Asp Pro Leu Glu Ser Thr Cys Ser Ala 1 5 10 15 Glu Ala Leu Leu Leu Pro Ala Gly Leu Ser Thr Gly Ala Leu He Ala 20 25 30 He Leu Leu Cys He He He Leu Leu Val He Val Val Leu Phe Ala 35 40 45 Ala Leu Lys Arg Gin Arg Lys Lys Glu Pro Leu He Leu Ser Lys Glu 50 55 60 Asp He Arg Asp Asn He Val Ser Tyr Asn Asp Glu Gly Gly Gly Glu 65 70 75 80 Glu Asp Thr Gin Ala Phe Asp He Gly Thr Leu Arg Asn Pro Ala Ala 85 90 95 He Glu Glu Lys Lys Leu Arg Arg Asp He He Pro Glu Thr Leu Phe 100 105 110 He Pro Arg Arg Thr Pro Thr Ala Pro Asp Asn Thr Asp Val Arg Asp 115 120 125 Phe He Asn Glu Arg Leu Lys Glu His Asp Leu Asp Pro Thr Ala Pro 130 135 140 Pro Tyr Asp Ser Leu Ala Thr Tyr Ala Tyr Glu Gly Asn Asp Ser He 145 150 155 160 Ala Glu Ser Leu Ser Ser Leu Glu Ser Gly Thr Thr Glu Gly Asp Gin 165 170 175 Asn Tyr Asp Tyr Leu Arg Glu Trp Gly Pro Arg Phe Asn Lys Leu Ala 180 185 190 Glu Met Tyr Gly Gly Gly Glu Ser Asp Lys Asp Ser Arg Arg He Tyr 195 200 205 Val Leu Phe Lys Gin Glu Lys Val Thr Leu Pro Met Leu Ser Pro Leu 210 215 220 His Asn He Tyr Ser Gly Ala Phe Pro Ala Val Ser Thr He Phe Phe 225 230 235 240 Ser (2) INFORMATION FOR SEQ ID NO:57: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2625 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: CGGCAGCCCT GACGTGATGA GCTCAACCAG CAGAGACATT CCATCCCAAG AGAGGTCTGC 60 GTGACGCGTC CGGGAGGCCA CCCTCAGCAA GACCACCGTA CAGTTGGTGG AAGGGGTGAC 120 AGCTGCATTC TCCTGTGCCT ACCACGTAAC CAAAAATGAA GGAGAACTAC TGTTTACAAG 180 CCGCCCTGGT GTGCCTGGGC ATGCTGTGCC ACAGCCATGC CTTTGCCCCA GAGCGGCGGG 240 GGCACCTGCG GCCCTCCTTC CATGGGCACC ATGAGAAGGG CAAGGAGGGG CAGGTGCTAC 300 AGCGCTCCAA GCGTGGCTGG GTCTGGAACC AGTTCTTCGT GATAGAGGAG TACACCGGGC 360 CTGACCCCGT GCTTGTGGGC AGGCTTCATT CAGATATTGA CTCTGGTGAT GGGAACATTA 420 AATACATTCT CTCAGGGGAA GGAGCTGGAA CCATTTTTGT GATTGATGAC AAATCAGGGA 480 ACATTCATGC CACCAAGACG TTGGATCGAG AAGAGAGAGC CCAGTACACG TTGATGGCTC 540 AGGCGGTGGA CAGGGACACC AATCGGCCAC TGGAGCCACC GTCGGAATTC ATTGTCAAGG 600 TCCAGGACAT TAATGACAAC CCTCCGGAGT TCCTGCACGA GACCTATCAT GCCAACGTGC 660 CTGAGAGGTC CAATGTGGGA ACGTCAGTAA TCCAGGTGAC AGCTTCAGAT GCAGATGACC 720 CCACTTATGG AAATAGCGCC AAGTTAGTGT ACAGTATCCT CGAAGGACAA CCCTATTTTT 780 CGGTGGAAGC ACAGACAGGT ATCATCAGAA CAGCCCTACC CAACATGGAC AGGGAGGCCA 840 AGGAGGAGTA CCACGTGGTG ATCCAGGCCA AGGACATGGG TGGACATATG GGCGGACTCT 900 CAGGGACAAC CAAAGTGACG ATCACACTGA CCGATGTCAA TGACAACCCA CCAAAGTTTC 960 CGCAGAGGCT ATACCAGATG TCTGTGTCAG AAGCAGCCGT CCCTGGGGAG GAAGTAGGAA 1020 GAGTGAAAGC TAAAGATCCA GACATTGGAG AAAATGGCTT AGTCACATAC AATATTGTTG 1080 ATGGAGATGG TATGGAATCG TTTGAAATCA CAACGGACTA TGAAACACAG GAGGGGGTGA 1140 TAAAGCTGAA AAAGCCTGTA GATTTTGAAA CCGAAAGAGC CTATAGCTTG AAGGTAGAGG 1200 CAGCCAACGT GCACATCGAC CCGAAGTTTA TCAGCAATGG CCCTTTCAAG GACACTGTGA 1260 CCGTCAAGAT CTCAGTAGAA GATGCTGATG AGCCCCCTAT GTTCTTGGCC CCAAGTTACA 1320 TCCACGAAGT CCAAGAAAAT GCAGCTGCTG GCACCGTGGT TGGGAGAGTG CATGCCAAAG 1380 ACCCTGATGC TGCCAACAGC CCGATAAGGT ATTCCATCGA TCGTCACACT GACCTCGACA 1440 GATTTTTCAC TATTAATCCA GAGGATGGTT TTATTAAAAC TACAAAACCT CTGGATAGAG 1500 AGGAAACAGC CTGGCTCAAC ATCACTGTCT TTGCAGCAGA AATCCACAAT CGGCATCAGG 1560 AAGCCCAAGT CCCAGTGGCC ATTAGGGTCC TTGATGTCAA CGATAATGCT CCCAAGTTTG 1620 CTGCCCCTTA TGAAGGTTTC ATCTGTGAGA GTGATCAGAC CAAGCCACTT TCCAACCAGC 1680 CAATTGTTAC AATTAGTGCA GATGACAAGG ATGACACGGC CAATGGACCA AGATTTATCT 1740 TCAGCCTACC CCCTGAAATC ATTCACAATC