SEMAPHORIN RECEPTORS

Abstract: The invention provides methods and compositions relating to two classes of semaphorin receptors, SR1 and SR2. The polypeptides may be produced recombinantly from transformed host cells from the disclosed SR encoding nucleic acids or purified from human cells. The invention provides isolated SR hybridization probes and primers capable of specifically hybridizing with the disclosed SR genes, SR-specific binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis, therapy and in the biopharmaceutical industry.

Description: Semaphorin Receptors This Application is a continuing application under 35USC120 of USSN 08/889,458 filed July 8, 1997 by Marc Tessier-Lavigne, Zhigang He and Hang Chen and entitled Semaphorin Receptors. The research carried out in the subject application was supported in part by grants from the National Institutes of Health. The government may have rights in any patent issuing on this application. INTRODUCTION Field of the Invention The field of this invention is proteins involved in nerve cell guidance. Background During nervous system development, axons migrate along prescribed pathways in the embryo to reach their appropriate synaptic targets (reviewed in Tessier-Lavigne and Goodman, 1996). One mechanism that contributes to accurate pathfinding is chemorepulsion, the guidance of axons away from non-target regions by diffusible chemorepellent factors secreted by non-target cells. Experiments in which axons are confronted with non-target tissues in tissue culture and are repelled by these tissues at a distance have demonstrated the existence of diffusible chemorepellent activities for numerous axonal classes (Pini, 1993; Fitzgerald et al., 1993; Colamarino and Tessier- Lavigne, 1995; Tamada et al., 1995; Guthrie and Pini, 1995; Shirasaki et al., 1996) as well as for migrating neuronal cells (Hu and Rutishauser, 1996). At the molecular level, two families of guidance cues, the netrin and semaphorin families, have been shown to comprise members that can function as chemorepellents. In Caenorhaditis elegans, the netrin UNC-6 is thought to repel axons that migrate away from the netrin source since these axons are misrouted at a certain frequency in unc-6 mutants; this presumed repulsion appears to be mediated by the candidate receptors UNC-5 and UNC-40, which are members of the immunoglobulin superfamily (Hedgecock et al., 1990; Leung- Hagesteijn et al, 1992; Hamelin et al., 1993; Wadsworth et al., 1996; Chan et al, 1996). Similarly, in vertebrates netrin- 1 can repel subsets of motor axons that migrate away from a source of netrin- 1 (Colamarino and Tessier-Lavigne, 1994; Varela-Echavarria et al., 1997), a process which might involve vertebrate homologues of UNC-5 and UNC-40, which have been shown to be netrin-binding proteins (Leonardo et al., 1997; Ackermann et al., 1997; Keino-Masu et al., 1996). The semaphorins are a large family of structurally diverse secreted and transmembrane proteins characterized by the presence of a conserved -500 amino acid semaphorin domain at their amino termini (reviewed in Kolodkin, 1996). The family was first described and implicated in axon guidance through antibody perturbation studies in insects (Kolodkin et al, 1992; Kolodkin et al., 1993). The connection of this family to chemorepulsion was made with the purification of chicken collapsin-1 as a factor that can cause collapse of sensory growth cones when added acutely in cell culture (Luo et al, 1993). Collapsin-1 and its mammalian homologues (Semaphorin III, also known as Semaphorin D) are secreted semaphorins that possess in addition to the semaphorin domain an immunoglobulin domain and a highly basic carboxy-terminal domain (Luo et al., 1993; Kolodkin et al., 1993; Messersmith et al., 1995; Puschel et al., 1995). When presented chronically from a point source, collapsin-1/SemaIII/D (hereafter referred to as Semalll) can repel sensory and sympathetic axons and has been implicated in patterning sensory axon projections into the ventral spinal cord (Messersmith et al., 1995; Puschel et al., 1995, 1996; Behar et al., 1996; Shepherd et al., 1997). Sema E, which is structurally- related to Semalll, has also been reported to repel sympathetic axons in culture (cited in Varela-Echavarria and Guthrie, 1997). In Drosophila, the secreted semaphorin Semall has been implicated as an inhibitor of axon terminal branch formation (Matthes et al., 1995). However, the mechanisms through which semaphorins produce their repellent or inhibitory actions have not been determined. To elucidate the mechanisms through which semaphorin proteins produce their repulsive actions on axons, we have sought to identify binding proteins for semphorins on the surfaces of sensory axons. Here we identify two classes of semaphorin receptors, SRI and SR2. expressed by axons whose function is required for the collapse-inducing and repulsive actions of semaphorins. SUMMARY OF THE INVENTION The invention provides methods and compositions relating to isolated semaphorin receptor class 1 and 2 (SRI and SR2, collectively SR) polypeptides, related nucleic acids, polypeptide domains thereof having SR-specific structure and activity, and modulators of SR function, particularly semaphorin-binding activity. SR polypeptides can regulate cell, especially nerve cell, function and morphology. The polypeptides may be produced recombinantly from transformed host cells from the subject SR polypeptide encoding nucleic acids or purified from mammalian cells. The invention provides isolated SR hybridization probes and primers capable of specifically hybridizing with the disclosed SR genes, SR-specific binding agents such as specific antibodies, and methods of making and using the subject compositions in diagnosis (e.g. genetic hybridization screens for SR transcripts), therapy (e.g. SR inhibitors to promote nerve cell growth) and in the biopharmaceutical industry (e.g. as immunogens, reagents for isolating other Srs, reagents for screening chemical libraries for lead pharmacological agents, etc.). BRIEF DESCRIPTION OF THE FIGURES Figure 1A-1B. Structure of rat and human SRI. (A) Alignment of the amino acid sequences of mouse, rat and human SRls. (B) Diagram displaying the modular structure of SRls conserved among different species, and the five SRI domains (al, a2, bl, b2, c). S: signal peptide; Clr/s, complement Clr/s homology domain (CUB domain); FV/VIII, regions of homology to coagulation factors V and VIII, the DDR tyrosine kinase, and MFGPs; MAM, MAM domain; TM, transmembrane domain. Figure 2. Equilibrium Binding of Fusion Proteins of AP and different portions of Semalll to SRI -Expressing cells. Figure 3. Alignment of the amino acid sequences of neuropilin-1 (SRI) and neuropilin-2 (SR2). Alignment of the mouse neuropilin-1 (m-npn-1), mouse neuropilin-2 (m-npn-2) and human neuropilin-2 (h-npn-2) sequences was performed using the Clustal V program. Different domains of the molecules, named according to Kawakami et al. (1996) (see Figure 2 A), are indicated. The aO isoform of neuropilin-2 (see Figure 2) was used to create the alignment. Figure 4A-4C. Domain structure and isoforms of neuropilin-2. (A) Diagram illustrating the domain structures of mouse neuropilin-1 (Kawakami, et al, 1996) and the full length mouse neuropilin-2(a0) and neuropilin-2(b0) isoforms. s: signal peptide; al and a2 domains are CUB domains (Busby and Ingham, 1990; Bork and Beckmann, 1993); bl and b2 domains show homology to the Cl and C2 domains of coagulation factors V and VIII and of milk fat globular membrane protein; c domain contains a MAM domain, which is found in the metalloendopeptidase meprin and receptor tyrosine phosphatases μ, λ,and K; TM: transmembrane domain; Cy: cytoplasmic domain. The numbers with arrows indicate percent amino acid identity in the indicated domains. The dashed line and arrow indicate the site in neuropilin-2 where the neuropilin-2a and -2b isoforms diverge; this is also the site of the 5-, 17- and 22- amino acid insertions (see also Figure 2B). (B) Isoforms of neuropilin-2(a) with 0, 5, 17 and 22 amino acid insertions after amino acid 809 (isoforms 2(a0), 2(a5), 2(al7) and 2(a22), respectively), and of neuropilin-2(b) without and with the 5 amino acid insertion (isoforms 2(b0) and 2(b5), respectively). Shown are the sequences of the insertions, flanked by 3 amino acids N terminal to the insertion (AFA) and 4 amino acids C terminal to the insertions (DEYE in neuropilin-2a, GGTL in neuropilin-2b). (C) Sequence of neuropilin-2(b0) and partial sequence of human neuropilin-2(b0) from EST (AA25804) in the region where the sequence of neuropilin-2(b0) diverges from that of neuropilin-2(a0). Three amino acids N terminal to the site of divergence (AFA) are shown. Figure 5A-5B. Equilibrium binding of semaphorin- AP fusion proteins to neuropilin- expressing cells. Transfected or control COS cells were incubated with concentrated media containing the indicated concentrations of semaphorin- AP fusion proteins. AP activity derived from bound fusion proteins was measured colorimetrically at 405 nm; specific binding was obtained after subtraction of background from control cells. Specific binding curves to cells expressing neuropilin-1 (closed circles) or neuropilin-1 (closed squares) are shown for Sema III-AP (A), Sema E-AP (B), and Sema IV-AP (C). Dissociation constants for interaction with neuropilin-2-expressing cells were 0.29 for Sema E-AP and 0.09 nM for Sema IV-AP. DETAILED DESCRIPTION OF THE INVENTION The nucleotide sequences of exemplary natural cDNAs encoding human, rat and mouse SRI polypeptides are shown as SEQ ID NOS:l, 3 and 5, respectively, and the full conceptual translates are shown as SEQ ID NOS:2, 4 and 6. Natural SR2 cDNAs are found in (a) and (b) forms deriving from two distinct genes, with transcripts of each found in four alternatively spliced forms designated 0, 5, 17 and 22, depending on the size of an insert (below). For example, the nucleotide sequences of exemplary natural cDNAs encoding mouse SR2(a)0, 5, 17 and 22 polypeptides are shown as SEQ ID NOS:9, 11, 13 and 15, respectively, and the full conceptual translates are shown as SEQ ID NOS: 10. 12, 14 and 16. Other sequences recited in the Sequence Listing include the nucleotide sequences of exemplary natural cDNAs encoding mouse SR2(b)0 and 5 polypeptides (SEQ ID NOS:21 and 23) and their full conceptual translates (SEQ ID NOS:22 and 24); rat SR2(a)0 polypeptide (SEQ ID NO:7) and its full conceptual translate (SEQ ID NO:8); human SR2(a)0 and 17 polypeptides (SEQ ID NOS: 17 and 19) and their full conceptual translates (SEQ ID NOS: 18 and 20); and human SR2(b)0 polypeptide (SEQ ID NO:25) and its full conceptual translate (SEQ ID NO:26). The SR polypeptides of the invention include incomplete translates of SEQ ID NOS: 1, 3, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25 and deletion mutants of SEQ ID NOS:2, 4, 8, 10, 12, 14, 16, 18, 20, 22, 24 and 26, which translates and deletion mutants have SR-specific amino acid sequence, binding specificity or function. Preferred translates/deletion mutants comprise at least a 6, preferably at least an 8, more preferably at least a 10, most preferably at least a 12 residue domain of the translates not found in mouse, drosophila or chick neuropilin-1. Other preferred mutants comprise a domain comprising at least one SR2 and/or human specific residue. Such domains are readily discernable from alignments of the disclosed SRI and SR2 polypeptides, e.g. Figures 1 and 3. For example, human SRI specific residues include VI 1, V15. P18, A19, N24, E26, D29, S35, D62, M68, F90, N96, H98, F99, R100, T153, S155, S170, V177, P196, D219, 1242, V269, S298, A303, R323, K360, 1361, V363, T372, 1373, P379, V380, L381, V393, A394, P399, A40, T411, S449, G453, S469, A476, S479, 1481, 1487, E491, 1498, G518, M528, T553, P555, A556, G572, A587, L599, D601, V634, N667, V669, K672, S674, N717, R737, A755, 1756, S805, A813, P820, G835, E838, E855, T916, Q917 and T919. The subject domains provide SR domain specific activity or function, such as SR- specific cell, especially neuron modulating or modulating inhibitory activity, semaphorin- binding or binding inhibitory activity. SR-specific activity or function may be determined by convenient in vitro, cell-based, or in vivo assays: e.g. in vitro binding assays, cell culture assays, in animals (e.g. gene therapy, transgenics, etc.), etc. Binding assays encompass any assay where the molecular interaction of an SR polypeptide with a binding target is evaluated. The binding target may be a natural intracellular binding target such as a semaphorin, a SR regulating protein or other regulator that directly modulates SR activity or its localization; or non-natural binding target such a specific immune protein such as an antibody, or an SR specific agent such as those identified in screening assays such as described below. SR-binding specificity may assayed by binding equilibrium constants (usually at least about 10 7 M " ', preferably at least about 10 8 M "1 , more preferably at least about 10 9 M "1 ), by the ability of the subject polypeptide to function as negative mutants in SR-expressing cells, to elicit SR specific antibody in a heterologous host (e.g a rodent or rabbit), etc. In any event, the SR binding specificity of the subject SR polypeptides necessarily distinguishes mouse, chick and drosophila neuropilin-1. For example, the al, a2, bl, b2, c, TM and Cy domains (Fig.4A) and the polypeptides comprising the inserts shown in Fig. 4B and 4C are all shown to exhibit SR specific binding. Similarly, high throughput screens (e.g. see below) using SR-specific binding agents such as semalll and anti-SR antibodies are used to readily demonstrate SR-specific binding agents in a wide variety of deletion mutants of the disclosed SR polypeptides. For example, human SRI peptides with assay demonstrable SR-specific activity include: SEQ ID NO:2, residues 24-34; SEQ ID NO:2, residues 57-68; SEQ ID NO:2, residues 85-111; SEQ ID NO:2, residues 147-155; SEQ ID NO:2, residues 166- 178; SEQ ID NO:2, residues 288-299 SEQ ID NO:2, residues 354-366; SEQ ID NO:2, residues 368-690; SEQ ID NO:2, residues 697-415; SEQ ID NO:2, residues 595-615; SEQ ID NO:2, residues 671-689; SEQ ID NO:2, residues 911-919. Human SR2 peptides with assay demonstrable SR- specific activity include: SEQ ID NO:20, residues 14-35; SEQ ID NO:20, residues 261- 278; SEQ ID NO:20, residues 285-301; SEQ ID NO:20, residues 471-485; SEQ ID NO:20, residues 616-628; SEQ ID NO:20, residues 651-685; SEQ ID NO:20, residues 682-696; SEQ ID NO:20, residues 719-745; SEQ ID NO:20, residues 802-825; SEQ ID NO:20, residues 815-830; SEQ ID NO:20, residues 827-839; and SEQ ID NO:20, residues 898-929. The claimed SR polypeptides are isolated or pure: an "isolated" polypeptide is unaccompanied by at least some of the material with which it is associated in its natural state, preferably constituting at least about 0.5%, and more preferably at least about 5% by weight of the total polypeptide in a given sample and a pure polypeptide constitutes at least about 90%, and preferably at least about 99% by weight of the total polypeptide in a given sample. A polypeptide, as used herein, is an polymer of amino acids, generally at least 6 residues, preferably at least about 10 residues, more preferably at least about 25 residues, most