CAAATTTCAC AGTCAGAGAC AACCGAGATA 1800 ACACAGCAGG CGTGTACGCC CGGCGTGGAG GGTTCAGTCG GCAGAAGCAG GACTTGTACC 1860 TTCTGCCCAT AGTGATCAGC GATGGCGGCA TCCCGCCCAT GAGTAGCACC AACACCCTCA 1920 CCATCAAAGT CTGCGGGTGC GACGTGAACG GGGCACTGCT CTCCTGCAAC GCAGAGGCCT 1980 ACATTCTGAA CGCCGGCCTG AGCACAGGCG CCCTGATCGC CATCCTCGCC TGCATCGTCA 2040 TTCTCCTGGT CATTGTAGTA TTGTTTGTGA CCCTGAGAAG GCAAAAGAAA GAACCACTCA 2100 TTGTCTTTGA GGAAGAAGAT GTCCGTGAGA ACATCATTAC TTATGATGAT GAAGGGGGTG 2160 GGGAAGAAGA CACAGAAGCC TTTGATATTG CCACCCTCCA GAATCCTGAT GGTATCAATG 2220 GATTTATCCC CCGCAAAGAC ATCAAACCTG AGTATCAGTA CATGCCTAGA CCTGGGCTCC 2280 GGCCAGCGCC CAACAGCGTG GATGTCGATG ACTTCATCAA CACGAGAATA CAGGAGGCAG 2340 ACAATGACCC CACGGCTCCT CCTTATGACT CCATTCAAAT CTACGGTTAT GAAGGCAGGG 2400 GCTCAGTGGC CGGGTCCCTG AGCTCCCTAG AGTCGGCCAC CACAGATTCA GACTTGGACT 2460 ATGATTATCT ACAGAACTGG GGACCTCGTT TTAAGAAACT AGCAGATTTG TATGGTTCCA 2520 AAGACACTTT TGATGACGAT TCTTAACAAT AACGATACAA ATTTGGCCTT AAGAACTGTG 2580 TCTGGCGTTC TCAAGAATCT AGAAGATGTG TAACAGGTAT TTTTT 2625 (2) INFORMATION FOR SEQ ID NO:58: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 796 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: Met Lys Glu Asn Tyr Cys Leu Gin Ala Ala Leu Val Cys Leu Gly Met 1 5 10 15 Leu Cys His Ser His Ala Phe Ala Pro Glu Arg Arg Gly His Leu Arg 20 25 30 Pro Ser Phe His Gly His His Glu Lys Gly Lys Glu Gly Gin Val Leu 35 40 45 Gin Arg Ser Lys Arg Gly Trp Val Trp Asn Gin Phe Phe Val He Glu 50 55 60 Glu Tyr Thr Gly Pro Asp Pro Val Leu Val Gly Arg Leu His Ser Asp 65 70 75 80 He Asp Ser Gly Asp Gly Asn He Lys Tyr He Leu Ser Gly Glu Gly 85 90 95 Ala Gly Thr He Phe Val He Asp Asp Lys Ser Gly Asn He His Ala 100 105 110 Thr Lys Thr Leu Asp Arg Glu Glu Arg Ala Gin Tyr Thr Leu Met Ala 115 120 125 Gin Ala Val Asp Arg Asp Thr Asn Arg Pro Leu Glu Pro Pro Ser Glu 130 135 140 Phe He Val Lys Val Gin Asp He Asn Asp Asn Pro Pro Glu Phe Leu 145 150 155 160 His Glu Thr Tyr His Ala Asn Val Pro Glu Arg Ser Asn Val Gly Thr 165 170 175 Ser Val He Gin Val Thr Ala Ser Asp Ala Asp Asp Pro Thr Tyr Gly 180 185 190 Asn Ser Ala Lys Leu Val Tyr Ser He Leu Glu Gly Gin Pro Tyr Phe 195 200 205 Ser Val Glu Ala Gin Thr Gly He He Arg Thr Ala Leu Pro Asn Met 210 215 220 Asp Arg Glu Ala Lys Glu Glu Tyr His Val Val He Gin Ala Lys Asp 225 230 235 240 Met Gly Gly His Met Gly Gly Leu Ser Gly Thr Thr Lys Val Thr He 245 250 255 Thr Leu Thr Asp Val Asn Asp Asn Pro Pro Lys Phe Pro Gin Arg Leu 260 265 270 Tyr Gin Met Ser Val Ser Glu Ala Ala Val Pro Gly Glu Glu Val Gly 275 280 285 Arg Val Lys Ala Lys Asp Pro Asp He Gly Glu Asn Gly Leu Val Thr 290 295 300 Tyr Asn He Val Asp Gly Asp Gly Met Glu Ser Phe Glu He Thr Thr 305 310 315 320 Asp Tyr Glu Thr Gin Glu Gly Val He Lys Leu Lys Lys Pro Val Asp 325 330 335 Phe Glu Thr Glu Arg Ala Tyr Ser Leu Lys Val Glu Ala Ala Asn Val 340 345 350 His He Asp Pro Lys Phe He Ser Asn Gly Pro Phe Lys Asp Thr Val 355 360 365 Thr Val Lys He Ser Val Glu Asp Ala Asp Glu Pro Pro Met Phe Leu 370 375 380 Ala Pro Ser Tyr He His Glu Val Gin Glu Asn Ala Ala Ala Gly Thr 385 390 395 400 Val Val Gly Arg Val His Ala Lys Asp Pro Asp Ala Ala Asn Ser Pro 405 410 415 He Arg Tyr Ser He Asp Arg His Thr Asp Leu Asp Arg Phe Phe Thr 420 425 430 He Asn Pro Glu Asp Gly Phe He Lys Thr Thr Lys Pro Leu Asp Arg 435 440 445 Glu Glu Thr Ala Trp Leu Asn He Thr Val Phe Ala Ala Glu He His 450 455 460 Asn Arg His Gin Glu Ala Gin Val Pro Val Ala He Arg Val Leu Asp 465 470 475 480 Val Asn Asp Asn Ala Pro Lys Phe Ala Ala Pro Tyr Glu Gly Phe He 485 490 495 Cys Glu Ser Asp Gin Thr Lys Pro Leu Ser Asn Gin Pro He Val Thr 500 505 510 He Ser Ala Asp Asp Lys Asp Asp Thr Ala Asn Gly Pro Arg Phe He 515 520 525 Phe Ser-Leu Pro Pro Glu He He His Asn Pro Asn Phe Thr Val Arg 530 535 540 Asp Asn Arg Asp Asn Thr Ala Gly Val Tyr Ala Arg Arg Gly Gly Phe 545 550 555 560 Ser Arg Gin Lys Gin Asp Leu Tyr Leu Leu Pro He Val He Ser Asp 565 570 575 Gly Gly He Pro Pro Met Ser Ser Thr Asn Thr Leu Thr He Lys Val 580 585 590 Cys Gly Cys Asp Val Asn Gly Ala Leu Leu Ser Cys Asn Ala Glu Ala 595 600 605 Tyr He Leu Asn Ala Gly Leu Ser Thr Gly Ala Leu He Ala He Leu 610 615 620 Ala Cys lie Val He Leu Leu Val He Val Val Leu Phe Val Thr Leu 625 630 635 640 Arg Arg Gin Lys Lys Glu Pro Leu He Val Phe Glu Glu Glu Asp Val 645 650 655 Arg Glu Asn He He Thr Tyr Asp Asp Glu Gly Gly Gly Glu Glu Asp 660 665 670 Thr Glu Ala Phe Asp He Ala Thr Leu Gin Asn Pro Asp Gly He Asn 675 680 685 Gly Phe He Pro Arg Lys Asp He Lys Pro Glu Tyr Gin Tyr Met Pro 690 695 700 Arg Pro Gly Leu Arg Pro Ala Pro Asn Ser Val Asp Val Asp Asp Phe 705 710 715 720 He Asn Thr Arg He Gin Glu Ala Asp Asn Asp Pro Thr Ala Pro Pro 725 730 735 Tyr Asp Ser He Gin He Tyr Gly Tyr Glu Gly Arg Gly Ser Val Ala 740 745 750 Gly Ser Leu Ser Ser Leu Glu Ser Ala Thr Thr Asp Ser Asp Leu Asp 755 760 765 Tyr Asp Tyr Leu Gin Asn Trp Gly Pro Arg Phe Lys Lys Leu Ala Asp 770 775 780 Leu Tyr Gly Ser Lys Asp Thr Phe Asp Asp Asp Ser 785 790 795 (2) INFORMATION FOR SEQ ID NO:59: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2521 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: CGGTGGAGGC CACAGACACC TCAAACCTGG ATTCCACAAT TCTACGTTAA GTGTTGGAGT 60 TTTTATTACT CTGCTGTAGG AAAGCCTTTG CCAATGCTTA CAAGGAACTG TTTATCCCTG 120 CTTCTCTGGG TTCTGTTTGA TGGAGGTCTC CTAACACCAC TACAACCACA GCCACAGCAG 180 ACTTTAGCCA CAGAGCCAAG AGAAAATGTT ATCCATCTGC CAGGACAACG GTCACATTTC 240 CAACGTGTTA AACGTGGCTG GGTATGGAAT CAATTTTTTG TGCTGGAAGA ATACGTGGGC 300 TCCGAGCCTC AGTATGTGGG AAAGCTCCAT TCCGACTTAG ACAAGGGAGA GGGCACTGTG 360 AAATACACCC TCTCAGGAGA TGGCGCTGGC ACCGTTTTTA CCATTGATGA AACCACAGGG 420 GACATTCATG CAATAAGGAG CCTAGATAGA GAAGAGAAAC CTTTCTACAC TCTTCGTGCT 480 CAGGCTGTGG ACATAGAAAC CAGAAAGCCC CTGGAGCCTG AATCAGAATT CATCATCAAA 540 GTGCAGGATA TTAATGATAA TGAGCCAAAG TTTTTGGATG GACCTTATGT TGCTACTGTT 600 CCAGAAATGT CTCCTGTGGG TGCATATGTA CTCCAGGTCA AGGCCACAGA TGCAGATGAC 660 CCGACCTATG GAAACAGTGC CAGAGTCGTT TACAGCATTC TTCAGGGACA ACCTTATTTC 720 TCTATTGATC CCAAGACAGG TGTTATTAGA ACAGCTTTGC CAAACATGGA CAGAGAAGTC 780 AAAGAACAAT ATCAAGTACT CATCCAAGCC AAGGATATGG GAGGACAGCT GCCGGAACAA CAATAGTCAA CATCACTCTC ACCGATGTCA ATGACAATCC CCCAAAAGCA TCTTCCACTT GAAAGTTCCT GAGTCTTCCC CTATTGGTTC AGAATAAGAG CTGTGGATCC TGATTTTGGA CAAAATGCAG AAATTGAATA CCAGGAGATG GGGGAAATTT GTTTGACATC GTCACAGATG AGGATACACA ATCAAATTGA AAAAGCCTTT AGATTTTGAA ACAAAGAAGG CATACACTTT GCTTCCAACC TTCACCTTGA CCACCGGTTT CACTCGGCGG GCCCTTTCAA ACGGTGAAGA TCAGCGTGCT GGACGTAGAT GAGCCACCGG TTTTCAGCAA ACCATGGAGG TTTATGAAGA CACTCCGGTA GGGACCATCA TTGGCGCTGT GACCTGGATG TAGGCAGCGG TGCTGTTAGG TACTTCATAG ATTGGAAGAG AGCTACTTTA CAATAGATGG AAATGAAGGA ACCATCGCCA CTAATGAATT GAAAGCACTG CGCAGTATAA TTTCTCCATA ATTGCGAGTA AAGTTAGTAA ACCAGCAAAG