preferably at least about 50 residues in length. The SR polypeptides and polypeptide domains may be synthesized, produced by recombinant technology, or purified from mammalian, preferably human cells. A wide variety of molecular and biochemical methods are available for biochemical synthesis, molecular expression and purification of the subject compositions, see e.g. Molecular Cloning, A Laboratory Manual (Sambrook, et al. Cold Spring Harbor Laboratory), Current Protocols in Molecular Biology (Eds. Ausubel, et al, Greene Publ. Assoc, Wiley-Interscience, NY) or that are otherwise known in the art. The invention provides binding agents specific to the claimed SR polypeptides, including natural intracellular binding targets, etc., methods of identifying and making such agents, and their use in diagnosis, therapy and pharmaceutical development. For example, specific binding agents are useful in a variety of diagnostic and therapeutic applications, especially where disease or disease prognosis is associated with improper or undesirable axon outgrowth or orientation. Novel SR-specific binding agents include SR- specific receptors, such as somatically recombined polypeptide receptors like specific antibodies or T-cell antigen receptors (see, e.g Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory), semaphorins and other natural intracellular binding agents identified with assays such as one-, two- and three-hybrid screens, non-natural intracellular binding agents identified in screens of chemical libraries such as described below, etc. Agents of particular interest modulate SR function, e.g. semaphorin-mediated cell modulation. For example, a wide variety of inhibitors of SR activity may be used to cell function involving SR, especially SR-semaphorin interations. Exemplary SR activity inhibitors include SR-derived peptide inhibitors, esp. dominant negative deletion mutants, etc., see Experimental, below. Accordingly, the invention provides methods for modulating cell function comprising the step of modulating SR activity, e.g. by contacting the cell with an SR inhibitor. The cell may reside in culture or in situ, i.e. within the natural host. Preferred inhibitors are orally active in mammalian hosts. For diagnostic uses, the inhibitors or other SR binding agents are frequently labeled, such as with fluorescent, radioactive, chemiluminescent, or other easily detectable molecules, either conjugated directly to the binding agent or conjugated to a probe specific for the binding agent. The amino acid sequences of the disclosed SR polypeptides are used to back- translate SR polypeptide-encoding nucleic acids optimized for selected expression systems (Holler et al. (1993) Gene 136, 323-328; Martin et al. (1995) Gene 154, 150-166) or used to generate degenerate oligonucleotide primers and probes for use in the isolation of natural SR-encoding nucleic acid sequences ("GCG" software, Genetics Computer Group, Inc, Madison WI). SR-encoding nucleic acids used in SR-expression vectors and incorporated into recombinant host cells, e.g. for expression and screening, transgenic animals, e.g. for functional studies such as the efficacy of candidate drugs for disease associated with SR-modulated cell function, etc. The invention also provides nucleic acid hybridization probes and replication / amplification primers having a SR cDNA specific sequence comprising SEQ ID NO:l, 3, 7, 9, 11, 13, 15, 17, 19, 21, 23, or 25, and sufficient to effect specific hybridization thereto (i.e. specifically hybridize with SEQ ID NO:l, 3, 7, 9, 11, 13, 15, 17, 19, 21, 23, or 25, respectively, in the presence of mouse, drosophila and chick neuropilin cDNA. Such primers or probes are at least 12, preferably at least 24, more preferably at least 36 and most preferably at least 96 bases in length. Demonstrating specific hybridization generally requires stringent conditions, for example, hybridizing in a buffer comprising 30% formamide in 5 x SSPE (0.18 M NaCl, 0.01 M NaPO 4 , pH7.7, 0.001 M EDTA) buffer at a temperature of 42°C and remaining bound when subject to washing at 42°C with 0.2 x SSPE; preferably hybridizing in a buffer comprising 50%) formamide in 5 x SSPE buffer at a temperature of 42°C and remaining bound when subject to washing at 42°C with 0.2 x SSPE buffer at 42°C. SR nucleic acids can also be distinguished using alignment algorithms, such as BLASTX (Altschul et al. (1990) Basic Local Alignment Search Tool, J Mol Biol 215, 403-410). The subject nucleic acids are of synthetic/non-natural sequences and/or are isolated, i.e. unaccompanied by at least some of the material with which it is associated in its natural state, preferably constituting at least about 0.5%, preferably at least about 5% by weight of total nucleic acid present in a given fraction, and usually recombinant, meaning they comprise a non-natural sequence or a natural sequence joined to nucleotide(s) other than that which it is joined to on a natural chromosome. The subject recombinant nucleic acids comprising the nucleotide sequence of SEQ ID NO:l, 3, 7, 9, 11, 13, 15, 17, 19, 21, 23, or 25, or fragments thereof, contain such sequence or fragment at a terminus, immediately flanked by (i.e. contiguous with) a sequence other than that which it is joined to on a natural chromosome, or flanked by a native flanking region fewer than 10 kb, preferably fewer than 2 kb, which is at a terminus or is immediately flanked by a sequence other than that which it is joined to on a natural chromosome. While the nucleic acids are usually RNA or DNA, it is often advantageous to use nucleic acids comprising other bases or nucleotide analogs to provide modified stability, etc. The subject nucleic acids find a wide variety of applications including use as translatable transcripts, hybridization probes, PCR primers, diagnostic nucleic acids, etc.; use in detecting the presence of SR genes and gene transcripts and in detecting or amplifying nucleic acids encoding additional SR homologs and structural analogs. In diagnosis, SR hybridization probes find use in identifying wild-type and mutant SR alleles in clinical and laboratory samples. Mutant alleles are used to generate allele- specific oligonucleotide (ASO) probes for high-throughput clinical diagnoses. In therapy, therapeutic SR nucleic acids are used to modulate cellular expression or intracellular concentration or availability of active SR. The invention provides efficient methods of identifying agents, compounds or lead compounds for agents active at the level of a SR modulatable cellular function. Generally, these screening methods involve assaying for compounds which modulate SR interaction with a natural SR binding target such as a semaphorin. A wide variety of assays for binding agents are provided including labeled in vitro protein-protein binding assays, immunoassays, cell based assays, etc. The methods are amenable to automated, cost-effective high throughput screening of chemical libraries for lead compounds. Identified reagents find use in the pharmaceutical industries for animal and human trials; for example, the reagents may be derivatized and rescreened in in vitro and in vivo assays to optimize activity and minimize toxicity for pharmaceutical development. In vitro binding assays employ a mixture of components including an SR polypeptide, which may be part of a fusion product with another peptide or polypeptide, e.g. a tag for detection or anchoring, etc. The assay mixtures comprise a natural intracellular SR binding target. In a particular embodiment, the binding target is a semaphorin polypeptide. While native full-length binding targets may be used, it is frequently preferred to use portions (e.g. peptides) thereof so long as the portion provides binding affinity and avidity to the subject SR polypeptide conveniently measurable in the assay. The assay mixture also comprises a candidate pharmacological agent. Candidate agents encompass numerous chemical classes, though typically they are organic compounds; preferably small organic compounds and are obtained from a wide variety of sources including libraries of synthetic or natural compounds. A variety of other reagents may also be included in the mixture. These include reagents like salts, buffers, neutral proteins, e.g. albumin, detergents, protease inhibitors, nuclease inhibitors, antimicrobial agents, etc. may be used. The resultant mixture is incubated under conditions whereby, but for the presence of the candidate pharmacological agent, the SR polypeptide specifically binds the cellular binding target, portion or analog with a reference binding affinity. The mixture components can be added in any order that provides for the requisite bindings and incubations may be performed at any temperature which facilitates optimal binding. Incubation periods are likewise selected for optimal binding but also minimized to facilitate rapid, high-throughput screening. After incubation, the agent-biased binding between the SR polypeptide and one or more binding targets is detected by any convenient way. Where at least one of the SR or binding target polypeptide comprises a label, the label may provide for direct detection as radioactivity, luminescence, optical or electron density, etc. or indirect detection such as an epitope tag, etc. A variety of methods may be used to detect the label depending on the nature of the label and other assay components, e.g. through optical or electron density, radiative emissions, nonradiative energy transfers, etc. or indirectly detected with antibody conjugates, etc. A difference in the binding affinity of the SR polypeptide to the target in the absence of the agent as compared with the binding affinity in the presence of the agent indicates that the agent modulates the binding of the SR polypeptide to the SR binding target. For example, in the cell-based assay also described below, a difference in SR- dependent modulation of axon outgrowth or orientation in the presence and absence of an agent indicates the agent modulates SR function. A difference, as used herein, is statistically significant and preferably represents at least a 50%>, more preferably at least a 90% difference. The following experimental section and examples are offered by way of illustration and not by way of limitation. EXPERIMENTAL Expression cloning of a cDNA encoding a Semalll-binding protein To facilitate isolation of Semalll-binding proteins through expression cloning, we fused the coding region of Semalll to that of alkaline phosphatase (AP), a readily detectable histochemical reporter, and expressed the resulting chimeric protein in human embryonic kidney 293 cells. This protein could be detected by Western blotting in conditioned medium from these cells as a major band of -180 kDa, consistent with the combined sizes of Semalll and AP; a few smaller products, apparently degradation products, were also detected in this medium. When this medium was applied to dissociated sensory neurons from dorsal root ganglia (DRG), AP-reactivity could be detected on the axons and cell bodies of neurons from El 4 DRG but not El 8 DRG. AP alone, also expressed in 293 cells, did not bind cells at either age. The binding of Sema- AP to E14 but not El 8 DRG cells is not unexpected since at E14 DRG axons are beginning to project into the spinal cord and can be repelled by a factor, likely Sema III, secreted by the ventral spinal cord (Fitzgerald et al., 1993; Messersmith et al, 1995; Shepherd et al., 1997), whereas by El 8 they are no longer repelled by ventral spinal cord tissue (Fitzgerald et al., 1993), perhaps reflecting a downregulation of their responsiveness to Semalll. To identify Semalll-binding proteins on E14 rat DRG neurons, a cDNA expression library was constructed in a COS cell expression vector using cDNA derived from E14 DRG tissue (see Experimental Procedures). Pools of -1000-2000 cDNA clones from the library were transfected into COS cells and screened for the presence of cells that bound Semalll-AP. A positive pool was identified after screening 70 pools. After three rounds of screening subpools from this pool, a single cDNA encoding a Semalll- AP binding activity was identified. COS-7 cells transfected with this cDNA specifically bound Semalll-AP but not AP or a netrin-Fc fusion protein (Keino-Masu et al., 1996). Nucleotide sequencing of the entire 5 kB cDNA insert revealed a single long open reading frame predicted to encode a protein (rat semaphorin receptor 1, rSRl) of 921 amino acids with sequence similarity with mouse, chicken and Xenopus neuropilin (Takagi et al., 1991, 1995; Kawakami et al, 1996). We further isolated a cDNA encoding a human homo log of our semphorin binding protein (hSRl ) from a fetal human brain library (see Experimental Procedures), and Figure IA shows an alignment of the full conceptual translated amino acid sequences of our rat and human proteins with mouse neuropilin. The rat and human proteins share a high degree of sequence homology with the mouse protein (97% and 93 % identity at the amino acid level, respectively), and are predicted to have the domain structure previously described for neuropilins from other species, including a short but highly conserved cytoplasmic domain (Figure IB). We next performed coimmunoprecipitation experiments to test whether the binding of Semalll- AP to COS-7 cells expressing rSRl reflected a direct interaction between Semalll and rSRlor required cellular factors made by the COS-7 cells. For this purpose we constructed a soluble version of the ectodomain of rSRl fused to AP. A myc- tagged Semalll protein could be precipitated by beads conjugated with this SR-AP fusion, but not with beads conjugated with a control fusion protein, c-kit-AP (Flanagan and Leder, 1990), indicating a direct interaction between the SRI ectodomain and Semalll. SRI binds both the semaphorin and the C-terminal domains of Semalll Semalll consists of a signature semaphorin domain, a single immunoglobulin (Ig) domain, and a carboxy terminal (C) domain that is rich in basic residues (Luo et al., 1993; Kolodkin et al., 1993; Messersmith et al., 1995; Puschel et al., 1995). The conservation of semaphorin domains among different semaphorin family members (reviewed in Tessi- Lavigne and Goodman, 1996; Kolokin, 1996) suggests the potential importance of this domain for function. The functions of the other two domains are unknown, although the basic nature of the C domain has suggested a role for this domain in mediating interactions with cell surfaces or the extracellular matrix (Luo et al, 1993). To determine which domain of Semalll mediates the interaction between Semalll and SRI, constructs encoding various fusions of AP to different portions of Semalll were expressed in COS cells. Media conditioned by these cells were applied to COS-7 cells expressing SRI to test for binding of AP fusion proteins ; in positive control experiments, binding was observed with medium containing full length Semalll- AP but not AP alone . Binding was also observed with an AP fusion protein comprising the semaphorin and Ig domains (AP-SI) and a fusion protein comprising just the semaphorin domain (AP-S), but not with a fusion protein comprising a truncated semaphorin domain, suggesting that the integrity of the semaphorin domain is required for binding. Surprisingly, binding was also observed with AP fusion proteins