TCAATATACT GATTAATGTC TTAGATGTAA ATGAATTTCC TCTGTGCCAT ATGAGACAGC CGTGTGTGAA AATGCCAAGC CAGGACAGAT GTCAGTGCTG CAGACCGAGA TCTTTCACCT GCTGGGCAAC AATTCTCCTT CCTGAGGCTG CTATCAAACC AAATTTTACA GTTCGTGACT TCAGAAACAA ATTGAAACCC GAAGAAATGG ATACAGCCGC AGGCAGCAAG AGTTGTATTT GTAATAGAAG ACAGCAGCTA CCCTGTCCAG AGCAGCACAA ACACAATGAC TGTAGATGTG ACTCTGATGG CACCATCCTG TCTTGTAATG TGGAAGCAAT GTAGGACTTA GCACTGGGGC GTTGATTGCA ATTCTACTAT GCATTGTTAT ATAGTTGTAC TGTATGTAGC ACTGCGAAGG CAGAAGAAAA AGCACACCCT AAAGAAGACA TCAGAGACAA CGTCATCCAT TACGATGATG AAGGAGGTGG ACCCAGGCTT TCGACATCGG GGCTCTGAGA AACCCAAAAG TGATTGAGGA CGCAGGGATA TAAAACCAGA CTCTCTCTGT TTACCTCGTC AGAGACCACC AACACAGACA TAAGGGATTT CATTCATCAA AGGCTACAGG AAAATGATGT GCCCCACCAA TCGATTCACT GGCCACATAT GCCTACGAAG GGAGTGGGTC TCCCTCAGCT CTATAGACTC TCTCACCACA GAAGCCGACC AGGACTATGA GACTGGGGAC CCCGCTTTAA AGTCTTGGCA GACATGTTTG GCGAAGAAGA CCTGATAAAG TCACTTAAGG GAGTCGTGGA GGCTAAAATA CAACCGAGAG T (2) INFORMATION FOR SEQ ID NO:60r (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 794 amino acids (B) TYPEt amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60: Met Leu Thr Arg Asn Cys Leu Ser Leu Leu Leu Trp Val Leu Phe Asp 1 5 10 15 Gly Gly Leu Leu Thr Pro Leu Gin Pro Gin Pro Gin Gin Thr Leu Ala 20 25 30 Thr Glu Pro Arg Glu Asn Val He His Leu Pro Gly Gin Arg Ser His 35 40 45 Phe Gin Arg Val Lys Arg Gly Trp Val Trp Asn Gin Phe Phe Val Leu 50 55 60 Glu Glu Tyr Val Gly Ser Glu Pro Gin Tyr Val Gly Lys Leu His Ser 65 70 75 80 Asp Leu Asp Lys Gly Glu Gly Thr Val Lys Tyr Thr Leu Ser Gly Asp 85 90 95 Gly Ala Gly Thr Val Phe Thr He Asp Glu Thr Thr Gly Asp He His 100 105 110 Ala He Arg Ser Leu Asp Arg Glu Glu Lys Pro Phe Tyr Thr Leu Arg 115 120 125 Ala Gin Ala Val Asp He Glu Thr Arg Lys Pro Leu Glu Pro Glu Ser 130 135 140 Glu Phe He He Lys Val Gin Asp He Asn Asp Asn Glu Pro Lys Phe 145 150 155 160 Leu Asp Gly Pro Tyr Val Ala Thr Val Pro Glu Met Ser Pro Val Gly 165 170 175 Ala Tyr Val Leu Gin Val Lys Ala Thr Asp Ala Asp Asp Pro Thr Tyr 180 185 190 Gly Asn Ser Ala Arg Val Val Tyr Ser He Leu Gin Gly Gin Pro Tyr 195 200 205 Phe Ser He Asp Pro Lys Thr Gly Val He Arg Thr Ala Leu Pro Asn 210 215 220 Met Asp Arg Glu Val Lys Glu Gin Tyr Gin Val Leu He Gin Ala Lys 225 230 235 240 Asp Met Gly Gly Gin Leu Gly Gly Leu Ala Gly Thr Thr He Val Asn 245 250 255 He Thr Leu Thr Asp Val Asn Asp Asn Pro Pro Arg Phe Pro Lys Ser 260 265 270 He Phe His Leu Lys Val Pro Glu Ser Ser Pro He Gly Ser Gly He 275 280 285 Gly Arg He Arg Ala Val Asp Pro Asp Phe Gly Gin Asn Ala Glu He 290 295 300 Glu Tyr Asn He Val Pro Gly Asp Gly Gly Asn Leu Phe Asp He Val 305 310 315 320 Thr Asp Glu Asp Thr Gin Glu Gly Val He Lys Leu Lys Lys Pro Leu 325 330 335 Asp Phe Glu Thr Lys Lys Ala Tyr Thr Phe Lys Val Glu Ala Ser Asn 340 345 350 Leu His Leu Asp His Arg Phe His Ser Ala Gly Pro Phe Lys Asp Thr 355 360 365 Ala Thr Val Lys He Ser Val Leu Asp Val Asp Glu Pro Pro Val Phe 370 375 380 Ser Lys Pro Leu Tyr Thr Met Glu Val Tyr Glu Asp Thr Pro Val Gly 385 390 395 400 Thr He He Gly Ala Val Thr Ala Gin Asp Leu Asp Val Gly Ser Gly 405 410 415 Ala Val Arg Tyr Phe He Asp Trp Lys Ser Asp Gly Asp Ser Tyr Phe 420 425 430 Thr He Asp Gly Asn Glu Gly Thr He Ala Thr Asn Glu Leu Leu Asp 435 440 445 Arg Glu Ser Thr Ala Gin Tyr Asn Phe Ser He He Ala Ser Lys Val 450 455 460 Ser Asn Pro Leu Leu Thr Ser Lys Val Asn He