comprising only the C domain (AP-C) and a fusion protein comprising the Ig and C domains. These results provide evidence that both the semaphorin and the C domains of Semalll can bind SRI. The binding of the C domain does not appear to reflect a non-specific interaction arising from the basic nature of the C domain since we found that the C terminal domain of netrin- 1 (Serafmi et al., 1994), which is also highly basic but does not share any sequence homology with the Semalll C domain, did not bind SRI . We next measured the binding affinity of the full-length and two of the truncated fusion ligands (AP-S and AP-C) to cells expressing SRI in equilibrium binding experiments, based on the relative amounts of AP activity in the supernatant and bound to cells (Figure 2). One limitation of these experiments is that we used partially purified conditioned media (see Experimental Procedures) which in the case of Semalll- AP and AP-C contain both the full length fusion proteins as well as truncated forms that are presumed to arise by proteolysis. For each of these fusions, the estimated dissociation constant would be accurate only if all the degradation products that possess AP activity bind with the same affinity as the intact fusion protein; this is unlikely to be the case since the media contain protein species that appear to correspond to AP or fragments of AP, which do not bind SRI. This limitation does not apply to AP-S since in this case only the full length species is found in the supernatant; the estimated dissociation constant should therefore accurately reflect the affinity of AP-S for the SRI -expressing cells. With these caveats, we found that the specific binding curves of Semalll- AP, AP-S and AP-C to cells expressing SRI showed saturation and could be fitted with the Hill equation (Figures 2A- C). Predicted values for the dissociation constants (Kd) for Semalll-AP, AP-S and AP-C binding to SRI -expressing cells were 0.325 nM, 1.45 nM, and 0.84 nM, respectively. For comparison, in the collapse assay , a half maximal collapse response is observed with conditioned medium containing 0.44 nM Semalll-AP. This value is comparable to the estimated Kd for the interaction of Semalll- AP with SRI. These results support the role of an interaction of Semalll with SRI on DRG axons in causally mediating collapse. For these experiments, control 293-EBNA cells or 293-EBNA cells stably expressing rat SRI were treated for 90 min with concentrated conditioned media containing the indicated concentrations of Semalll- AP (A), AP-S (B), or AP-C (C). After washing six times in HBHA buffer, the cells were lysed and endogenous AP activity was heat-inactivated. AP activity derived from the bound recombinant AP fusion proteins was measured colorimetrically (optical density at 405 nm). Specific binding was determined by subtraction of values obtained from binding to SRI -expressing cells and to control cells; values obtained in this way were fitted to the Hill equation. Insets in Fig. 2 show raw data (circles, total binding to SRI -expressing cells; triangles, total binding to control cells). Kd values for the interactions of SemaIII-.AP, AP-S and AP-C with SRI were 55.3 ± 6.5 ng/ml, 218.6 ± 11.0 ng/ml, and 67.2 ± 3.0 ng/ml, respectively (1 nM corresponds to 170 ng/ml, 150 ng/ml, and 80 ng/ml for Semalll-AP, AP-S and AP-C, respectively). Bars indicated s.e.m. for triplicates. Hill coefficients for Semalll-AP, AP- S and AP-C were 1.51 ± 0.24, 1.70 ± 0.10, and 1.44 ± 0.07, respectively. SRI function is required for the repulsive action of Semalll We next raised antibodies to a portion of the SRI ectodomain for use in tests of the functional role of SRI in mediating responses to Semalll (see Experimental Procedures). To verify the potential usefulness of the antiserum, we first examined whether it could detect SRI protein on axons. The spatial and temporal pattern of expression of SRI detected with this antiserum in transverse sections of rat embryos at spinal levels corresponded to the sites of SRI gene expression detected by in situ hybridization, and matched the pattern previously observed in mouse and chick embryos (Kawakami et al., 1995; Takagi et al., 1995). At E14, when afferent fibers of DRG neurons start to penetrate the dorsal spinal cord (Windle and Baxter, 1936; Smith, 1983; Altman and Bayer, 1994; Snider et al., 1992; Zhang et al., 1994), SRI transcripts were found in the DRG as well as in the ventral and dorsal spinal cord, and corresponding immunoreactivity for SRI protein was detected on sensory and motor axons, as well as in the dorsal spinal cord. SRI immunoreactivity could also be detected with this antiserum on the axons and growth cones of E14 rat DRG neurons in culture, as previously shown for neuropilin with chick DRG axons (Takagi et al., 1995). At El 8, much lower levels of SRJ transcripts were detected in DRG and the ventral horn (see also Kawakami et al, 1995; Takagi et al., 1995 for similar results with neuropilin in mice and chickens). The timing of expression in DRG is consistent with the pattern of Semalll-AP binding to E14 and El 8 DRG cells in culture and with what might be expected of a Semalll receptor (see Fitzgerald et al., 1993; Messersmith et al., 1995; and discussions therein) Protein A-purified anti-SRl antiserum was used to test the involvement of SRI in mediating the function of Semalll. Inclusion of the antiserum in the culture medium inhibited the repulsive effect of Semalll-AP and Semalll on E14 rat DRG axons in collagen gel cultures in a dose-dependent manner, whereas preimmune IgG, also purified on protein A, did not inhibit the repulsion. To verify that this neutralizing effect was due to antibodies directed against SRI in the antiserum, aliquots of the antiserum were subjected to immunodepletion by incubation with beads conjugated with the portion of the SRI ectodomain used to make the antiserum (depleted antiserum) or with control beads (mock-depleted antiserum). The mock-depleted antiserum still detected the SRI ectodomain- AP fusion protein by Western blotting and was still capable of blocking the inhibitory effect of Semalll- AP. In contrast, the depleted antiserum did not detect the SRI ectodomain-AP fusion protein by Western blotting and did not block the inhibitory activity of Semalll- AP, consistent with the hypothesis that the starting antiserum blocks Semalll-AP activity by interfering with SRI function. To rule out the possibility that the antiserum to SRI affected a general mechanism required for axonal repulsion, the same protein A-purified antiserum was tested for its effect on netrin-mediated repulsion of trochlear motor axons (Colamarino and Tessier-Lavigne, 1995), a group of axons that can also be repelled by Semalll (Serafini et al., 1996; Varela-Echavaria et al., 1997). The anti-SRl antiserum stained these axons but did not block the repulsive effect of netrin- 1 on these axons, consistent with a specific involvement of SRI in Semalll-mediated repulsion. SRI function is also required for the collapse-inducing effect of Semalll In addition to steering DRG axons away when presented chronically from a point source, Semalll can also induce collapse of DRG growth cones when added acutely and uniformly to growth cones in culture (Luo et al., 1993). We therefore examined whether the anti-SRl antiserum could affect the activity of Semalll in the collapse assay. The anti-SRl antiserum inhibited collapse of E14 rat DRG growth cones elicited by Semalll- AP or Semalll-myc; the blocking effect showed a dose-dependence that was similar to that observed for the block of repulsion (Table 1). As expected, the mock-depleted antiserum also blocked the collapse, whereas the depleted antiserum did not. To test the specificity of this blockade, we took advantage of the fact that lysophosphatidic acid (LPA) can also cause collapse of DRG growth cones (Jalink et al., 1994). Neither the preimmune serum nor the anti-SRl antiserum inhibited the collapse of DRG growth cones induced by LPA, consistent with the hypothesis that the antiserum blocks Semalll- induced collapse by specifically inhibiting SRI function. Cloning of a cDNA encoding SR2 To identify additional members of the SR family, we designed PCR primers which would selectively amplify rat cDNA molecules containing both the CUB the MAM motifs of SRI . A single cDNA (SEQ ID NO:7) encoding an 936 amino acid SRI homolog, designated SR2 (SEQ ID NO:8) was identified. With these data, we were able to identify and composite ESTs in public databases to generate a cDNA sequence encoding hSR2. CDNA's comprising this clone are also isolated from a fetal human brain library (see Experimental Procedures). SR-specific function, including semaphorin binding and neuron axon outgrowth and/or orientation modulating activity are demonstrated as described herein for SRI polypeptides. SRI is a Semalll receptor Neuropilin is a transmembrane protein initially identified by Fujisawa and colleagues as an epitope recognized by a monoclonal antibody (A5) that labels specific subsets of axons in the developing Xenopus nervous system (Takagi et al., 1987; Fujisawa et al., 1989; Takagi et al., 1991). Neuropilin comprises in its extracellular domain two so-called CUB motifs, which are found in the noncatalytic regions of the complement components Clr and Cis and several metalloproteinases (for review see Bork and Beckmann, 1993). These domains are followed in neuropilin by two domains with significant similarity to many proteins, including the Cl and C2 domains of coagulation factors V and VIII (Toole et al., 1984; Jenny et al., 1987), the milk fat globule membrane proteins (MFGPs) (Stubbs et al., 1990), and the discoidin domain receptor (DDR) (Johnson et al., 1993; Sanchez et al., 1994). More proximal to the transmembrane region is a MAM domain, a type of motif implicated in protein-protein interactions (Beckmann and Bork, 1993). The cytoplasmic domain of neuropilin is short (40 amino acids) and does not possess obvious motifs, but is highly conserved among Xenopus, mouse and chick (Takagi et al., 1995; Kawakami et al., 1996). In the developing nervous systems of these three species, neuropilin is expressed in dynamic fashion by a variety of different classes of axons (including motor and sensory axons) as they project to their targets (e.g., Takagi et al., 1987, 1991, 1995; Kawakami et al., 1996). Neuropilin can promote neurite outgrowth in vitro (Hirata et al., 1993) and forced expression of neuropilin under control of the β-actin promoter in transgenic mice results in axonal defasciculation (Kitsukawa et al., 1995). The forced ectopic expression of neuropilin also leads to abnormalities in development of the heart and limbs, two of the non-neural regions where neuropilin is expressed, which has suggested a role for neuropilin in organogenesis outside the nervous system (Kitsukawa et al., 1995). We have identified SRI and SR2 semaphorin receptors with sequence similarity to the neuropilin proteins. The spatiotemporal expression pattern of SRI is consistant with SRl's role as a Semalll receptor. In the region of the developing spinal cord, SRI is most prominently expressed by sensory neurons in the DRG, particularly on their axons in the spinal nerves, the dorsal roots, and the dorsal funiculus and SRI can also be detected on the growth cones of axons derived from dissociated DRG neurons in culture. The period during which SRI and neuropilin is expressed by DRG neurons (between E9 and E15.5 in the mouse, decreasing sharply thereafter (Kawakami et al., 1995)) correponds to the timing of projection of Semalll-responsive DRG axon projections into the spinal cord. During this period, Sema III is expressed at a high level in the ventral spinal cord and has been implicated as a diffusible chemorepellent that prevents inappropriate targeting of NGF-responsive axons that normally terminate in the dorsal spinal cord (Messersmith et al., 1995, Puschel et al, 1995, 1996; Shepherd et al., 1997). Our in situ hybridization studies suggest that SRI may be expressed in only some populations of rat DRG cells at E14 - possibly the NGF-responsive neurons, which are Semalll responsive. In addition to developing DRG axons, several other classes of developing axons are repelled by or collapse in response to Semalll, including sympathetic axons (Puschel et al., 1996), spinal motor axons (Shepherd et al., 1996; Varela-Echavarria et al., 1997), and many cranial motor axons such as trochlear, trigeminal motor, glossopharyngeal and vagal axons (Serafini et al., 1996; Varela- Echavarria et al., 1997). All of these axons express SRI. SRI also plays a role in mediating actions of Semalll outside the nervous system. SRI, the neuropilins and Semalll are expressed in a variety of non-neural tissues, including the developing cardiovascular system and limbs (Takagi et al., 1987, 1991, 1995; Kitsukawa et al., 1995; Puschel et al., 1995; Behar et al., 1996). Ectopic expression of m-neuropilin under control of the β-actin promoter in transgenic mice, in addition to causing sprouting and defasciculation of axons, leads to a variety of morphological abnormalities in non-neural tissues including the presence of excess capillaries and blood vessels, dilation of blood vessels, malformed hearts, and extra digits (Kitsukawa et al, 1995; see also, the defects in axonal, heart and skeletal development seen in Semalll knock-out mice, Behar et al., 1996). Our experiments have provided evidence that both the C domain and the semaphorin domain of Semalll can independently bind SRI . The ability of both poles of the full length Semalll molecule to bind SRI could provide an explanation for the data suggesting that full length Semalll has a higher affinity for SRI than do either of the individual domains alone, since sequential binding of the two domains of each Semalll molecule to neighboring SRI molecules in the cell membrane would result in a higher apparent affinity. This observation indicates that signaling in response to Semalll might be triggered by dimerization of SRI molecules brought together by single Semalll molecules; which is also supported by the observation that AP-S and AP-C, the fusions of AP to the semaphorin domain or the C domain, failed to induce repulsion or to cause collapse of DRG axons in vitro. SRI contains at its amino terminus two CUB domains, motifs implicated in protein-protein interactions whose structure is predicted to be an antiparallel β-barrel similar to those in two adhesive domains, immunoglobulin-like domains and fibronectin type III repeats (Bork et al., 1993; Bork and Beckmann, 1993). CUB domains in complement Clr/s appear to mediate calcium-dependent tetrameric complex formation between Clr/s dimers, as well as their association with Clq to form the mature Cl complex (Busby and Ingham, 1988, 1990), whereas a CUB domain in the metalloproteinase Tolloid (a relative of BMP- 1) is suggested from genetic evidence to mediate an interaction with the BMP family member decapentaplegic (Childs and O'Connor, 1994; Finelli et al., 1995). In the central portion of the SRI molecule, the bl and b2 domains show homology to protein binding domains of coagulation factors V and VIII (Toole et al., 1984; Jenny et al., 1987), MFGF (Larocca et al., 1991) and two receptor protein-tyrosine kinases, DDR (Johnson et al., 1993) and Ptk-3 (Sanchez et al., 