Leu He Asn Val Leu 465 470 475 480 Asp Val Asn Glu Phe Pro Pro Glu He Ser Val ~r~ Tyr Glu Thr Ala 485 490 495 Val Cys Glu Asn Ala Lys Pro Gly Gin He He Gin He Val Ser Ala 500 505 510 Ala Asp Arg Asp Leu Ser Pro Ala Gly Gin Gin Phe Ser Phe Arg Leu 515 520 525 Ser Pro Glu Ala Ala He Lys Pro Asn Phe Thr Val Arg Asp Phe Arg 530 535 540 Asn Asn Thr Ala Gly He Glu Thr Arg Arg Asn Gly Tyr Ser Arg Arg 545 550 555 560 Gin Gin Glu Leu Tyr Phe Leu Pro Val Val He Glu Asp Ser Ser Tyr 565 570 575 Pro Val Gin Ser Ser Thr Asn Thr Met Thr He Arg Val Cys Arg Cys 580 585 590 Asp Ser Asp Gly Thr He Leu Ser Cys Asn Val Glu Ala He Phe Leu 595 600 605 Pro Val Gly Leu Ser Thr Gly Ala Leu He Ala He Leu Leu Cys He 610 615 620 Val He Leu Leu Ala He Val Val Leu Tyr Val Ala Leu Arg Arg Gin 625 630 635 640 Lys Lys Lys His Thr Leu Met Thr Ser Lys Glu Asp He Arg Asp Asn 645 650 655 Val He His Tyr Asp Asp Glu Gly Gly Gly Glu Glu Asp Thr Gin Ala 660 665 670 Phe Asp He Gly Ala Leu Arg Asn Pro Lys Val He Glu Glu Asn Lys 675 680 685 He Arg Arg Asp He Lys Pro Asp Ser Leu Cys Leu Pro Arg Gin Arg 690 695 700 Pro Pro Met Glu Asp Asn Thr Asp He Arg Asp Phe He His Gin Arg 705 710 715 720 Leu Gin Glu Asn Asp Val Asp Pro Thr Ala Pro Pro He Asp Ser Leu 725 730 735 Ala Thr Tyr Ala Tyr Glu Gly Ser Gly Ser Val Ala Glu Ser Leu Ser 740 745 750 Ser He Asp Ser Leu Thr Thr Glu Ala Asp Gin Asp Tyr Asp Tyr Leu 755 760 765 Thr Asp Trp Gly Pro Arg Phe Lys Val Val Ala Asp Met Phe Gly Glu 770 775 780 Glu Glu Ser Tyr Asn Pro Asp Lys Val Thr 785 790 (2) INFORMATION FOR SEQ ID NO:61: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2690 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: CTTCAAGGTT TTGCTGACTC AGTCTGGTAG TCAGAGTCTG CAGGAGAAGA CAGTTCAAGG 60 CAGGGCCTGG AGGATTGGAT CAGTTTAGGG ACAGGTCAAA GGCTGGCTTA GAGACCTTAG 120 AGGCAGGTTG CTTGGGTCGT TGAATGCTAG TCTGGTCCTG AGAGCCCTTT TCTCTGGCAA 180 CTGTGGACTC AGAGCTAACC AATTGTAGTT GGCAGTGGGG GTGAAGGGTG ATCCAGAGGC 240 CTGAGCTGCA GAGGGCACAA GAGAGAAAAG ATGTCTTAGA AAGAGCTTTG AGAACATGCC 300 TTGGCTGCTG GCAGGGACCT TGGATGGGGT AGTCTACACC CGGAAGTGCC TGCCTGCCAT 360 CCTCTAGTGG CTGCCTTGCA AAATATGCTC AGTGCAGCCG CGTGCATGAA TGAAAACGCC 420 GCCGGGCGCT TCTAGTCGGA CAAAATGCAG CCGAGAACTC CGCTCGTTCT GTGCGTTCTC 480 CTGTCCCAGG TGCTGCTGCT AACATCTGCA GAAGATTTGG ACTGCACTCC TGGATTTCAG 540 CAGAAAGTGT TCCATATCAA TCAGCCAGCT GAATTCATTG AGGACCAGTC AATTCTAAAC 600 TTGACCTTCA GTGACTGTAA GGGAAACGAC AAGCTACGCT ATGAGGTCTC GAGCCCATAC 660 TTCAAGGTGA ACAGCGATGG CGGCTTAGTT GCTCTGAGAA ACATAACTGC AGTGGGCAAA 720 : ACTCTGTTCG TCCATGCACG GACCCCCCAT GCGGAAGATA TGGCAGAACT CGTGATTGTC 780 GGGGGGAAAG ACATCCAGGG CTCCTTGCAG GATATATTTA AATTTGCAAG AACTTCTCCT 840 GTCCCAAGAC AAAAGAGGTC CATTGTGGTA TCTCCCATTT TAATTCCAGA GAATCAGAGA 900 CAGCCTTTCC CAAGAGATGT TGGCAAGGTA GTCGATAGTG ACAGGCCAGA AAGGTCCAAG 960 TTCCGGCTCA CTGGAAAGGG AGTGGATCAA GAGCCTAAAG GAATTTTCAG AATCAATGAG 1020 AACACAGGGA GCGTCTCCGT GACACGGACC TTGGACAGAG AAGTAATCGC TGTTTATCAA 1080 CTATTTGTGG AGACCACTGA TGTCAATGGC AAAACTCTCG AGGGGCCGGT GCCTCTGGAA 1140 GTCATTGTGA TTGATCAGAA TGACAACCGA CCGATCTTTC GGGAAGGCCC CTACATCGGC 1200 CACGTCATGG AAGGGTCACC CACAGGCACC ACAGTGATGC GGATGACAGC CTTTGATGCA 1260 GATGACCCAG CCACCGATAA TGCCCTCCTG CGGTATAATA TCCGTCAACA GACGCCTGAC 1320 AAGCCATCTC CCAACATGTT CTACATCGAT CCTGAGAAAG GAGACATTGT CACTGTTGTG 1380 TCACCTGCGC TGCTGGACCG AGAGACTCTG GAAAATCCCA AGTATGAACT GATCATCGAG 1440 GCTCAAGATA TGGCTGGACT GGATGTTGGA TTAACAGGCA CGGCCACAGC CACGATCATG 1500 ATCGATGACA AAAATGATCA CTCACCAAAA TTCACCAAGA AAGAGTTTCA AGCCACAGTC 1560 GAGGAAGGAG CTGTGGGAGT TATTGTCAAT TTGACAGTTG AAGATAAGGA TGACCCCACC 1620 ACAGGTGCAT GGAGGGCTGC CTACACCATC ATCAACGGAA ACCCCGGGCA GAGCTTTGAA 1680 ATCCACACCA ACCCTCAAAC CAACGAAGGG ATGCTTTCTG TTGTCAAACC ATTGGACTAT 1740 GAAATTTCTG CCTTCCACAC CCTGCTGATC AAAGTGGAAA ATGAAGACCC ACTCGTACCC 1800 GACGTCTCCT ACGGCCCCAG CTCCACAGCC ACCGTCCACA TCACTGTCCT GGATGTCAAC 1860 GAGGGCCCAG TCTTCTACCC AGACCCCATG ATGGTGACCA GGCAGGAGGA CCTCTCTGTG 1920 GGCAGCGTGC TGCTGACAGT GAATGCCACG GACCCCGACT CCCTGCAGCA TCAAACCATC 1980 AGGTATTCTG TTTACAAGGA CCCAGCAGGT TGGCTGAATA TTAACCCCAT CAATGGGACT 2040 GTTGACACCA CAGCTGTGCT GGACCGTGAG TCCCCATTTG TCGACAACAG CGTGTACACT 2100 GCTCTCTTCC TGGCAATTGA CAGTGGCAAC CCTCCCGCTA CGGGCACTGG GACTTTGCTG 2160 ATAACCCTGG AGGACGTGAA TGACAATGCC CCGTTCATTT ACCCCACAGT AGCTGAAGTC 2220 TGTGATGATG CCAAAAACCT CAGTGTAGTC ATTTTGGGAG CATCAGATAA GGATCTTCAC 2280 CCGAATACAG ATCCTTTCAA ATTTGAAATC CACAAACAAG CTGTTCCTGA TAAAGTCTGG 2340 AAGATCTCCA AGATCAACAA TACACACGCC CTGGTAAGCC TTCTTCAAAA TCTGAACAAA 2400 GCAAACTACA ACCTGCCCAT CATGGTGACA GATTCAGGGA AACCACCCAT GACGAATATC 2460 ACAGATCTCA GGGTACAAGT GTGCTCCTGC AGGAATTCCA AAGTGGACTG CAACGCGGCG 2520 GGGGCCCTGC GCTTCAGCCT GCCCTCAGTC CTGCTCCTCA GCCTCTTCAG CTTAGCTTGT 2580 CTGTGAGAAC TCCTGACGTC TGAAGCTTGA CTCCCAAGTT TCCATAGCAA CAGGAAAAAA 2640 AAAAAATCTA TCCAAATCTG AAGATTGCGG TTTACAGCTA TCGAACTTCG 2690 (2) INFORMATION FOR SEQ ID NO:62: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 713 amino acids (B) TYPEs amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: Met Gin Pro Arg Thr Pro Leu Val Leu Cys Val Leu Leu Ser Gin Val 1 5 10 15 Leu Leu Leu Thr Ser Ala Glu Asp Leu Asp Cys Thr Pro Gly Phe Gin 20 25 30 Gin Lys Val Phe His He Asn Gin Pro Ala Glu Phe He Glu Asp Gin 35 40 45 Ser He Leu Asn Leu Thr Phe Ser Asp Cys Lys Gly Asn Asp Lys Leu 50 55 60 Arg Tyr Glu Val Ser Ser Pro Tyr Phe Lys Val Asn Ser Asp Gly Gly 65 70 75 80 Leu Val Ala Leu Arg Asn He Thr Ala Val Gly Lys Thr Leu Phe Val 85 90 95 His Ala Arg Thr Pro His Ala Glu Asp Met Ala Glu Leu Val He Val 100 105 110 Gly Gly Lys Asp He Gin Gly Ser Leu Gin Asp He Phe Lys Phe Ala 115 120 125 Arg Thr Ser Pro Val Pro Arg Gin Lys Arg Ser He Val Val Ser Pro 130 135 140 He Leu He Pro Glu Asn Gin Arg Gin Pro Phe Pro Arg Asp Val Gly 145 150 155 160 Lys Val Val Asp Ser Asp Arg Pro Glu Arg Ser Lys Phe Arg Leu Thr 165 170 175 Gly Lys Gly Val Asp Gin Glu Pro Lys Gly He Phe Arg He Asn Glu 180 185 190 Asn Thr Gly Ser Val Ser Val Thr Arg Thr Leu Asp Arg Glu Val He 195 200 205 Ala Val Tyr Gin Leu Phe Val Glu Thr Thr Asp Val Asn Gly Lys Thr 210 215 220 Leu Glu Gly Pro Val Pro Leu Glu Val He Val He Asp Gin Asn Asp 225 230 235 240 Asn Arg Pro He Phe Arg Glu Gly Pro Tyr He Gly His Val Met Glu 245 250 255 Gly Ser Pro Thr Gly Thr Thr Val Met Arg Met Thr Ala Phe Asp Ala 260 265 270 Asp Asp Pro Ala Thr Asp Asn Ala Leu Leu Arg Tyr Asn He Arg Gin 275 280 285 Gin Thr Pro Asp Lys Pro Ser Pro Asn Met Phe Tyr He Asp Pro Glu 290 295 300 Lys Gly Asp He Val Thr Val Val Ser Pro Ala Leu Leu Asp Arg Glu 305 310 315 320 Thr Leu Glu Asn Pro Lys Tyr Glu Leu lie He Glu Ala Gin Asp Met 325 330 335 Ala Gly Leu Asp Val Gly Leu Thr Gly Thr Ala Thr Ala Thr He Met 