1994). Finally, SRI also possesses a MAM domain, a -170 amino acid module found in diverse transmembrane proteins (Beckmann and Bork, 1993), which has been suggested to mediate homophilic interactions (Zondag et al., 1995). We found that a truncated form of SRI which lacks the amino terminal-most 264 amino acids retains the ability to bind Semalll- AP, indicating that at least one of the semaphorin and C domains of Semalll may interact with domains bl or b2 or the MAM domain of SRI. Semalll may also modulate the interactions of SRI with other SRI binding partner. In the repulsion assay the most obvious effect of Sema III is the steering away of DRG axons from a local source of Semalll, rather than a change in fasciculation patterns (Messersmith et al, 1995). Furthermore, individual growth cones can be induced to collapse in vitro in response to Semalll (Luo et al., 1993) in a SRI -dependent fashion, indicating a distinct signaling pathway involving SRI that can be triggered by Semalll. The semaphorin family comprises over 20 proteins, secreted and transmembrane, which have been divided into five subfamilies based on sequence and structural similarity (reviewed by Tessier-Lavigne and Goodman, 1996; Kolodkin, 1996). We have found that the secreted semaphorins SemaA, SemaE and SemalV, which belong to the same subfamily as Semalll, can all bind SRI, suggesting promiscuity in interactions between SRI and members of this subfamily of the semaphorin family. The bewildering diversity of semaphorin proteins may mask an underlying simplicity in interactions of these proteins and their receptors, much as the diversity of Eph receptors and ephrin ligands masks simpler binding relations, in which GPI-anchored ligands of the ephrin-A subclass interact primarily and promiscuously with EphA class receptors, and ligands of the ephrin-B subclass interact primarily and promiscuously with EphB class receptors (Gale et al.; 1996; Eph Nomenclature Committee, 1997). Experimental procedures: Construction and expression of AP fusion proteins To produce a Sema III-AP fusion protein, the cDNA encoding full-length Sema III was amplified by PCR and subcloned into APTag-1 (Flanagan and Leder, 1990). From the resulting plasmid, the fragment encoding both Sema III and AP was then transferred to the expression vector pCEP4 (Invitrogen), and used to transfect 293-EBNA cells (Invitrogen). A cell line stably expressing Sema-AP was established after selection with geneticin and hygromycin. Cells were grown to confluence and then cultured in Optimen medium (BRL) for 3 days. The conditioned medium was collected and partially purified using a Centriprep-100 device (Amicon). A construct encoding the ectodomain of SRI (amino acids 1 to 857) fused to AP was similarly made in pCEP4 and used to derived a stable cell line. Conditioned medium from this line was prepared in the same way. For other AP fusion proteins, sequences encoding the Sema domain and Ig domain (amino acids 25 to 654), the Sema domain alone (amino acids 25 to 585), a truncated Sema domain (amino acids 25 to 526), the Ig domain and C-domain together (amino acids 586 to 755), or the C-domain alone (amino acids 655 to 755) were amplified by PCR, fused to the sequence encoding AP, and subcloned into cloning sites after the Ig_κ-chain signal sequence of the expression vector pSecTag B (Invitrogen). These resulting constructs were transiently transfected into Cos-1 or Cos-7 cells with Lipofectamine (GIBCO BRL). Conditioned media were collected as described above. Expression library construction and screening 80 mg of DRG tissue was dissected from two litters of El 4 rat embryos (with kind help of K. Wang) and frozen on dry ice. mRNA was isolated from these rat DRGs using a QuickPrep mRNA purification kit (Pharmicia), and used to generate cDNA using a Stratagene cDNA synthesis kit according to manufacturer's instructions, except that the cDNA was size-fractionated using a DNA Size Fractionation Column (GIBCO BRL). Fractions containing cDNA larger than 500 bp were collected and ligated to the EcoRI- Xhol sites of the COS cell expression vector pMT21 (Genetics Institute). Ligated DNA was ethanol precipitated, resuspended in water at 10 nglμl, electroporated into SURE 2 supercompetent cells (Stratagene) (1 μl DNA to 40 μl bacteria), and the resulting transformants were divided into pools of- 1000 to 2000 colonies. To screen the library, DNA was extracted from the bacteria in each pool using the SNAP miniprep kit (Invitrogen) and transiently transfected into COS-1 cells in six wells plates with lipofectamine (GIBCO BRL). After 48 hr, the cells were washed once with Hank's balanced salt solution (HBHA, Cheng and Flanagen, 1994), and then incubated in HBHA containing 50-100 ng/ml Semalll-AP fusion protein for 75 min at room temperature. Plates were washed in HBHA six times, fixed with acetone-formaldehyde, then washed twice in HBS as described by Cheng and Flanagen (1994). Plates were kept in a 65 C incubator for 2 hr to inactivate the endogenous alkaline phosphatase activity in COS cells. The cells in the plates were stained for 2-6 hr in AP buffer containing the AP substrate BCIP and NBT (GIBCO BRL) as described previously by Cheng and Flanagan (1994). Staining of the cells was monitored using a dissecting microscope. After identification of a positive pool, 10 ng of DNA from the pool was transfected into DH5α_competent cells and the transformants were subdivided into subpools of 200-300 colonies. These subpools were rescreened as described above, and a positive subpool subdivided further through two more rounds until a single positive plasmid (p28) was isolated. The insert DNA in the p28 plasmid was sequenced from both 33 strands using a Licor (L4000) automated sequencer as well as by P cycle sequencing. Human cDNA library screening A search of the human expressed sequence tag (EST) databases with the sequence of rat SRI (p28) revealed many short sequences with homology to its middle portion . An EST clone (Genbank accession number R61632) was obtained from Genome System Inc. and used as a probe to screen a human fetal brain cDNA library (Stratagene) at high stingency, leading to the isolation of four overlapping cDNAs covering the full-length coding region of human SRI. In situ hybridization Cryosat sections (10 μm) were made from the brachial region of E14 rat embryos prefixed with 4%> paraformaldehyde (PFA). In situ hybridization of these sections was performed as described by Schaeren-Wiemers and Gerfin-Moser (1993) and Kennedy et al (1994). A 1285 bp fragment including 490 bp of 5 '-untranslated region and 795 bp of 5' SRI coding region was released by Pst I digestion of the p28 plasmid and subcloned into pBluescript (Stratagene). Antisense and sense RNA probes were transcribed in the presence of digoxygenin-UTP (Boehringer Mannheim) using T7 and T3 polymerases as recommended by the manufacturer. Cell surface binding and kinetic analysis To examine the binding of Semalll- AP to dissociated DRG cells, DRGs dissected from E14 or E18 rat embryos were digested with 0.25% of trypsin for 10 min at 37°C and further dissociated by trituration with a fire-polished pipette. After removing the undissociated tissue clumps by precipitation, dissociated cells were collected by spinning at 430 x g for 5 min, then cultured in eight-well chamber slides at 37°C in 5% CO2 for 20 hr in F12/N3 medium (Tessier-Lavigne et al., 1988) containing 0.5% fetal calf serum (FCS) and 25 ng/ml 2.5S NGF ((Bioproducts for Science Inc.). To examine binding activity, cells were incubated with HBHA buffer containing the indicated recombinant protein for 90 min, followed by washing, fixing, heating, and staining as described above. 293-EBNA cells stably expressing the full-length rat SRI protein were established by transfection of a pCEP4-SRl plasmid and selection with geneticin and hygromycin. The equilibrium-binding experiments were performed essentially as described (Flanagan and Leder, 1990; Cheng and Flanagan, 1994) using control 293-EBNA cells or SRI - expressing 293-EBNA cells cultured on six -well plates precoated with poly-D-lysine. Generation of antibodies to Semalll and SRI For Western blotting studies on Semalll, purified AP-S, a fusion of AP to the Sema domain of Semalll, was used to raise a rabbit anti-serum. For function-blocking studies on SRI, a 1775 bp DNA fragment encoding amino acids 265 to 857 of SRI was PCR amplified and subcloned into a bacterial expression vector pQE-9 (Qiagen) for the generation in E. Coli of a fusion protein comprising six histidine residues at its amino terminus. The His-tagged SRI was expressed in XLl-Blue cells and purified according to manufacturer's instructions, and used to raise a rabbit anti-SRl antiserum. Immunoglobulins in the anti-SRl or preimmune sera were purified on protein A-Agarose (GIBCO BRL) columns. After application of the sera to the columns, the columns were washed first with 15 bed-volumns of 100 mM Tris (pH 8.0) and then with another 20 bed- volumns of 10 mM Tris (pH 8.0), then eluted with 5 bed volumns of 50 mM glycine (pH 3.0). The eluates from the columns were immediately neutralized by addition of 1/10 volume of 1 M Tris (pH 8.0), followed by concentration on a Centricon-10 device (Amicon). To deplete anti-SRl antibodies from the antiserum, an equal volume of nickle-agarose beads was incubated with (or, for control, without) purified His-SRl protein (1 mg/ml) at 4 °C for 4 hr. After washing three times with F12 medium, the beads were incubated at 4°C for 3 hr with an equal volume of anti-SRl serum. The supernatants were collected and then subjected to protein A-agarose affinity purification as described above. Immunoprecipitation and Western analysis To detect AP or AP fusion proteins by Western blotting, aliquots of the concentrated conditioned media were resolved by SDS-PAGE (8% gel). After transfer to nitrocellulose (Amersham), the proteins were probed with rabbit anti-AP antibody (DAKO). The blot was developed with BCIP and NBT as the substrate. To detect an interaction between SRI and Semalll, 100 μl protein A-agarose beads (GIBCO BRL) were first incubated with 5 μg of anti-AP monoclonal antibody (Medix Biotech) in IP buffer (20 mM Hepes, pH 7.0, 100 mM NaCl, 1 mM EDTA, 1 mM DTT, and 0.02% NP-40) at 4°C for 2 hr. After washing three times with 1 ml of IP buffer, half of the beads (50 μl) were incubated with 2 μg of Kit-AP (Flanagan and Leder, 1990) or SRI -AP protein (containing the entire SRI ectodomain) at 4 ° C for another 2 hr. Beads conjugated with recombinant proteins were then washed three times with IP buffer, and resuspended into 40 μl IP buffer containing 2 μg of myc-tagged Sema III protein. After the mixtures were incubated at 4°C for 3 hr, the beads were washed six times with 1 ml IP buffer. The bound proteins were released by boiling the beads in 50 μl SDS- containing sample buffer and analyzed by SDS-PAGE (8% gel) and Western blotting with a monoclonal antibody (9E10) against a C-terminal Myc-epitope tag. Immunohistochemistrv For immunostaining to detect the expression of SRI in E14 rat spinal cord, cryostat sections (10 μm) from unfixed frozen embryos were collected and fixed with acetone for 5 min. The staining was performed with preimmune serum (1 :500), or anti- SRl serum (1 :500) as the primary antibody and biotinylated goat anti-rabbit Ig (5 ng/ml, Biorad) as the secondary antibody. Diaminobenzidine (Sigma) was used as a chromogen, with signal enhancement by a Vectastain Elite ABC kit (Vector). For staining of cultured cells, E14 rat DRG were cultured as above for 20 hr, incubated with the anti-SRl antiserum or preimmune serum (1/500 dilution) for 1 hr at room temperature, washed 3 times, fixed with methanol, and the bound antibody was visualized using a Cy3- conjugated secondary antibody (Jackson Immunological Laboratories). Collapse assay The collapse assay was performed essentially as described by Raper and Kapfhammer (1990) and Luo et al. (1993), with minor modifications. In brief, DRG explants were dissected from E14 rat embryos, and cultured at 37°C in 5% CO2 for 16- 20 hr on six-well plates precoated with poly-D-lysine (Sigma) and laminin (Becton Dickinson Labware) in F12/N3 medium containing 0.5% FCS and 25 ng ml 2.5 S NGF. Small volumes of concentrated conditioned medium containing .AP, Semalll- AP, or Semalll-myc were gently added into the culture medium, and the cultures were kept at 37°C for 1 hr. The explants were fixed with 4%> PFA in PBS containing 10% sucrose for 15 min, then incubated with PHTX (PBS / 1 % heat-inactivated goat serum / 1 % Triton X- 100) for 15 min. The explants were then stained with 2 μg/ml Rhodamine-Phalloidin (Molecular Probes) for 30 min, washed, and mounted with Fluoromount G (Fisher). As a control, aliquots of L-a-lysophosphatidic acid (LPA, Sigma) were added into the cultures at a final concentration of 1 μM (Jalink et al., 1994) and the cultures were incubated at 37 °C for 3 min prior to fixation and staining. To examine the effect of preimmune or anti-SRl antisera, aliquots of each antiserum were added into the explant cultures, which were kept at 37 °C for 30 min prior to the addition of Semalll protein or LPA. Repulsion assay The repulsion assay was essentially as previously described (Messersmith et al., 1995). In brief, E14 rat DRG explants were dissected and embedded in collagen gels with control 293 EBNA cells or 293 EBNA cells expressing Semalll- AP. The indicated amount of antibodies were included into the culture medium (F12/N3 medium containing 0.5% FCS and 25 ng/ml 2.5 S NGF). After incubation at 37 °C for 40 hr, the explants were fixed with 4% PFA in PBS for 2 hr, and followed by immunostaining with a neurofilament-specific antibody (NF-M, 1:1500; Lee et al., 1987) and a horseradish peroxidase-conjugated secondary antibody (Boehringer-Mannheim; 1:250) as described (Kennedy et al., 1994; Messersmith et al., 1995). The quantification of neurite outgrowth was performed as described (Messersmith et al., 1995). Identification of Neuropilin-2 The extracellular domain of neuropilin- 1 is comprised of several predicted structural domains: two CUB motifs (domains al and a2), two domains of homology to coagulation factors V and VIII (domains bl and b2) and a MAM domain (domain c) (Takagi et al., 1991; Kawakami et al, 1996) (Figure 1 and 2a). To determine whether neuropilin- 1 is a member of a family of related molecules, we searched for relatives by reverse transcription-PCR (RT-PCR) using three sets of degenerate forward primers (5.1, 5.2 and 5.3) and three sets of degenerate reverse primers (3.1, 3.2, and 3.3). The primers were designed based on the sequences conserved among domain a2 and other CUB domain proteins (primer set 5.1), domains bl and/or b2 and coagulation factors V and VIII (primer sets 5.2, 5.3 and 3.1), domain c and other MAM domain proteins (primer set 3.2), or a sequence in the cytoplasmic domain that is highly conserved among neuropilin homologues from different species (primer set 3.3) (see Experimental Procedures). Sequences were amplified from whole El l mouse embryo mRNA and adult mouse brain mRNA using all pairwise combinations of 5' and 3' primer sets (except 5.3 and 3.1). In all cases, products of the size expected for neuropilin- 1 were amplified and subcloned. More than a dozen cDNAs for each pair of primer sets were sequenced, and in all cases mouse neuropilin- 1 sequences were recovered. In addition, several of the cDNAs obtained by RT-PCR using primer sets 5.2 (bl domain, KEWIQVD) and 3.3 (cytoplasmic domain, ENYNFE) encoded overlapping sequences that were related but not identical to a portion of the neuropilin- 1 sequence. These sequences were extended in both the 5' and 3' directions using a combination of cDNA library screening and RACE (rapid amplification of cDNA ends) (see Experimental Procedures). From these experiments, the full length sequence of a new neuropilin- 1 -related molecule was assembled (Figure 3), which has been named neuropilin-2. By screening the expressed sequence tag (EST) data bases, we were also able to assemble the sequences of several human ESTs to predict the sequence of human neuropilin-2, which shares high homology (90% identity) with that of mouse neuropilin-2. The overall structure predicted for neuropilin-2 is identical to that of neuropilin- 1, with all the same functional domains (Figure 4A). At the amino acid level, the sequence of neuropilin-2 is 44% identical to that of neuropilin- 1, in both mouse and human. The homology is distributed over the entire length of the proteins, with highest homology in the transmembrane domain. In the course of these experiments (see Experimental Procedures), we also discovered evidence for the existence of alternative forms of neuropilin-2 which may arise by alternative splicing. First, an alternate form with a divergent carboxy terminus was identified, which we have named neuropilin-2(b0) (we will use the names neuropilin- 2 and neuropilin-2(a0) interchangeably to refer to the original isoform). The sequence of neuropilin-2(b0) diverges from that of neuropilin-2(a0) at amino acid 809, between the MAM domain and the transmembrane domain of neuropilin-2(a0) (Figure 4C). Neuropilin-2(b0) is predicted from hydrophobicity analysis to have a transmembrane domain, followed by a cytoplasmic domain of similar length to that in neuropilin-2(a0), but these two domains are highly divergent from those of neuropilin-2(a0), sharing only 10%) identity. An expressed sequence tag (EST) encoding human sequences (346bp fragment) corresponding to a portion of this diverged sequence was also found in the dbEST database (AA25840) (Figure 4C). To test the prediction that neuropilin-2(b0) is a transmembrane protein, we tagged this protein at its carboxyl terminus with a myc- epitope, expressed the tagged construct by transient transfection into COS 7 cells, and examined expression of the tagged protein using monoclonal antibody 9E10 directed against the epitope tag (Evan et al., 1985). Detection of the myc-tag at the carboxyl terminus of neuropilin-2(b0) by immunostaining required detergent permeabilization of the transfected cells, indicating that neuropilin-2 is indeed a transmembrane protein. In addition, we found other isoforms of neuropilin-2(a0), including isoforms with insertions of 5, 17, or 22 (5+17) amino acids at amino acid 809 in neuropilin-2(a0), i.e. at the site of divergence of the a and b isoforms of neuropilin-2 (Figure 4B). The 22 amino acid insertion is the sum of the 5 and the 17 amino acid insertions (Figure 4B). We term these isoforms neuropilin-2(a5), neuropilin-2(al7) and neuropilin-2(a22). The isoform reported by Kolodkin et al. (1997) appears to be the rat neuropilin-2(al7) isoform. Similarly, we have found an isoform of neuropilin-2(b0) with the very same 5 amino acid insertion at amino acid 809, and which we name neuropilin-2(b5) (Figure 4B). The pattern of combinations of the 5 and 17 amino acid inserts that we have observed in different neuropilin-2 isoforms indicates that these different isoforms arise from splicing in of separate exons encoding the 5 and 17 amino acid stretches. To determine whether the a and b isoforms of neuropilin-2 show different temporal patterns of expression, we performed RT-PCR using a 5' primer designed to a sequence shared between all neuropilin-2 isoforms, and two 3' primers unique to the sequences in the cytoplasmic domains of neuropilin-2(a) and of neuropilin-2(b) (see Experimental Procedures). Using El 1 whole mouse embryo mRNA as a template we found that at El 1 only an amplification product corresponding to neuropilin-2(a) could be detected. However, using adult mouse brain mRNA as a template, we detected amplification products corresponding to both neuropilin-2(a) and neuropilin-2(b). Taken together, these results indicate that different isoforms of neuropilin-2 might arise by alternative splicing and that this splicing are regulated in a time-dependent or a cell type- dependent fashion. Neuropilin-2 is expressed by specific classes of developing neurons. To determine whether neuropilin-2, like neuropilin, is a candidate for a receptor involved in axonal growth or guidance, we examined by in situ hybridization whether neuropilin-2 mRNA is expressed by embyronic neurons during the period of axonal extension. Given the large number of isoforms of neuropilin-2 that appear to exist, we decided in this first survey to use a probe corresponding to sequences that extend from domain b2 through the cytoplasmic domain of neuropilin-2(a0) (see Experimental Procedures). Most of this probe corresponds to sequences that are shared between all isoforms. Spinal cord. We first examined the pattern of expression of neuropilin-2 in the region of the developing mouse spinal cord during the period of initial extension of axons of motor and sensory neurons (from E9.5), at the level of the forelimbs. This pattern was highly dynamic. Neuropilin-2 mRNA was detected in the ventral spinal cord of E9.5 embryos, including the region of developing motorneurons. Expression was also strong in the floor plate and in tissue adjacent to the neural tube, including the somites and prospective dorsal root ganglia (DRGs) but not the notochord. Between E10.5 and E13.5 we compared the expression of neuropilin-2 to that of neuropilin- 1, which has already been described (Kawakami et al., 1996). By E10.5, the level of neuropilin- expression had increased in the spinal cord. The whole ventral half of the spinal cord including the floor plate was heavily labeled, but expression was also strong in cells localized in the lateral margin of the dorsal aspect of the spinal cord, which may include commissural neuron cell bodies. Neuropilin-1 expression was also detected in the ventral spinal cord but only in motorneurons, and was very weak or absent from the floor and roof plates. Neuropilin-2 and neuropilin-1 mRNAs were also coexpressed in prospective DRGS, although neuropilin-2 expression was in addition high in non-neural tissues surrounding the spinal cord. A similar pattern of neuropilin-2 expression was observed at El 1.5. At E13.5, neuropilin-2 expression had decreased and was now restricted to the ventral portion of the spinal cord. Both neuropilins were still expressed in motorneurons, but neuropilin-2-expressing cells were found througout in the entire ventral spinal cord whereas the expression pattern of neuropilin- 1 was more restricted. In addition, neuropilin-1 was now strongly expressed in the dorsal spinal cord and in the DRGs, whereas neuropilin-2 expression in the DRGs was very weak, and only just above background level. Weak expression of neuropilin- 1 was also detected in the floor plate at this stage, but contrary to neuropilin-2, it was absent form the roof plate. Expression of neuropilin-2 at El 5.5 was unchanged in the spinal cord, though no expression was detectable in DRGs at this stage. Sympathetic ganglia. As early as El 1.5, neuropilin-2 was detected in the ganglia of the sympathetic chain. This expression was more intense by E13.5, and had slightly decreased by E15.5). At this stage neuropilin-2 mRNA could also be detected in neurons of the superior cervical ganglion. Expression was also observed in the region of the enteric nervous system. Olfactory system. High level neuropilin-2 expression was detected in all components of the olfactory system. Intense staining was observed at E13.5 and E15.5 in the vomeronasal organ, as well as in the accessory olfactory bulb, its target territory in the forebrain. Neuropilin-1 is not expressed in the accessory olfactory system (Kawakami et al., 1996). By E15.5, the olfactory epithelium strongly expressed neuropilin-2, but this expression was not homogenous, being higher rostrally. A high level of neuropilin-2 mRNA was observed in the anterior olfactory nucleus and in the telencephalic regions interconnected to the olfactory bulb, such as the amygdala, the piriform cortex and the entorhinal cortex. Neocortex. Neuropilin-2 expression in the cortex was first detected around E13.5, and was restricted to the intermediate zone of the ventral and lateral regions of the cortex. The mesenchymal cells covering the cortex also showed high level expression of neuropilin-2. By E15.5 the staining was still confined to the intermediate zone, and was stronger in its lower portion. At birth, neuropilin-2 expression was no longer detected in the cortex, with the exception of the cingulate cortex. Hippocampal formation. The pattern of expression of neuropilin-2 was particularly interesting in the components of the hippocampal formation. Neuropilin-2 could be detected as early as E13.5 in the hippocampus, and by E15.5 expression was evident in both the dentate gyrus and in cells of CA3 and CA1 fields. The hybridization signal was uninterrupted and formed a continuum with neuropilin-2 expressing cells in the intermediate zone of the neocortex. By PO, expression of neuropilin-2 was still very high in granule cells of the dentate gyrus, the hilus, and in the pyramidal cell layer, intermediate zone, and in the interneurons of the CA3-CA1 fields. Expression was also observed in the subiculum but not the presubiculum or the parasubiculum. At this stage, neuropilin-2 expression was also very intense in most of the brain regions that project to the hippocampus. The neurons of the entorhinal cortex which project massively through the so-called perforant pathway to the dentate gyrus, the hippocampus and the subiculum, expressed neuropilin-2. Cells in the septal region (medial septum, diagonal band of Broca), another major source of afferent fibers to the hippocampal formation, also strongly expressed neuropilin-2 at El 5.5 and at birth. Visual system. At El 1.5, neuropilin-2 was very highly expressed in the mesenchyme surrounding the eye-cup and the optic nerve, but was absent from the retina. At E15.5, low expression of neuropilin-2 mRNA was detected in the ganglion cell layer, and diffuse expression was observed in the superior colliculus, one of the targets of retinal axons. By PO, neuropilin-2 was very highly expressed in the most superficial layers of the superior colliculus, and at a lower level in the other layers. Expression stopped abruptly at the boundary between superior and inferior colliculus. Expression was not observed in the lateral geniculate nucleus of the thalamus at birth. Thalamus. Neuropilin-2 was also expressed at birth in several thalamic nuclei such as the medial habenula. Cerebellum. Neuropilin-2 expression was detected as early as El 3.5 in the cerebellar primordium, and increased in level by E15.5. At PO, neuropilin-2 was expressed in subsets of deep nuclei neurons as well as in stripes of Purkinje cells. Neuropilin- 1, in contrast, is not expressed in the cerebellum (Kawakami et al., 1996). Hindbrain nuclei. Neuropilin-2 was detected at El 5.5 and at birth (PO), in several branchiomotor nuclei, such as the trigeminal, facial and hypoglossal motor nuclei, but not in the dorsal motor nucleus of the vagus. We have not determined when expression in these nuclei starts. Lower levels of expression were observed in the regions of the inferior olive and vestibular nuclei. Expression was not detected in the pons, a region known to express neuropilin- 1 at high level (Kawakami et al., 1996). Expression of neuropilin-2 in non-neural tissues. In addition to its expression in the CNS, neuropilin-2 was also detected in many non-neural tissues. At El 0.5 it was expressed in the limb bud in restricted areas in the regions of the dorsal and ventral muscle masses. Later on, expression was also observed in the developing bones, in particular in the vertebrae, ribs and digits. Expression of neuropilin-2 was also observed in several muscles such as the back muscles and the tongue, and the strongest expression was observed in the region of the smooth muscles of the gut. Expression was also observed in the intestinal epithelium, as well as in cells in the kidney, the submandibular gland, the lung, the whisker follicles of the snout, and in the inner ear In contrast to neuropilin-1 (Kawakami et al., 1996), neuropilin-2 expression was not detected in the heart or in capillaries, but was found in the dorsal aorta. Different binding patterns of neuropilin- 1 and neuropilin-2 to different semaphorin family members. To test whether neuropilin-2, like neuropilin- 1, is also a receptor for Sema III, we transiently expressed neuropilin- 1, neuropilin-2(a0), -2(a5), - 2(a22) and -2(b5) in COS-7 cells, for use in binding experiments. We were able to detect expression of neuropilin- 1 and the different isoforms of neuropilin-2 in COS cells by immunostaining using either a polyclonal antibody against neuropilin- 1 (He and Tessier- Lavigne, 1997) or monoclonal antibody 9E10 against the myc-tag at the carboxy terminus of all the neuropilin-2 isoforms. Western blot analysis showed that neuropilin-2 isoforms expressed in COS cells had the expected size of ~120kDa. To test for interactions with Sema III, we used a chimeric molecule in which Sema III was fused at its carboxy terminus to the histochemical reporter alkaline phosphatase (Sema III-AP: He and Tessier-Lavigne, 1997). Partially purified conditioned medium containing Sema III-AP was incubated with COS cells expressing neuropilins, and bound protein was detected by alkaline phosphatase histochemistry. As expected, Sema III-AP bound cells expressing neuropilin- 1 (He and Tessier-Lavigne, 1997), and the alkaline phosphatase protein (AP) itself did not bind mock-transfected cells, cells expressing neuropilin- 1, or any of the neuropilin-2 isoforms. Surprisingly, none of the isoforms of neuropilin-2 tested showed any detectable binding of Sema III-AP. We considered the possibility that neuropilin-2 binds the C terminal domain of Sema III and that the absence of binding was an artifact resulting from fusion of AP to the carboxy terminal portion of Sema III, masking the binding site. To address this possibility, we made use of a chimeric molecule in which AP is fused to the amino terminus of C domain of Sema III (AP-C: He and Tessier- Lavigne, 1997). The AP-C protein bound cells expressing neuropilin- 1 but not cells expressing any of the neuropilin-2 isoforms. Thus, the absence of binding of full length Sema III-AP to cells expressing the different neuropilin-2 isoforms reflects a bona fide absence of binding of Sema III to neuropilin-2. Since Sema III itself does not appear to bind neuropilin-2, we wondered whether neuropilin-2 might be a receptor for other members of the semaphorin family. Sema III is a member of a subfamily of structurally-related molecules within the semaphorin family that includes the members Sema E/Collapsin-3 (Luo et al., 1995; Puschel et al., 1995), Sema IV/Sema 3F (Sekido et al., 1996; Roche et al., 1996; Xiang et al., 1996), Sema A Sema V (Sekido et al., 1996), and Sema H. Like Sema III, all of these proteins are secreted proteins possessing a semaphorin domain, an immunoglubulin domain and a basic carboxy terminal domain (Piishel et al., 1995; Luo et al., 1995). We therefore examined whether two of these molecules, Sema E and Sema IV, are ligands for neuropilin- 1 and/or neuropilin-2. In addition, we tested another secreted semaphorin, Drosophila Sema II (Kolodkin et al., 1993), which is more distantly related in sequence, as well as a more divergent semaphorin, the transmembrane Sema Via (Zhou, et al 1997). As for Sema III, we tested the ability of COS cells expressing neuropilin- 1 or neuropilin- 2 to bind chimeric molecules in which alkaline phosphatase was fused to Sema E, Sema IV, Drosophila D-Sema II or the ectodomain of Sema Via (see Experimental Procedures). These AP fusion proteins were presented to the cells in the form of partially purified conditioned media from cells expressing each of the proteins; media were matched for AP activity. We found that both neuropilin and different isoforms of neuropilin-2 expressing cells bound Sema E-AP and Sema IV- AP. In contrast, neither neuropilin- 1 nor any of the neuropilin-2 isoforms expressed in COS cells showed detectable binding to the AP fusions with D-Sema II or the Sema Via ectodomain. In control experiments, we found that Sema E-AP and Sema IV-AP did not bind mock-transfected COS cells or COS cells expressing the netrin- 1 receptor DCC. We estimated the binding affinity of the .AP fusions of Sema III, Sema E and Sema IV to cells expressing neuropilin- 1 or neuropilin-2 in equilibrium binding experiments. For these experiments, we used the a5 isoform of neuropilin-2. Specific binding curves of these molecules showed saturation and could be fitted with the Hill equation (Fig. 5A-5C). The estimated dissociation constants (Kd) for Sema E binding to neuropilin- 1 and neuropilin-2 were 5 nM and 18 nM, respectively. Those for Sema IV binding to neuropilin- 1 and neuropilin-2 were 30 nM and 5 nM, respectively. No detectable binding of Sema III to neuropilin-2 expressing cells was detected, while the estimated Kd for Sema III binding to neuropilin- 1 was 0.325 nM (see also He and Tessier-Lavigne, 1997). Similar Kd values were obtained using the b5 isoform of neuropilin-2 and the degree of binding of different semaphorins to cells all isoforms tested appeared similar. Dynamic expression of neuropilin- 2 complementary to that of neuropilin- 1. The specific pattern of expression of neuropilin-2 indicates the involvement of members of the Sema III subfamily other than Sema III itself in the guidance of a variety of different axonal classes, in particular in the spinal cord, olfactory system, and hippocampus. In the spinal cord, commissural axons are guided along a dorso-ventral trajectory at least partly in response to the diffusible chemoattractant netrin- 1 (Serafini et al., 1996). Neuropilin-2 transcripts are detected in the region of commissural neuron cell bodies, indicating that commissural neurons express neuropilin-2. Since Sema E is expressed in the ventral spinal cord (Puschel et al., 1995), this semaphorin might contribute to the guidance of commissural axons. Our in situ hybridization studies also indicate that different motorneuron populations express different complements of neuropilins, and therefore might respond differentially to different secreted semaphorins expressed in the periphery (Puschel et al., 1995; Wright et al., 1995; Giger et al., 1996). Thus, different semaphorins can contribute to patterning the projections of motor axons to distinct peripheral targets (Tsushida et al., 1994). The olfactory system is another site of significant neuropilin-2 expression, suggesting a role for secreted semaphorins distinct from Sema III in guidance in this system. Axons from the olfactory bulb are known to be repelled by an unidentified septum-derived chemorepellent (Pini, 1993). Neuropilin-2 transcripts are expressed in the region of the cell bodies of origin of these axons in the bulb, indicating that a secreted semaphorin can function as a septal-derived chemorepellent. Another interesting finding is that neuropilin-2 expression in the olfactory epithelium (presumably by primary olfactory neurons) is not uniform, indicating that secreted semaphorins can play a role in differential guidance of different complements of primary olfactory axons, contributing to the creation of an olfactory map. Neuropilins are also expressed in the sites of origin of afferent projections to the hippocampus. Afferents to the hippocampus are known to be topographically organized, with septal, hippocampal, and entorhinal axons projecting to distinct dendritic locations on granule and pyramidal neurons (Paxinos 1995). Neuropilin- 1 and-2 are expressed by the septal and hippocampal neurons, whereas only neuropilin-2 is expressed by entorhinal neurons. Sema E and Sema IV are highly expressed in the hippocampus (Puschel et al., 1995; Sekido et al., 1996), and these semaphorins can therefore contribute to the patterning of hippocampal afferent projections as well. Finally, the observation that neuropilin-2 is expressed in many non-neuronal tissues also indicates the involvement of semaphorins other than Sema III in organogenesis outside the nervous system. A role for secreted semaphorins in tumor suppression is indicated by the fact that neuropilin-2 is expressed in the lung, since Sema IV and Sema A/V map to a region of chromosome 3p that is frequently deleted in small cell lung cancer, and which is thought to contain a tumor suppressor gene for lung cancer (Roche et al., 1996; Sekido et al, 1996; Xiang et al., 1996). Experimental Procedures: Isolation of neuropilin-2 and its splice variants Six sets of fully degenerate oligonucleotides were used to perform RT-PCR using pfu polymerase (Stratagene) on mRNA isolated from El 1 whole mouse embryo and adult mouse brain. Primers were designed to conserved amino acid sequences in the a2 domain of neuropilin, the bl domain, the b2 domain , the MAM domain and the cytoplasmic domain. For each of the reactions, DNA bands of the size expected for neuropilin- 1 were excised, and the gel purified DNA was subjected to secondary PCR amplification using the same primers but with an EcoR I site at the 5' terminus of forward primers and an Xba I site in the reverse primers. The PCR products were cloned into pBluescript KS(-) and sequenced. From one of these reactions, a novel sequence corresponding to neuropilin-2 was isolated (see Results). A 1.2kb fragment of neuropilin-2 was used as a probe to screen an adult mouse brain gtl 1 lambda phage library (Clontech). Partial cDNA fragments isolated in this way corresponded to two presumptive differential splicing isoforms, the a and b forms, with or without the 5, 17 and 22 amino acid insertions (Figure 4). In order to obtain a full length cDNA, 5' RACE was performed on cDNA isolated from El l mouse whole embryo and adult mouse brain. The 5'-RACE products were cloned into pBluescript KS(-) with 5' Not I and 3' Xho I sites, and sequenced. cDNAs containing the entire coding regions of the a and b isoforms of neuropilin-2 were assembled, with and without various combinations of the 5, 17 and 22 amino acid insertions (see Results). In situ hybridization. A 1200 nucleotide fragment of neuropilin-2 was used to 35 generate digoxygenin (DIG)-labeled and S-labeled antisense and sense RNA probes. In situ hybridization was performed on vibratome sections of PO mouse brain with the DIG- labeled probe, and using the radioactive probe on cryosections taken at various stages between E9.5 and PO. The in situ hybridization procedures using digoxygenin-labeled probes were as described previously (Chedotal et al., 1996), and procedure using radioactive probes was as described by Messersmith et al. (1995). Plasmid construction. The coding regions of neuropilin-2 of alternative splicing forms, deleted of their signal sequences, were subcloned into the expression vector pSecTag-A (Invitrogen) in the Hind III (5'-end) and Xba I (3'-end) sites and transiently transfected into COS 7 cells using Lipofectamine (GIBCO BRL). Expression of neuropilin-2 isoforms was detected by immunocytochemistry and Western analysis using monoclonal antibody 9E10 (to the myc tag at the C terminus of the neuropilin-2 isoforms). The semaphorin III-AP fusion protein was described previously (He and Tessier- Lavigne, 1997). The mouse Sema E clone was obtained by PCR from PO mouse brain cDNAs, using the PCR primers. The amplified band was subcloned into the expression vector, APtag-4 vector which a sequence coding for secreted alkaline phosphatase. The human Sema IV clone was subcloned in pSecTag-A (Invitrogen), which also contains the secreted alkaline phosphatase. Semaphorin- AP fusion protein binding assay. The semaphorin-AP fusion protein binding experiments was as described by Cheng and Flanagan (1994), with the exception that in order to reduce background binding, 2 μg/ml of heparin was included in the binding mixture. Briefly, neuropilin- 1 and neuropilin-2 expression constructs were transiently expressed in COS 7 cells as described above. After 48 hours of transfection, expressing cells were rinsed with HBHA buffer (Hank's balanced salt solution with 20 mM HEPES pH 7.0, 0.05% sodium azide) (Cheng and Flanagan, 1994). Concentrated supernatant containing semaphorin-AP fusion proteins in the presence of 20 mM HEPES and 0.05 % of sodium azide was incubated with expressing COS cells at room temperature for 75 minutes, followed by heat inactivation of endogenous alkaline phosphatase, washing, and color development as described by Cheng and Flanagan (1994). Protocol for high throughput SR-Semalll binding assay. A. Reagents: - Neutralite Avidin: 20 μg/ml in PBS. - Blocking buffer: 5% BSA, 0.5% Tween 20 in PBS; 1 hour at room temperature. - Assay Buffer: 100 mM KC1, 20 mM HEPES pH 7.6, 1 mM MgCl 2 , 1 % glycerol, 0.5%) NP-40, 50 mM β-mercaptoethanol, 1 mg/ml BSA, cocktail of protease inhibitors. - ^P SR polypeptide lOx stock: 10 "8 - 10- 6 M "cold" SR polypeptide specific SR domain supplemented with 200,000-250,000 cpm of labeled SR (Beckman counter). Place in the 4°C microfridge during screening. - Protease inhibitor cocktail (1000X1: 10 mg Trypsin Inhibitor (BMB # 109894), 10 mg Aprotinin (BMB # 236624), 25 mg Benzamidine (Sigma # B-6506), 25 mg Leupeptin (BMB # 1017128), 10 mg APMSF (BMB # 917575), and 2mM NaVO 3 (Sigma # S-6508) in l0 ml ofPBS. -Semalll: 10 "7 - 10 "5 M biotinylated Semalll in PBS. B . 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All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Tessier-Lavigne, Marc He , Zhigang Chen , Hang (ii) TITLE OF INVENTION: Semaphorin Receptors (iii) NUMBER OF SEQUENCES: 26 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: SCIENCE & TECHNOLOGY LAW GROUP (B) STREET: 75 DENISE DRIVE (C) CITY: HILLSBOROUGH (D) STATE: CALIFORNIA (E) COUNTRY: USA (F) ZIP: 94010 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentln Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: OSMAN, RICHARD A (B) REGISTRATION NUMBER: 36,627 (C) REFERENCE/DOCKET NUMBER: UC97-288-2 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (650) 343-4341 (B) TELEFAX: (650) 343-4342 (2) INFORMATION FOR SEQ ID Nθ:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2772 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:l: ATGGAGAGGG GGCTGCCGCT CCTCTGCGCC GTGCTCGCCC TCGTCCTCGC CCCGGCCGGC 60 GCTTTTCGCA ACGATGAATG TGGCGATACT ATAAAAATTG AAAGCCCCGG GTACCTTACA 120 TCTCCTGGTT ATCCTCATTC TTATCACCCA AGTGAAAAAT GCGAATGGCT GATTCAGGCT 180 CCGGACCCAT ACCAGAGAAT TATGATCAAC TTCAACCCTC ACTTCGATTT GGAGGACAGA 240 GACTGCAAGT ATGACTACGT GGAAGTCTTC GATGGAGAAA ATGAAAATGG ACATTTTAGG 300 GGAAAGTTCT GTGGAAAGAT AGCCCCTCCT CCTGTTGTGT CTTCAGGGCC ATTTCTTTTT 360 ATCAAATTTG TCTCTGACTA CG.AAACACAT GGTGCAGGAT TTTCCATACG TTATGAAATT 420 TTCAAGAGAG GTCCTGAATG TTCCCAGAAC TACACAACAC CTAGTGGAGT GATAAAGTCC 480 CCCGGATTCC CTGAAAAATA TCCCAACAGC CTTGAATGCA CTTATATTGT CTTTGCGCCA 540 AAGATGTCAG AGATTATCCT GGAATTTGAA AGCTTTGACC TGGAGCCTGA CTCAAATCCT 600 CCAGGGGGGA TGTTCTGTCG CTACGACCGG CTAGAAATCT GGGATGGATT CCCTGATGTT 660 GGCCCTCACA TTGGGCGTTA CTGTGGACAG AAAACACCAG GTCGAATCCG ATCCTCATCG 720 GGCATTCTCT CCATGGTTTT TTACACCGAC AGCGCGATAG CAAAAGAAGG TTTCTCAGCA 780 AACTACAGTG TCTTGCAGAG CAGTGTCTCA GAAGATTTCA AATGTATGGA AGCTCTGGGC 840 ATGGAATCAG GAGAAATTCA TTCTGACCAG ATCACAGCTT CTTCCCAGTA TAGCACCAAC 900 TGGTCTGCAG AGCGCTCCCG CCTGAACTAC CCTGAGAATG GGTGGACTCC CGGAGAGGAT 960 TCCTACCGAG AGTGGATACA GGTAGACTTG GGCCTTCTGC GCTTTGTCAC GGCTGTCGGG 1020 ACACAGGGCG CCATTTCAAA AGAAACCAAG AAGAAATATT ATGTCAAGAC TTACAAGATC 1080 GACGTTAGCT CCAACGGGGA AGACTGGATC ACCATAAAAG AAGGAAACAA ACCTGTTCTC 1140 TTTCAGGGAA ACACCAACCC CACAGATGTT GTGGTTGCAG TATTCCCCAA ACCACTGATA 1200 ACTCGATTTG TCCGAATCAA GCCTGCAACT TGGGAAACTG GCATATCTAT GAGATTTGAA 1260 GTATACGGTT GCAAGATAAC AGATTATCCT TGCTCTGGAA TGTTGGGTAT GGTGTCTGGA 1320 CTTATTTCTG ACTCCCAGAT CACATCATCC AACCAAGGAG ACAGJAAACTG GATGCCTGAA 1380 AACATCCGCC TGGTAACCAG TCGCTCTGGC TGGGCACTTC CACCCGCACC TCATTCCTAC 1440 ATCAATGAGT GGCTCCAAAT AGACCTGGGG GAGGAGAAGA TCGTGAGGGG CATCATCATT 1500 CAGGGTGGGA AGCACCGAGA GAACAAGGTG TTCATGAGGA AGTTCAAGAT CGGGTACAGC 1560 AACAACGGCT CGGACTGGAA GATGATCATG GATGACAGCA AACGCAAGGC GAAGTCTTTT 1620 GAGGGCAACA ACAACTATGA TACACCTGAG CTGCGGACTT TTCCAGCTCT CTCCACGCGA 1680 TTCATCAGGA TCTACCCCGA GAGAGCCACT CATGGCGGAC TGGGGCTCAG AATGGAGCTG 1740 CTGGGCTGTG AAGTGG.AAGC CCCTACAGCT GGACCGACCA CTCCCAACGG GAACTTGGTG 1800 GATGAATGTG ATGACGACCA GGCCAACTGC CACAGTGGAA CAGGTGATGA CTTCCAGCTC 1860 ACAGGTGGCA CCACTGTGCT GGCCACAGAA AAGCCCACGG TCATAGACAG CACCATACAA 1920 TCAGAGTTTC CAACATATGG TTTTAACTGT GAATTTGGCT GGGGCTCTCA CAAGACCTTC 1980 TGCCACTGGG AACATGACAA TCACGTGCAG CTCAAGTGGA GTGTGTTGAC CAGCAAGACG 2040 GGACCCATTC AGGATCACAC AGGAGATGGC AACTTCATCT ATTCCCAAGC TGACGAAAAT 2100 CAGAAGGGCA AAGTGGCTCG CCTGGTGAGC CCTGTGGTTT ATTCCCAGAA CTCTGCCCAC 2160 TGCATGACCT TCTGGTATCA CATGTCTGGG TCCCACGTCG GCACACTCAG GGTCAAACTG 2220 CGCTACCAGA AGCCAGAGGA GTACGATCAG CTGGTCTGGA TGGCCATTGG ACACCAAGGT 2280 GACCACTGGA AGGAAGGGCG TGTCTTGCTC CACAAGTCTC TGAAACTTTA TCAGGTGATT 2340 TTCGAGGGCG AAATCGGAAA AGGAAACCTT GGTGGGATTG CTGTGGATGA CATTAGTATT 2400 AATAACCACA TTTCACAAGA AGATTGTGCA AAACCAGCAG ACCTGGATAA AAAGAACCCA 2460 GAAATTAAAA TTGATGAAAC AGGGAGCACG CCAGGATACG AAGGTGAAGG AGAAGGTGAC 2520 AAGAACATCT CCAGGAAGCC AGGCAATGTG TTGAAGACCT TAGAACCCAT CCTCATCACC 2580 ATCATAGCCA TGAGCGCCCT GGGGGTCCTC CTGGGGGCTG TCTGTGGGGT CGTGCTGTAC 2640 TGTGCCTGTT GGCATAATGG GATGTCAGAA AGAAACTTGT CTGCCCTGGA GAACTATAAC 2700 TTTGAACTTG TGGATGGTGT GAAGTTGAAA AAAGACAAAC TGAATACACA GAGTACTTAT 2760 TCGGAGGCAT GA 2772 (2) INFORMATION FOR SEQ ID NO : 2 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2588 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:2: Met Glu Thr Gly Leu Ala Arg Gly Gly Leu Tyr Leu Glu Pro Arg Leu 1 5 10 15 Glu Leu Glu Cys Tyr Ser Ala Leu Ala Val Ala Leu Leu Glu Ala Leu 20 25 30 Ala Leu Glu Val Ala Leu Leu Glu Ala Leu Ala Pro Arg Ala Leu Ala 35 40 45 Gly Leu Tyr Ala Leu Ala Pro His Glu Ala Arg Gly Ala Ser Asn Ala 50 55 60 Ser Pro Gly Leu Cys Tyr Ser Gly Leu Tyr Ala Ser Pro Thr His Arg 65 70 75 80 lie Leu Glu Leu Tyr Ser lie Leu