340 345 350 He Asp Asp Lys Asn Asp His Ser Pro Lys Phe Thr Lys Lys Glu Phe 355 360 365 Gin Ala Thr Val Glu Glu Gly Ala Val Gly Val He Val Asn Leu Thr 370 375 380 Val Glu Asp Lys Asp Asp Pro Thr Thr Gly Ala Trp Arg Ala Ala Tyr 385 390 395 400 Thr He He Asn Gly Asn Pro Gly Gin Ser Phe Glu He His Thr Asn 405 410 415 Pro Gin Thr Asn Glu Gly Met Leu Ser Val Val Lys Pro Leu Asp Tyr 420 425 430 Glu He Ser Ala Phe His Thr Leu Leu He Lys Val Glu Asn Glu Asp 435 440 445 Pro Leu Val Pro Asp Val Ser Tyr Gly Pro Ser Ser Thr Ala Thr Val 450 455 460 His He Thr Val Leu Asp Val Asn Glu Gly Pro Val Phe Tyr Pro Asp 465 470 475 480 Pro Met Met Val Thr Arg Gin Glu Asp Leu Ser Val Gly Ser Val Leu 485 490 495 Leu Thr Val Asn Ala Thr Asp Pro Asp Ser Leu Gin His Gin Thr He 500 505 510 Arg Tyr Ser Val Tyr Lys Asp Pro Ala Gly Trp Leu Asn He Asn Pro 515 520 525 He Asn Gly Thr Val Asp Thr Thr Ala Val Leu Asp Arg Glu Ser Pro 530 535 540 Phe Val Asp Asn Ser Val Tyr Thr Ala Leu Phe Leu Ala He Asp Ser 545 550 555 560 Gly Asn Pro Pro Ala Thr Gly Thr Gly Thr Leu Leu He Thr Leu Glu 565 570 575 Asp Val Asn Asp Asn Ala Pro Phe He Tyr Pro Thr Val Ala Glu Val 580 585 590 Cys Asp Asp Ala Lys Asn Leu Ser Val Val He Leu Gly Ala Ser Asp 595 600 605 Lys Asp Leu His Pro Asn Thr Asp Pro Phe Lys Phe Glu He His Lys 610 615 620 Gin Ala Val Pro Asp Lys Val Trp Lys He Ser Lys He Asn Asn Thr 625 630 635 640 - His Ala Leu Val Ser Leu Leu Gin Asn Leu Asn Lys Ala Asn Tyr Asn .645 650 655 Leu Pro He Met Val Thr Asp Ser Gly Lys Pro Pro Met Thr Asn He 660 665 670 Thr Asp Leu Arg Val Gin Val Cys Ser Cys Arg Asn Ser Lys Val Asp 675 680 685 Cys Asn Ala Ala Gly Ala Leu Arg Phe Ser Leu Pro Ser Val He Leu 690 695 700 Leu Ser Leu Phe Ser Leu Ala Cys Leu 705 710 INDICATIONS RELATING TO A DEPOSITED MICROORGANISM (PCT Rufe 13bis) A. The indications made below relate to the microorganism referred to in the description on page , line 12-21 B. IDENTIFICATION OF DEPOSIT jfjggjjgr deposits are identified on an additional sheet Name of depositary institution AMERICAN TYPE CULTURE COLLECTION Address of depositary institution (including postal code and country) 12301 Parklawn Drive Rockville, MD 20852 UNITED STATES OF AMERICA Date of deposit Accession Number See attached sheet See attached sheet C. ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet | | "In respect of those designations in which a European patent is sought, a sample of the deposited microorganism will be made available until the publication of the mention of the grant of the European patent or until the date on which the application has been refused or withdrawn or is deemed to be withdrawn, only by the issue of such a sample to an expert nominated by the person requesting the sample (Rule 23(4) EPC) ." D. DESIGNATEDSTATES FORWHICHINDICATIONSAREMADE (ifthe indications are not for all designated States) EP E. SEPARATE FURNISHING OF INDICATIONS (leave blank if not applicable) Theiπdicationslϊstedbelowwillbesubmitted to the International Bureau \&tsτ (specify thegeneral nature of theindications e.g., "Accession Number of Deposit ") For receiving Office use only For International Bureau use only LZP This sheet was received with the international application [ I This sheet was received by the International Bureau on: Authorized officer Authorized officer Form PCI7R jOt/1e3l4 (tJuly 1fi992)S