Glu Gly Leu Ser Glu Arg Pro Arg 85 90 95 Gly Leu Tyr Thr Tyr Arg Leu Glu Thr His Arg Ser Glu Arg Pro Arg 100 105 110 Gly Leu Tyr Thr Tyr Arg Pro Arg His lie Ser Ser Glu Arg Thr Tyr 115 120 125 Arg His lie Ser Pro Arg Ser Glu Arg Gly Leu Leu Tyr Ser Cys Tyr 130 135 140 Ser Gly Leu Thr Arg Pro Leu Glu lie Leu Glu Gly Leu Asn Ala Leu 145 150 155 160 Ala Pro Arg Ala Ser Pro Pro Arg Thr Tyr Arg Gly Leu Asn Ala Arg 165 170 175 Gly lie Leu Glu Met Glu Thr lie Leu Glu Ala Ser Asn Pro His Glu 180 185 190 Ala Ser Asn Pro Arg His He Ser Pro His Glu Ala Ser Pro Leu Glu 195 200 205 Gly Leu Ala Ser Pro Ala Arg Gly Ala Ser Pro Cys Tyr Ser Leu Tyr 210 215 220 Ser Thr Tyr Arg Ala Ser Pro Thr Tyr Arg Val Ala Leu Gly Leu Val 225 230 235 240 Ala Leu Pro His Glu Ala Ser Pro Gly Leu Tyr Gly Leu Ala Ser Asn 245 250 255 Gly Leu Ala Ser Asn Gly Leu Tyr His He Ser Pro His Glu Ala Arg 260 265 270 Gly Gly Leu Tyr Leu Tyr Ser Pro His Glu Cys Tyr Ser Gly Leu Tyr 275 280 285 Leu Tyr Ser He Leu Glu Ala Leu Ala Pro Arg Pro Arg Pro Arg Val 290 295 300 Ala Leu Val Ala Leu Ser Glu Arg Ser Glu Arg Gly Leu Tyr Pro Arg 305 310 315 320 Pro His Glu Leu Glu Pro His Glu He Leu Glu Leu Tyr Ser Pro His 325 330 335 Glu Val Ala Leu Ser Glu Arg Ala Ser Pro Thr Tyr Arg Gly Leu Thr 340 345 350 His Arg His He Ser Gly Leu Tyr Ala Leu Ala Gly Leu Tyr Pro His 355 360 365 Glu Ser Glu Arg He Leu Glu Ala Arg Gly Thr Tyr Arg Gly Leu He 370 375 380 Leu Glu Pro His Glu Leu Tyr Ser Ala Arg Gly Gly Leu Tyr Pro Arg 385 390 395 400 Gly Leu Cys Tyr Ser Ser Glu Arg Gly Leu Asn Ala Ser Asn Thr Tyr 405 410 415 Arg Thr His Arg Thr His Arg Pro Arg Ser Glu Arg Gly Leu Tyr Val 420 425 430 Ala Leu He Leu Glu Leu Tyr Ser Ser Glu Arg Pro Arg Gly Leu Tyr 435 440 445 Pro His Glu Pro Arg Gly Leu Leu Tyr Ser Thr Tyr Arg Pro Arg Ala 450 455 460 Ser Asn Ser Glu Arg Leu Glu Gly Leu Cys Tyr Ser Thr His Arg Thr 465 470 475 480 Tyr Arg He Leu Glu Val Ala Leu Pro His Glu Ala Leu Ala Pro Arg 485 490 495 Leu Tyr Ser Met Glu Thr Ser Glu Arg Gly Leu He Leu Glu He Leu 500 505 510 Glu Leu Glu Gly Leu Pro His Glu Gly Leu Ser Glu Arg Pro His Glu 515 520 525 Ala Ser Pro Leu Glu Gly Leu Pro Arg Ala Ser Pro Ser Glu Arg Ala 530 535 540 Ser Asn Pro Arg Pro Arg Gly Leu Tyr Gly Leu Tyr Met Glu Thr Pro 545 550 555 560 His Glu Cys Tyr Ser Ala Arg Gly Thr Tyr Arg Ala Ser Pro Ala Arg 565 570 575 Gly Leu Glu Gly Leu He Leu Glu Thr Arg Pro Ala Ser Pro Gly Leu 580 585 590 Tyr Pro His Glu Pro Arg Ala Ser Pro Val Ala Leu Gly Leu Tyr Pro 595 600 605 Arg His He Ser He Leu Glu Gly Leu Tyr Ala Arg Gly Thr Tyr Arg 610 615 620 Cys Tyr Ser Gly Leu Tyr Gly Leu Asn Leu Tyr Ser Thr His Arg Pro 625 630 635 640 Arg Gly Leu Tyr Ala Arg Gly He Leu Glu Ala Arg Gly Ser Glu Arg 645 650 655 Ser Glu Arg Ser Glu Arg Gly Leu Tyr He Leu Glu Leu Glu Ser Glu 660 665 670 Arg Met Glu Thr Val Ala Leu Pro His Glu Thr Tyr Arg Thr His Arg 675 680 685 Ala Ser Pro Ser Glu Arg Ala Leu Ala He Leu Glu Ala Leu Ala Leu 690 695 700 Tyr Ser Gly Leu Gly Leu Tyr Pro His Glu Ser Glu Arg Ala Leu Ala 705 710 715 720 Ala Ser Asn Thr Tyr Arg Ser Glu Arg Val Ala Leu Leu Glu Gly Leu 725 730 735 Asn Ser Glu Arg Ser Glu Arg Val Ala Leu Ser Glu Arg Gly Leu Ala 740 745 750 Ser Pro Pro His Glu Leu Tyr Ser Cys Tyr Ser Met Glu Thr Gly Leu 755 760 765 Ala Leu Ala Leu Glu Gly Leu Tyr Met Glu Thr Gly Leu Ser Glu Arg 770 775 780 Gly Leu Tyr Gly Leu He Leu Glu His He Ser Ser Glu Arg Ala Ser 785 790 795 800 Pro Gly Leu Asn He Leu Glu Thr His Arg Ala Leu Ala Ser Glu Arg 805 810 815 Ser Glu Arg Gly Leu Asn Thr Tyr Arg Ser Glu Arg Thr His Arg Ala 820 825 830 Ser Asn Thr Arg Pro Ser Glu Arg Ala Leu Ala Gly Leu Ala Arg Gly 835 840 845 Ser Glu Arg Ala Arg Gly Leu Glu Ala Ser Asn Thr Tyr Arg Pro Arg 850 855 860 Gly Leu Ala Ser Asn Gly Leu Tyr Thr Arg Pro Thr His Arg Pro Arg 865 870 875 880 Gly Leu Tyr Gly Leu Ala Ser Pro Ser Glu Arg Thr Tyr Arg Ala Arg 885 890 895 Gly Gly Leu Thr Arg Pro He Leu Glu Gly Leu Asn Val Ala Leu Ala 900 905 910 Ser Pro Leu Glu Gly Leu Tyr Leu Glu Leu Glu Ala Arg Gly Pro His 915 920 925 Glu Val Ala Leu Thr His Arg Ala Leu Ala Val Ala Leu Gly Leu Tyr 930 935 940 Thr His Arg Gly Leu Asn Gly Leu Tyr Ala Leu Ala He Leu Glu Ser 945 950 955 960 Glu Arg Leu Tyr Ser Gly Leu Thr His Arg Leu Tyr Ser Leu Tyr Ser 965 970 975 Leu Tyr Ser Thr Tyr Arg Thr Tyr Arg Val Ala Leu Leu Tyr Ser Thr 980 985 990 His Arg Thr Tyr Arg Leu Tyr Ser He Leu Glu Ala Ser Pro Val Ala 995 1000 1005 Leu Ser Glu Arg Ser Glu Arg Ala Ser Asn Gly Leu Tyr Gly Leu Ala 1010 1015 1020 Ser Pro Thr Arg Pro He Leu Glu Thr His Arg He Leu Glu Leu Tyr 1025 1030 1035 1040 Ser Gly Leu Gly Leu Tyr Ala Ser Asn Leu Tyr Ser Pro Arg Val Ala 1045 1050 1055 Leu Leu Glu Pro His Glu Gly Leu Asn Gly Leu Tyr Ala Ser Asn Thr 1060 1065 1070 His Arg Ala Ser Asn Pro Arg Thr His Arg Ala Ser Pro Val Ala Leu 1075 1080 1085 Val Ala Leu Val Ala Leu Ala Leu Ala Val Ala Leu Pro His Glu Pro 1090 1095 1100 Arg Leu Tyr Ser Pro Arg Leu Glu He Leu Glu Thr His Arg Ala Arg 1105 1110 1115 1120 Gly Pro His Glu Val Ala Leu Ala Arg Gly He Leu Glu Leu Tyr Ser 1125 1130 1135 Pro Arg Ala Leu Ala Thr His Arg Thr Arg Pro Gly Leu Thr His Arg 1140 1145 1150 Gly Leu Tyr He Leu Glu Ser Glu Arg Met Glu Thr Ala Arg Gly Pro 1155 1160 1165 His Glu Gly Leu Val Ala Leu Thr Tyr Arg Gly Leu Tyr Cys Tyr Ser 1170 1175 1180 Leu Tyr Ser He Leu Glu Thr His Arg Ala Ser Pro Thr Tyr Arg Pro 1185 1190 1195 1200 Arg Cys Tyr Ser Ser Glu Arg Gly Leu Tyr Met Glu Thr Leu Glu Gly 1205 1210 1215 Leu Tyr Met Glu Thr Val Ala Leu Ser Glu Arg Gly Leu Tyr Leu Glu 1220 1225 1230 He Leu Glu Ser Glu Arg Ala Ser Pro Ser Glu Arg Gly Leu Asn He 1235 1240 1245 Leu Glu Thr His Arg Ser Glu Arg Ser Glu Arg Ala Ser Asn Gly Leu 1250 1255 1260 Asn Gly Leu Tyr Ala Ser Pro Ala Arg Gly Ala Ser Asn Thr Arg Pro 1265 1270 1275 1280 Met Glu Thr Pro Arg Gly Leu Ala Ser Asn He Leu Glu Ala Arg Gly 1285 1290 1295 Leu Glu Val Ala Leu Thr His Arg Ser Glu Arg Ala Arg Gly Ser Glu 1300 1305 1310 Arg Gly Leu Tyr Thr Arg Pro Ala Leu Ala Leu Glu Pro Arg Pro Arg 1315 1320 1325 Ala Leu Ala Pro Arg His He Ser Ser Glu Arg Thr Tyr Arg He Leu 1330 1335 1340 Glu Ala Ser Asn Gly Leu Thr Arg Pro Leu Glu Gly Leu Asn He Leu 1345 1350 1355 1360 Glu Ala Ser Pro Leu Glu Gly Leu Tyr Gly Leu Gly Leu Leu Tyr Ser 1365 1370 1375 He Leu Glu Val Ala Leu Ala Arg Gly Gly Leu Tyr He Leu Glu He 1380 1385 1390 Leu Glu He Leu Glu Gly Leu Asn Gly Leu Tyr Gly Leu Tyr Leu Tyr 1395 1400 1405 Ser His He Ser Ala Arg Gly Gly Leu Ala Ser Asn Leu Tyr Ser Val 1410 1415 1420 Ala Leu Pro His Glu Met Glu Thr Ala Arg Gly Leu Tyr Ser Pro His 1425 1430 1435 1440 Glu Leu Tyr Ser He Leu Glu Gly Leu Tyr Thr Tyr Arg Ser Glu Arg 1445 1450 1455 Ala Ser Asn Ala Ser Asn Gly Leu Tyr Ser Glu Arg Ala Ser Pro Thr 1460 1465 1470 Arg Pro Leu Tyr Ser Met Glu Thr He Leu Glu Met Glu Thr Ala Ser 1475 1480 1485 Pro Ala Ser Pro Ser Glu Arg Leu Tyr Ser Ala Arg Gly Leu Tyr Ser 1490 1495 1500 Ala Leu Ala Leu Tyr Ser Ser Glu Arg Pro His Glu Gly Leu Gly Leu 1505 1510 1515 1520 Tyr Ala Ser Asn Ala Ser Asn Ala Ser Asn Thr Tyr Arg Ala Ser Pro 1525 1530 1535 Thr His Arg Pro Arg Gly Leu Leu Glu Ala Arg Gly Thr His Arg Pro 1540 1545 1550 His Glu Pro Arg Ala Leu Ala Leu Glu Ser Glu Arg Thr His Arg Ala 1555 1560 1565 Arg Gly Pro His Glu He Leu Glu Ala Arg Gly He Leu Glu Thr Tyr 1570 1575 1580 Arg Pro Arg Gly Leu Ala Arg Gly Ala Leu Ala Thr His Arg His He 1585 1590 1595 1600 Ser Gly Leu Tyr Gly Leu Tyr Leu Glu Gly Leu Tyr Leu Glu Ala Arg 1605 1610 1615 Gly Met Glu Thr Gly Leu Leu Glu Leu Glu Gly Leu Tyr Cys Tyr Ser 1620 1625 1630 Gly Leu Val Ala Leu Gly Leu Ala Leu Ala Pro Arg Thr His Arg Ala 1635 1640 1645 Leu Ala Gly Leu Tyr Pro Arg Thr His Arg Thr His Arg Pro Arg Ala 1650 1655 1660 Ser Asn Gly Leu Tyr Ala Ser Asn Leu Glu Val Ala Leu Ala Ser Pro 1665 1670 1675 1680 Gly Leu Cys Tyr Ser Ala Ser Pro Ala Ser Pro Ala Ser Pro Gly Leu 1685 1690 1695 Asn Ala Leu Ala Ala Ser Asn Cys Tyr Ser His He Ser Ser Glu Arg 1700 1705 1710 Gly Leu Tyr Thr His Arg Gly Leu Tyr Ala Ser Pro Ala Ser Pro Pro 1715 1720 1725 His Glu Gly Leu Asn Leu Glu Thr His Arg Gly Leu Tyr Gly Leu Tyr 1730 1735 1740 Thr His Arg Thr His Arg Val Ala Leu Leu Glu Ala Leu Ala Thr His 1745 1750 1755 1760 Arg Gly Leu Leu Tyr Ser Pro Arg Thr His Arg Val Ala Leu He Leu 1765 1770 1775 Glu Ala Ser Pro Ser Glu Arg Thr His Arg He Leu Glu Gly Leu Asn 1780 1785 1790 Ser Glu Arg Gly Leu Pro His Glu Pro Arg Thr His Arg Thr Tyr Arg 1795 1800 1805 Gly Leu Tyr Pro His Glu Ala Ser Asn Cys Tyr Ser Gly Leu Pro His 1810 1815 1820 Glu Gly Leu Tyr Thr Arg Pro Gly Leu Tyr Ser Glu Arg His He Ser 1825 1830 1835 1840 Leu Tyr Ser Thr His Arg Pro His Glu Cys Tyr Ser His He Ser Thr 1845 1850 1855 Arg Pro Gly Leu His He Ser Ala Ser Pro Ala Ser Asn His He Ser 1860 1865 1870 Val Ala Leu Gly Leu Asn Leu Glu Leu Tyr Ser Thr Arg Pro Ser Glu 1875 1880 1885 Arg Val Ala Leu Leu Glu Thr His Arg Ser Glu Arg Leu Tyr Ser Thr 1890 1895 1900 His Arg Gly Leu Tyr Pro Arg He Leu Glu Gly Leu Asn Ala Ser Pro 1905 1910 1915 1920 His He Ser Thr His Arg Gly Leu Tyr Ala Ser Pro Gly Leu Tyr Ala 1925 1930 1935 Ser Asn Pro His Glu He Leu Glu Thr Tyr Arg Ser Glu Arg Gly Leu 1940 1945 1950 Asn Ala Leu Ala Ala Ser Pro Gly Leu Ala Ser Asn Gly Leu Asn Leu 1955 1960 1965 Tyr Ser Gly Leu Tyr Leu Tyr Ser Val Ala Leu Ala Leu Ala Ala Arg 1970 1975 1980 Gly Leu Glu Val Ala Leu Ser Glu Arg Pro Arg Val Ala Leu Val Ala 1985 1990 1995 2000 Leu Thr Tyr Arg Ser Glu Arg Gly Leu Asn Ala Ser Asn Ser Glu Arg 2005 2010 2015 Ala Leu Ala His He Ser Cys Tyr Ser Met Glu Thr Thr His Arg Pro 2020 2025 2030 His Glu Thr Arg Pro Thr Tyr Arg His He Ser Met Glu Thr Ser Glu 2035 2040 2045 Arg Gly Leu Tyr Ser Glu Arg His He Ser Val Ala Leu Gly Leu Tyr 2050 2055 2060 Thr His Arg Leu Glu Ala Arg Gly Val Ala Leu Leu Tyr Ser Leu Glu 2065 2070 2075 2080 Ala Arg Gly Thr Tyr Arg Gly Leu Asn Leu Tyr Ser Pro Arg Gly Leu 2085 2090 2095 Gly Leu Thr Tyr Arg Ala Ser Pro Gly Leu Asn Leu Glu Val Ala Leu 2100 2105 2110 Thr Arg Pro Met Glu Thr Ala Leu Ala He Leu Glu Gly Leu Tyr His 2115 2120 2125 He Ser Gly Leu Asn Gly Leu Tyr Ala Ser Pro His He Ser Thr Arg 2130 2135 2140 Pro Leu Tyr Ser Gly Leu Gly Leu Tyr Ala Arg Gly Val Ala Leu Leu 2145 2150 2155 2160 Glu Leu Glu His He Ser Leu Tyr Ser Ser Glu Arg Leu Glu Leu Tyr 2165 2170 2175 Ser Leu Glu Thr Tyr Arg Gly Leu Asn Val Ala Leu He Leu Glu Pro 2180 2185 2190 His Glu Gly Leu Gly Leu Tyr Gly Leu He Leu Glu Gly Leu Tyr Leu 2195 2200 2205 Tyr Ser Gly Leu Tyr Ala Ser Asn Leu Glu Gly Leu Tyr Gly Leu Tyr 2210 2215 2220 He Leu Glu Ala Leu Ala Val Ala Leu Ala Ser Pro Ala Ser Pro He 2225 2230 2235 2240 Leu Glu Ser Glu Arg He Leu Glu Ala Ser Asn Ala Ser Asn His He 2245 2250 2255 Ser He Leu Glu Ser Glu Arg Gly Leu Asn Gly Leu Ala Ser Pro Cys 2260 2265 2270 Tyr Ser Ala Leu Ala Leu Tyr Ser Pro Arg Ala Leu Ala Ala Ser Pro 2275 2280 2285 Leu Glu Ala Ser Pro Leu Tyr Ser Leu Tyr Ser Ala Ser Asn Pro Arg 2290 2295 2300 Gly Leu He Leu Glu Leu Tyr Ser He Leu Glu Ala Ser Pro Gly Leu 2305 2310 2315 2320 Thr His Arg Gly Leu Tyr Ser Glu Arg Thr His Arg Pro Arg Gly Leu 2325 2330 2335 Tyr Thr Tyr Arg Gly Leu Gly Leu Tyr Gly Leu Gly Leu Tyr Gly Leu 2340 2345 2350 Gly Leu Tyr Ala Ser Pro Leu Tyr Ser Ala Ser Asn He Leu Glu Ser 2355 2360 2365 Glu Arg Ala Arg Gly Leu Tyr Ser Pro Arg Gly Leu Tyr Ala Ser Asn 2370 2375 2380 Val Ala Leu Leu Glu Leu Tyr Ser Thr His Arg Leu Glu Gly Leu Pro 2385 2390 2395 2400 Arg He Leu Glu Leu Glu He Leu Glu Thr His Arg He Leu Glu He 2405 2410 2415 Leu Glu Ala Leu Ala Met Glu Thr Ser Glu Arg Ala Leu Ala Leu Glu 2420 2425 2430 Gly Leu Tyr Val Ala Leu Leu Glu Leu Glu Gly Leu Tyr Ala Leu Ala 2435 2440 2445 Val Ala Leu Cys Tyr Ser Gly Leu Tyr Val Ala Leu Val Ala Leu Leu 2450 2455 2460 Glu Thr Tyr Arg Cys Tyr Ser Ala Leu Ala Cys Tyr Ser Thr Arg Pro 2465 2470 2475 2480 His He Ser Ala Ser Asn Gly Leu Tyr Met Glu Thr Ser Glu Arg Gly 2485 2490 2495 Leu Ala Arg Gly Ala Ser Asn Leu Glu Ser Glu Arg Ala Leu Ala Leu 2500 2505 2510 Glu Gly Leu Ala Ser Asn Thr Tyr Arg Ala Ser Asn Pro His Glu Gly 2515 2520 2525 Leu Leu Glu Val Ala Leu Ala Ser Pro Gly Leu Tyr Val Ala Leu Leu 2530 2535 2540 Tyr Ser Leu Glu Leu Tyr Ser Leu Tyr Ser Ala Ser Pro Leu Tyr Ser 2545 2550 2555 2560 Leu Glu Ala Ser Asn Thr His Arg Gly Leu Asn Ser Glu Arg Thr His 2565 2570 2575 Arg Thr Tyr Arg Ser Glu Arg Gly Leu Ala Leu Ala 2580 2585 (2 ) INFORMATION FOR SEQ ID NO : 3 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2766 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: ATGGAGAGGG GGCTGCCGTT GCTGTGCGCC ACGCTCGCCC TTGCCCTCGC CCTGGGGGCT 60 TTCCGCAGCG ATAAATGTGG CGGGACTATA AAAATTGAAA ACCCGGGGTA CCTTACATCT 120 CCCGGCTACC CTCATTCTTA CCATCCAAGT GAGAAATGTG AATGGCTAAT CCAAGCTCCG 180 GAGCCCTACC AGAGAATCAT GATCAACTTC AACCCACATT TCGATTTGGA GGACAGAGAC 240 TGCAAGTATG ACTATGTGGA AGTGATCGAT GGAGAGAATG AAGGTGGCCG CCTGTGGGGG 300 AAGTTCTGTG GGAAGATCGC ACCTTCACCT GTGGTGTCTT CAGGGCCATT TCTCTTCATC 360 AAATTTGTCT CTGACTATGA GACCCACGGG GCAGGATTTT CCATCCGCTA TGAAATCTTC 420 AAGAGAGGGC CCGAATGTTC TCAGAACTAT ACAGCACCTA CTGGAGTGAT AAAGTCCCCT 480 GGGTTCCCTG AAAAATACCC CAACAGCTTG GAGTGCACCT ACATCATCTT TGCACCAAAG 540 ATGTCTGAGA TAATCCTAGA GTTTGAAAGT TTTGACCTGG AGCAAGACTC AAATCCTCCC 600 GGAGGAATGT TCTGTCGCTA TGACCGGCTG GAGATCTGGG ATGGATTCCC TGAAGTTGGC 660 CCTCACATTG GGCGTTACTG TGGGCAGAAA ACTCCTGGCC GGATCCGCTC CTCTTCAGGC 720 ATTCTATCCA TGGTCTTCTA CACTGACAGC GCAATAGCAA AGGAAGGTTT CTCAGCCAAC 780 TACAGCGTGC XGCAGAGCAG CATCTCTGAA GATTTCAAGT GTATGGAGGC TCTGGGCATG 840 GAATCTGGAG AGATCCATTC TGACCAGATC ACTGCATCTT CCCAGTATGG TACCAACTGG 900 TCTGTTGAGC GCTCCCGCCT GAACTACCCT GAAAACGGGT GGACACCAGG AGAGGACTCC 960 TACAGGGAGT GGATCCAGGT GGACTTGGGC CTCCTGCGAT TCGTTACTGC TGTGGGGACA 1020 CAGGGTGCCA TTTCCAAGGA AACCAAGAAG AAATATTATG TCAAGACTTA CAGAGTAGAC 1080 ATCAGCTCCA ACGGAGAGGA CTGGATCACC CTGAAGGAGG GAAATAAAGC CATTATCTTT 1140 CAGGGAAACA CCAATCCCAC GGATGTTGTC TTTGGAGTTT TCCCCAAACC ACTGATAACT 1200 CGATTTGTCC GAATCAAACC TGCATCCTGG GAAACTGGAA TATCTATGAG ATTTGAAGTT 1260 TATGGCTGCA AGATAACAGA TTACCCTTGC TCTGGAATGT TGGGCATGGT GTCTGGACTT 1320 ATTTCAGACT CCCAGATTAC AGCATCCAAC CAAGGAGACA GGAACTGGAT GCCAGAAAAC 1380 ATCCGCCTGG TGACCAGTCG AACCGGCTGG GCCCTGCCAC CCTCACCCCA CCCATACATC 1440 AATGAATGGC TCCAAGTGGA CCTGGGAGAT GAGAAGATAG TAAGAGGTGT CATCATTCAA 1500 GGTGGGAAGC ACCGAGAAAA CAAAGTGTTC ATGAGGAAGT TCAAGATCGC CTACAGTAAC 1560 AATGGTTCTG ACTGGAAAAT GATCATGGAT GACAGCAAGC GCAAGGCTAA GTCTTTTGAA 1620 GGCAACAACA ACTATGACAC ACCTGAGCTC CGGGCCTTTA CACCTCTCTC CACAAGATTC 1680 ATCAGGATCT ACCCCGAGAG AGCCACACAT AGTGGGCTCG GACTGAGGAT GGAGCTACTG 1740 GGCTGTGAAG TAGAAGTGCC TACAGCTGGA CCCACGACAC CCAATGGGAA CCCCGTGGAC 1800 GAGTGTGACG ATGACCAGGC CAACTGCCAC AGTGGCACAG GTGATGACTT CCAGCTCACA 1860 GGAGGCACCA CTGTCCTGGC CACAGAGAAG CCCACCATTA TAGACAGCAC CATCCAATCA 1920 GAGTTCCCGA CATACGGTTT TAACTGCGAG TTTGGCTGGG GCTCTCACAA GACATTCTGC 1980 CACTGGGAAC ATGACAGCCA CGCGCAGCTC AGGTGGAGGG TGCTGACCAG CAAGACGGGG 2040 CCCATTCAGG ACCACACAGG AGATGGCAAC TTCATCTATT CCCAAGCTGA TGAAAATCAG 2100 AAAGGCAAAG TAGCCCGCCT GGTGAGCCCT GTGGTCTATT CCCAGAGTTC TGCCCACTGC 2160 ATGACCTTCT GGTATCACAT GTCCGGCTCT CATGTGGGTA CACTGAGGGT CAAACTGCAC 2220 TACCAGAAGC CAGAGGAATA TGATCAACTG GTCTGGATGG TGGTCGGGCA CCAAGGAGAC 2280 CACTGGAAGG AAGGGCGTGT CTTGCTGCAC AAATCTCTGA AACTGTATCA GGTTATTTTT 2340 GAAGGTGAAA TCGGAAAAGG AAACCTCGGT GGGATTGCTG TGGATGATAT CAGTATTAAC 2400 AACCACATTC CTCAGGAGGA CTGTGCAAAA CCAACAGACC TAGATAAAAA GAACACAGAA 2460 ATTAAAATAG ATGAAACAGG GAGCACCCCA GGATATGAAG AAGGGAAAGG CGACAAGAAC 2520 ATCTCCAGGA AGCCAGGCAA TGTGCTTAAG ACCCTGGACC CCATCCTGAT CACCATCATA 2580 GCCATGAGTG CCCTGGGGGT GCTCCTGGGT