Claims: What is claimed is: 1. A purified and isolated polynucleotide encoding a cadherin selected from the group consisting of cadherin-6, cadherin-7, cadherin-9 and cadherin-10. 2. The polynucleotide of claim 1 which is a DNA sequence. 3. The polynucleotide of claim 2 which is a cDNA sequence or biological replica thereof. 4. The polynucleotide of claim 3 which is SEQ ID NO: 51. 5. The polynucleotide of claim 3 which is SEQ ID NO: 15. 6. The polynucleotide of claim 3 which is SEQ ID NO: 19 or SEQ ID NO: 33. 7. The polynucleotide of claim 3 which is SEQ ID NO: 55. 8. The polynucleotide of claim 2 which is a genomic DNA or a biological replica thereof. 9. The DNA of claim 2 which is a wholly or partially chemically synthesized DNA or a biological replica thereof. 10. A biologically functional DNA vector comprising a DNA according to claim 2. 11. The vector of claim 10 wherein said DNA is operatively linked to an expression control DNA sequence. 12. A host cell stably transformed or transfected with a DNA according to claim 2 in a manner allowing the expression in said host cell of the cadherin polypeptide encoded thereby. 13. A method for producing a cadherin polypeptide comprising the steps of growing a host cell according to claim 12 in a suitable nutrient medium and isolating the cadherin from said cell or from the medium of its growth. 14. A purified and isolated full length cadherin polypeptide selected from the group consisting of cadherin-6 polypeptide (SEQ ID NO: 52), cadherin-7 polypeptide (SEQ ID NO: 16), cadherin-9 polypeptide (SEQ ID NO: 20 or 34) and cadherin-10 polypeptide (SEQ ID NO: 56). 15. A hybridoma cell line producing a monoclonal antibody specific for a cadherin selected from the group consisting of cadherin-6, cadherin- 7, cadherin-9 and cadherin-10. 16. A hybridoma cell line producing a monoclonal antibody specific for cadherin-5 selected from the group consisting of 30Q8A (ATCC HB11316), 30Q4H (ATCC HB11317), 45A5G (ATCC HB11318), 30S2F (ATCC HB11319), 45C6A (ATCC HB11320) and 30T11G (ATCC 11324). 17. A monoclonal antibody produced by the hybridoma cell line of claim 16. 18. An antibody substance specific for a cadherin selected from the group consisting of cadherin-6, cadherin-7, cadherin-9 and cadherin-10. 19. A method for modulating the binding capability of a cadherin selected from the group consisting of cadherin-6, cadherin-7, cadherin-9 and cadherin-10 comprising contacting the cadherin with an antibody substance specific for said cadherin according to claim 18. 20. A method for modulating the binding capability of a cadherin selected from the group consisting of cadherin-6, cadherin-7, cadherin-9 and cadherin-10 comprising contacting the cadherin with a polypeptide or peptide ligand of the cadherin. 21. A method for modulating the binding capability of a cadherin selected from the group consisting of cadherin-6, cadherin-7, cadherin-9 and cadherin-10 comprising contacting the cadherin with a peptide of said cadherin.

Inventors: SUZUKI SHINTARO, SUZUKI, SHINTARO
Applicants: DOHENY EYE INST, DOHENY EYE INSTITUTE
Application year: 1993
Main classification: C12N1
IPC codes: A61K38, A61K39, A61K45, A61P1, A61P9, A61P25, A61P35, A61P37, A61P43, C07K14, C07K16, C12N1, C12N5, C12N15, C12P21, C12Q1, C12R1