GCAGTCTGTG GAGTTGTGCT GTACTGTGCC 2640 TGTTGGCACA ATGGGATGTC GGAAAGGAAC CTATCTGCCC TGGAGAACTA TAACTTTGAA 2700 CTTGTGGATG GTGTAAAGTT GAAAAAAGAT AAACTGAACC CACACAGTAA TTACTCAGAG 2760 GCGTGA 2766 (2) INFORMATION FOR SEQ ID NO : 4 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2584 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:4: Met Glu Thr Gly Leu Ala Arg Gly Gly Leu Tyr Leu Glu Pro Arg Leu 1 5 10 15 Glu Leu Glu Cys Tyr Ser Ala Leu Ala Thr His Arg Leu Glu Ala Leu 20 25 30 Ala Leu Glu Ala Leu Ala Leu Glu Ala Leu Ala Leu Glu Gly Leu Tyr 35 40 45 Ala Leu Ala Pro His Glu Ala Arg Gly Ser Glu Arg Ala Ser Pro Leu 50 55 60 Tyr Ser Cys Tyr Ser Gly Leu Tyr Gly Leu Tyr Thr His Arg He Leu 65 70 75 80 Glu Leu Tyr Ser He Leu Glu Gly Leu Ala Ser Asn Pro Arg Gly Leu 85 90 95 Tyr Thr Tyr Arg Leu Glu Thr His Arg Ser Glu Arg Pro Arg Gly Leu 100 105 110 Tyr Thr Tyr Arg Pro Arg His He Ser Ser Glu Arg Thr Tyr Arg His 115 120 125 He Ser Pro Arg Ser Glu Arg Gly Leu Leu Tyr Ser Cys Tyr Ser Gly 130 135 140 Leu Thr Arg Pro Leu Glu He Leu Glu Gly Leu Asn Ala Leu Ala Pro 145 150 155 160 Arg Gly Leu Pro Arg Thr Tyr Arg Gly Leu Asn Ala Arg Gly He Leu 165 170 175 Glu Met Glu Thr He Leu Glu Ala Ser Asn Pro His Glu Ala Ser Asn 180 185 190 Pro Arg His He Ser Pro His Glu Ala Ser Pro Leu Glu Gly Leu Ala 195 200 205 Ser Pro Ala Arg Gly Ala Ser Pro Cys Tyr Ser Leu Tyr Ser Thr Tyr 210 215 220 Arg Ala Ser Pro Thr Tyr Arg Val Ala Leu Gly Leu Val Ala Leu He 225 230 235 240 Leu Glu Ala Ser Pro Gly Leu Tyr Gly Leu Ala Ser Asn Gly Leu Gly 245 250 255 Leu Tyr Gly Leu Tyr Ala Arg Gly Leu Glu Thr Arg Pro Gly Leu Tyr 260 265 270 Leu Tyr Ser Pro His Glu Cys Tyr Ser Gly Leu Tyr Leu Tyr Ser He 275 280 285 Leu Glu Ala Leu Ala Pro Arg Ser Glu Arg Pro Arg Val Ala Leu Val 290 295 300 Ala Leu Ser Glu Arg Ser Glu Arg Gly Leu Tyr Pro Arg Pro His Glu 305 310 315 320 Leu Glu Pro His Glu He Leu Glu Leu Tyr Ser Pro His Glu Val Ala 325 330 335 Leu Ser Glu Arg Ala Ser Pro Thr Tyr Arg Gly Leu Thr His Arg His 340 345 350 He Ser Gly Leu Tyr Ala Leu Ala Gly Leu Tyr Pro His Glu Ser Glu 355 360 365 Arg He Leu Glu Ala Arg Gly Thr Tyr Arg Gly Leu He Leu Glu Pro 370 375 380 His Glu Leu Tyr Ser Ala Arg Gly Gly Leu Tyr Pro Arg Gly Leu Cys 385 390 395 400 Tyr Ser Ser Glu Arg Gly Leu Asn Ala Ser Asn Thr Tyr Arg Thr His 405 410 415 Arg Ala Leu Ala Pro Arg Thr His Arg Gly Leu Tyr Val Ala Leu He 420 425 430 Leu Glu Leu Tyr Ser Ser Glu Arg Pro Arg Gly Leu Tyr Pro His Glu 435 440 445 Pro Arg Gly Leu Leu Tyr Ser Thr Tyr Arg Pro Arg Ala Ser Asn Ser 450 455 460 Glu Arg Leu Glu Gly Leu Cys Tyr Ser Thr His Arg Thr Tyr Arg He 465 470 475 480 Leu Glu He Leu Glu Pro His Glu Ala Leu Ala Pro Arg Leu Tyr Ser 485 490 495 Met Glu Thr Ser Glu Arg Gly Leu He Leu Glu He Leu Glu Leu Glu 500 505 510 Gly Leu Pro His Glu Gly Leu Ser Glu Arg Pro His Glu Ala Ser Pro 515 520 525 Leu Glu Gly Leu Gly Leu Asn Ala Ser Pro Ser Glu Arg Ala Ser Asn 530 535 540 Pro Arg Pro Arg Gly Leu Tyr Gly Leu Tyr Met Glu Thr Pro His Glu 545 550 555 560 Cys Tyr Ser Ala Arg Gly Thr Tyr Arg Ala Ser Pro Ala Arg Gly Leu 565 570 575 Glu Gly Leu He Leu Glu Thr Arg Pro Ala Ser Pro Gly Leu Tyr Pro 580 585 590 His Glu Pro Arg Gly Leu Val Ala Leu Gly Leu Tyr Pro Arg His He 595 600 605 Ser He Leu Glu Gly Leu Tyr Ala Arg Gly Thr Tyr Arg Cys Tyr Ser 610 615 620 Gly Leu Tyr Gly Leu Asn Leu Tyr Ser Thr His Arg Pro Arg Gly Leu 625 630 635 640 Tyr Ala Arg Gly He Leu Glu Ala Arg Gly Ser Glu Arg Ser Glu Arg 645 650 655 Ser Glu Arg Gly Leu Tyr He Leu Glu Leu Glu Ser Glu Arg Met Glu 660 665 670 Thr Val Ala Leu Pro His Glu Thr Tyr Arg Thr His Arg Ala Ser Pro 675 680 685 Ser Glu Arg Ala Leu Ala He Leu Glu Ala Leu Ala Leu Tyr Ser Gly 690 695 700 Leu Gly Leu Tyr Pro His Glu Ser Glu Arg Ala Leu Ala Ala Ser Asn 705 710 715 720 Thr Tyr Arg Ser Glu Arg Val Ala Leu Leu Glu Gly Leu Asn Ser Glu 725 730 735 Arg Ser Glu Arg He Leu Glu Ser Glu Arg Gly Leu Ala Ser Pro Pro 740 745 750 His Glu Leu Tyr Ser Cys Tyr Ser Met Glu Thr Gly Leu Ala Leu Ala 755 760 765 Leu Glu Gly Leu Tyr Met Glu Thr Gly Leu Ser Glu Arg Gly Leu Tyr 770 775 780 Gly Leu He Leu Glu His He Ser Ser Glu Arg Ala Ser Pro Gly Leu 785 790 795 800 Asn He Leu Glu Thr His Arg Ala Leu Ala Ser Glu Arg Ser Glu Arg 805 810 815 Gly Leu Asn Thr Tyr Arg Gly Leu Tyr Thr His Arg Ala Ser Asn Thr 820 825 830 Arg Pro Ser Glu Arg Val Ala Leu Gly Leu Ala Arg Gly Ser Glu Arg 835 840 845 Ala Arg Gly Leu Glu Ala Ser Asn Thr Tyr Arg Pro Arg Gly Leu Ala 850 855 860 Ser Asn Gly Leu Tyr Thr Arg Pro Thr His Arg Pro Arg Gly Leu Tyr 865 870 875 880 Gly Leu Ala Ser Pro Ser Glu Arg Thr Tyr Arg Ala Arg Gly Gly Leu 885 890 895 Thr Arg Pro He Leu Glu Gly Leu Asn Val Ala Leu Ala Ser Pro Leu 900 905 910 Glu Gly Leu Tyr Leu Glu Leu Glu Ala Arg Gly Pro His Glu Val Ala 915 920 925 Leu Thr His Arg Ala Leu Ala Val Ala Leu Gly Leu Tyr Thr His Arg 930 935 940 Gly Leu Asn Gly Leu Tyr Ala Leu Ala He Leu Glu Ser Glu Arg Leu 945 950 955 960 Tyr Ser Gly Leu Thr His Arg Leu Tyr Ser Leu Tyr Ser Leu Tyr Ser 965 970 975 Thr Tyr Arg Thr Tyr Arg Val Ala Leu Leu Tyr Ser Thr His Arg Thr 980 985 990 Tyr Arg Ala Arg Gly Val Ala Leu Ala Ser Pro He Leu Glu Ser Glu 995 1000 1005 Arg Ser Glu Arg Ala Ser Asn Gly Leu Tyr Gly Leu Ala Ser Pro Thr 1010 1015 1020 Arg Pro He Leu Glu Thr His Arg Leu Glu Leu Tyr Ser Gly Leu Gly 1025 1030 1035 1040 Leu Tyr Ala Ser Asn Leu Tyr Ser Ala Leu Ala He Leu Glu He Leu 1045 1050 1055 Glu Pro His Glu Gly Leu Asn Gly Leu Tyr Ala Ser Asn Thr His Arg 1060 1065 1070 Ala Ser Asn Pro Arg Thr His Arg Ala Ser Pro Val Ala Leu Val Ala 1075 1080 1085 Leu Pro His Glu Gly Leu Tyr Val Ala Leu Pro His Glu Pro Arg Leu 1090 1095 1100 Tyr Ser Pro Arg Leu Glu He Leu Glu Thr His Arg Ala Arg Gly Pro 1105 1110 1115 1120 His Glu Val Ala Leu Ala Arg Gly He Leu Glu Leu Tyr Ser Pro Arg 1125 1130 1135 Ala Leu Ala Ser Glu Arg Thr Arg Pro Gly Leu Thr His Arg Gly Leu 1140 1145 1150 Tyr He Leu Glu Ser Glu Arg Met Glu Thr Ala Arg Gly Pro His Glu 1155 1160 1165 Gly Leu Val Ala Leu Thr Tyr Arg Gly Leu Tyr Cys Tyr Ser Leu Tyr 1170 1175 1180 Ser He Leu Glu Thr His Arg Ala Ser Pro Thr Tyr Arg Pro Arg Cys 1185 1190 1195 1200 Tyr Ser Ser Glu Arg Gly Leu Tyr Met Glu Thr Leu Glu Gly Leu Tyr 1205 1210 1215 Met Glu Thr Val Ala Leu Ser Glu Arg Gly Leu Tyr Leu Glu He Leu 1220 1225 1230 Glu Ser Glu Arg Ala Ser Pro Ser Glu Arg Gly Leu Asn He Leu Glu 1235 1240 1245 Thr His Arg Ala Leu Ala Ser Glu Arg Ala Ser Asn Gly Leu Asn Gly 1250 1255 1260 Leu Tyr Ala Ser Pro Ala Arg Gly Ala Ser Asn Thr Arg Pro Met Glu 1265 1270 1275 1280 Thr Pro Arg Gly Leu Ala Ser Asn He Leu Glu Ala Arg Gly Leu Glu 1285 1290 1295 Val Ala Leu Thr His Arg Ser Glu Arg Ala Arg Gly Thr His Arg Gly 1300 1305 1310 Leu Tyr Thr Arg Pro Ala Leu Ala Leu Glu Pro Arg Pro Arg Ser Glu 1315 1320 1325 Arg Pro Arg His He Ser Pro Arg Thr Tyr Arg He Leu Glu Ala Ser 1330 1335 1340 Asn Gly Leu Thr Arg Pro Leu Glu Gly Leu Asn Val Ala Leu Ala Ser 1345 1350 1355 1360 Pro Leu Glu Gly Leu Tyr Ala Ser Pro Gly Leu Leu Tyr Ser He Leu 1365 1370 1375 Glu Val Ala Leu Ala Arg Gly Gly Leu Tyr Val Ala Leu He Leu Glu 1380 1385 1390 He Leu Glu Gly Leu Asn Gly Leu Tyr Gly Leu Tyr Leu Tyr Ser His 1395 1400 1405 He Ser Ala Arg Gly Gly Leu Ala Ser Asn Leu Tyr Ser Val Ala Leu 1410 1415 1420 Pro His Glu Met Glu Thr Ala Arg Gly Leu Tyr Ser Pro His Glu Leu 1425 1430 1435 1440 Tyr Ser He Leu Glu Ala Leu Ala Thr Tyr Arg Ser Glu Arg Ala Ser 1445 1450 1455 Asn Ala Ser Asn Gly Leu Tyr Ser Glu Arg Ala Ser Pro Thr Arg Pro 1460 1465 1470 Leu Tyr Ser Met Glu Thr He Leu Glu Met Glu Thr Ala Ser Pro Ala 1475 1480 1485 Ser Pro Ser Glu Arg Leu Tyr Ser Ala Arg Gly Leu Tyr Ser Ala Leu 1490 1495 1500 Ala Leu Tyr Ser Ser Glu Arg Pro His Glu Gly Leu Gly Leu Tyr Ala 1505 1510 1515 1520 Ser Asn Ala Ser Asn Ala Ser Asn Thr Tyr Arg Ala Ser Pro Thr His 1525 1530 1535 Arg Pro Arg Gly Leu Leu Glu Ala Arg Gly Ala Leu Ala Pro His Glu 1540 1545 1550 Thr His Arg Pro Arg Leu Glu Ser Glu Arg Thr His Arg Ala Arg Gly 1555 1560 1565 Pro His Glu He Leu Glu Ala Arg Gly He Leu Glu Thr Tyr Arg Pro 1570 1575 1580 Arg Gly Leu Ala Arg Gly Ala Leu Ala Thr His Arg His He Ser Ser 1585 1590 1595 1600 Glu Arg Gly Leu Tyr Leu Glu Gly Leu Tyr Leu Glu Ala Arg Gly Met 1605 1610 1615 Glu Thr Gly Leu Leu Glu Leu Glu Gly Leu Tyr Cys Tyr Ser Gly Leu 1620 1625 1630 Val Ala Leu Gly Leu Val Ala Leu Pro Arg Thr His Arg Ala Leu Ala 1635 1640 1645 Gly Leu Tyr Pro Arg Thr His Arg Thr His Arg Pro Arg Ala Ser Asn 1650 1655 1660 Gly Leu Tyr Ala Ser Asn Pro Arg Val Ala Leu Ala Ser Pro Gly Leu 1665 1670 1675 1680 Cys Tyr Ser Ala Ser Pro Ala Ser Pro Ala Ser Pro Gly Leu Asn Ala 1685 1690 1695 Leu Ala Ala Ser Asn Cys Tyr Ser His He Ser Ser Glu Arg Gly Leu 1700 1705 1710 Tyr Thr His Arg Gly Leu Tyr Ala Ser Pro Ala Ser Pro Pro His Glu 1715 1720 1725 Gly Leu Asn Leu Glu Thr His Arg Gly Leu Tyr Gly Leu Tyr Thr His 1730 1735 1740 Arg Thr His Arg Val Ala Leu Leu Glu Ala Leu Ala Thr His Arg Gly 1745 1750 1755 1760 Leu Leu Tyr Ser Pro Arg Thr His Arg He Leu Glu He Leu Glu Ala 1765 1770 1775 Ser Pro Ser Glu Arg Thr His Arg He Leu Glu Gly Leu Asn Ser Glu 1780 1785 1790 Arg Gly Leu Pro His Glu Pro Arg Thr His Arg Thr Tyr Arg Gly Leu 1795 1800 1805 Tyr Pro His Glu Ala Ser Asn Cys Tyr Ser Gly Leu Pro His Glu Gly 1810 1815 1820 Leu Tyr Thr Arg Pro Gly Leu Tyr Ser Glu Arg His He Ser Leu Tyr 1825 1830 1835 1840 Ser Thr His Arg Pro His Glu Cys Tyr Ser His He Ser Thr Arg Pro 1845 1850 1855 Gly Leu His He Ser Ala Ser Pro Ser Glu Arg His He Ser Ala Leu 1860 1865 1870 Ala Gly Leu Asn Leu Glu Ala Arg Gly Thr Arg Pro Ala Arg Gly Val 1875 1880 1885 Ala Leu Leu Glu Thr His Arg Ser Glu Arg Leu Tyr Ser Thr His Arg 1890 1895 1900 Gly Leu Tyr Pro Arg He Leu Glu Gly Leu Asn Ala Ser Pro His He 1905 1910 1915 1920 Ser Thr His Arg Gly Leu Tyr Ala Ser Pro Gly Leu Tyr Ala Ser Asn 1925 1930 1935 Pro His Glu He Leu Glu Thr Tyr Arg Ser Glu Arg Gly Leu Asn Ala 1940 1945 1950 Leu Ala Ala Ser Pro Gly Leu Ala Ser Asn Gly Leu Asn Leu Tyr Ser 1955 1960 1965 Gly Leu Tyr Leu Tyr Ser Val Ala Leu Ala Leu Ala Ala Arg Gly Leu 1970 1975 1980 Glu Val Ala Leu Ser Glu Arg Pro Arg Val Ala Leu Val Ala Leu Thr 1985 1990 1995 2000 Tyr Arg Ser Glu Arg Gly Leu Asn Ser Glu Arg Ser Glu Arg Ala Leu 2005 2010 2015 Ala His He Ser Cys Tyr Ser Met Glu Thr Thr His Arg Pro His Glu 2020 2025 2030 Thr Arg Pro Thr Tyr Arg His He Ser Met Glu Thr Ser Glu Arg Gly 2035 2040 2045 Leu Tyr Ser Glu Arg His He Ser Val Ala Leu Gly Leu Tyr Thr His 2050 2055 2060 Arg Leu Glu Ala Arg Gly Val Ala Leu Leu Tyr Ser Leu Glu His He 2065 2070 2075 2080 Ser Thr Tyr Arg Gly Leu Asn Leu Tyr Ser Pro Arg Gly Leu Gly Leu 2085 2090 2095 Thr Tyr Arg Ala Ser Pro Gly Leu Asn Leu Glu Val Ala Leu Thr Arg 2100 2105 2110 Pro Met Glu Thr Val Ala Leu Val Ala Leu Gly Leu Tyr His He Ser 2115 2120 2125 Gly Leu Asn Gly Leu Tyr Ala Ser Pro His He Ser Thr Arg Pro Leu 2130 2135 2140 Tyr Ser Gly Leu Gly Leu Tyr Ala Arg Gly Val Ala Leu Leu Glu Leu 2145 2150 2155 2160 Glu His He Ser Leu Tyr Ser Ser Glu Arg Leu Glu Leu Tyr Ser Leu 2165 2170 2175 Glu Thr Tyr Arg Gly Leu Asn Val Ala Leu He Leu Glu Pro His Glu 2180 2185 2190 Gly Leu Gly Leu Tyr Gly Leu He Leu Glu Gly Leu Tyr Leu Tyr Ser 2195 2200 2205 Gly Leu Tyr Ala Ser Asn Leu Glu Gly Leu Tyr Gly Leu Tyr He Leu 2210 2215 2220 Glu Ala Leu Ala Val Ala Leu Ala Ser Pro Ala Ser Pro He Leu Glu 2225 2230 2235 2240 Ser Glu Arg He Leu Glu Ala Ser Asn Ala Ser Asn His He Ser He 2245 2250 2255 Leu Glu Pro Arg Gly Leu Asn Gly Leu Ala Ser Pro Cys Tyr Ser Ala 2260 2265 2270 Leu Ala Leu Tyr Ser Pro Arg Thr His Arg Ala Ser Pro Leu Glu Ala 2275 2280 2285 Ser Pro Leu Tyr Ser Leu Tyr Ser Ala Ser Asn Thr His Arg Gly Leu 2290 2295 2300 He Leu Glu Leu Tyr Ser He Leu Glu Ala Ser Pro Gly Leu Thr His 2305 2310 2315 2320 Arg Gly Leu Tyr Ser Glu Arg Thr His Arg Pro Arg Gly Leu Tyr Thr 2325 2330 2335 Tyr Arg Gly Leu Gly Leu Gly Leu Tyr Leu Tyr Ser Gly Leu Tyr Ala 2340 2345 2350 Ser Pro Leu Tyr Ser Ala Ser Asn He Leu Glu Ser Glu Arg Ala Arg 2355 2360 2365 Gly Leu Tyr Ser Pro Arg Gly Leu Tyr Ala Ser Asn Val Ala Leu Leu 2370 2375 2380 Glu Leu Tyr Ser Thr His Arg Leu Glu Ala Ser Pro Pro Arg He Leu 2385 2390 2395 2400 Glu Leu Glu He Leu Glu Thr His Arg He Leu Glu He Leu Glu Ala 2405 2410 2415 Leu Ala Met Glu Thr Ser Glu Arg Ala Leu Ala Leu Glu Gly Leu Tyr 2420 2425 2430 Val Ala Leu Leu Glu Leu Glu Gly Leu Tyr Ala Leu Ala Val Ala Leu 2435 2440 2445 Cys Tyr Ser Gly Leu Tyr Val Ala Leu Val Ala Leu Leu Glu Thr Tyr 2450 2455 2460 Arg Cys Tyr Ser Ala Leu Ala Cys Tyr Ser Thr Arg Pro His He Ser 2465 2470 2475 2480 Ala Ser Asn Gly Leu Tyr Met Glu Thr Ser Glu Arg Gly Leu Ala Arg 2485 2490 2495 Gly Ala Ser Asn Leu Glu Ser Glu Arg Ala Leu Ala Leu Glu Gly Leu 2500 2505 2510 Ala Ser Asn Thr Tyr Arg Ala Ser Asn Pro His Glu Gly Leu Leu Glu 2515 2520 2525 Val Ala Leu Ala Ser Pro Gly Leu Tyr Val Ala Leu Leu Tyr Ser Leu 2530 2535 2540 Glu Leu Tyr Ser Leu Tyr Ser Ala Ser Pro Leu Tyr Ser Leu Glu Ala 2545 2550 2555 2560 Ser Asn Pro Arg His He Ser Ser Glu Arg Ala Ser Asn Thr Tyr Arg 2565 2570 2575 Ser Glu Arg Gly Leu Ala Leu Ala 2580 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3652 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: TTTTTTTTTT XXTTTTTTTT ^TTTTTTTTT TTTTTCCTCC TTCTTCTTCT TCCTGAGACA 60 TGGCCCGGGC AGTGGCTCCT GGAAGAGGAA CAAGTGTGGG AAAAGGGAGA GGAAATCGGA 120 GCTAAATGAC AGGATGCAGG CGACTTGAGA CACAAAAAGA GAAGCGCTTC TCGCGAATTC 180 AGGCATTGCC TCGCCGCTAG CCTTCCCCGC CAAGACCCGC TGAGGATTTT ATGGTTCTTA 240 GGCGGACTTA AGAGCGTTTC GGATTGTTAA GATTATCGTT TGCTGGTTTT TCGTCCGCGC 300 AATCGTGTTC TCCTGCGGCT GCCTGGGGAC TGGCTTGGCG AAGGAGGATG GAGAGGGGGC 360 TGCCGTTGCT GTGCGCCACG CTCGCCCTTG CCCTCGCCCT GGCGGGCGCT TTCCGCAGCG 420 ACAAATGTGG CGGGACCATA AAAATCGAAA ACCCAGGGTA CCTCACATCT CCCGGTTACC 480 CTCATTCTTA CCATCCAAGT GAGAAGTGTG AATGGCTAAT CCAAGCTCCG GAACCCTACC 540 AGAGAATCAT AATCAACTTC AACCCACATT TCGATTTGGA GGACAGAGAC TGCAAGTATG 600 ACTACGTGGA AGTAATTGAT GGGGAGAATG AAGGCGGCCG CCTGTGGGGG AAGTTCTGTG 660 GGAAGATTGC ACCTTCTCCT GTGGTGTCTT CAGGGCCCTT TCTCTTCATC AAATTTGTCT 720 CTGACTATGA GACACATGGG GCAGGGTTTT CCATCCGCTA TGAAATCTTC AAGAGAGGGC 780 CCGAATGTTC TCAGAACTAT ACAGCACCTA CTGGAGTGAT AAAGTCCCCT GGGTTCCCTG 840 AAAAATACCC CAACTGCTTG GAGTGCACCT ACATCATCTT TGCACCAAAG ATGTCTGAGA 900 TJAATCCTGGA GTTTGAAAGT TTTGACCTGG AGCAAGACTC GAATCCTCCC GGAGGAATGT 960 TCTGTCGCTA TGACCGGCTG GAGATCTGGG ATGGATTCCC TGAAGTTGGC CCTCACATTG 1020 GGCGTTATTG TGGGCAGAAA ACTCCTGGCC GGATCCGCTC CTCTTCAGGC GTTCTATCCA 1080 TGGTCTTTTA CACTGACAGC GCAATAGCAA AAGAAGGTTT CTCAGCCAAC TACAGTGTGC 1140 TACAGAGCAG CATCTCTGAA GATTTTAAGT GTATGGAGGC TCTGGGCATG GAATCTGGAG 1200 AGATCCATTC TGATCAGATC ACTGCATCTT CACAGTATGG TACCAACTGG TCTGTAGAGC 1260 GCTCCCGCCT GAACTACCCT GAAAATGGGT GGACTCCAGG AGAAGACTCC TACAAGGAGT 1320 GGATCCAGGT GGACTTGGGC CTCCTGCGAT TCGTTACTGC TGTAGGGACA CAGGGTGCCA 1380 TTTCCAAGGA AACCAAGAAG AAATATTATG TCAAGACTTA CAGAGTAGAC ATCAGCTCCA 1440 ACGGAGAGGA CTGGATCTCC CTGAAAGAGG GAAATAAAGC CATTATCTTT CAGGGAAACA 1500 CCAACCCCAC AGATGTTGTC TTAGGAGTTT TCTCCAAACC ACTGATAACT CGATTTGTCC 1560 GAATCAAACC TGTATCCTGG GAAACTGGTA TATCTATGAG ATTTGAAGTT TATGGCTGCA 1620 AGATAACAGA TTATCCTTGC TCTGGAATGT TGGGCATGGT GTCTGGACTT ATTTCAGACT 1680 CCCAGATTAC AGCATCCAAT CAAGCCGACA GGAATTGGAT GCCAGAAAAC ATCCGTCTGG 1740 TGACCAGTCG TACCGGCTGG GCACTGCCAC CCTCACCCCA CCCATACACC AATGAATGGC 1800 TCCAAGTGGA CCTGGGAGAT GAGAAGATAG TAAGAGGTGT CATCATTCAG GGTGGGAAGC 1860 ACCGAGAAAA CAAGGTGTTC ATGAGGAAGT TCAAGATCGC CTATAGTAAC AATGGCTCTG 1920 ACTGGAAAAC TATCATGGAT GACAGCAAGC GCAAGGCTAA GTCGTTCGAA GGCAACAACA 1980 ACTATGACAC ACCTGAGCTT CGGACGTTTT CACCTCTCTC CACAAGGTTC ATCAGGATCT 2040 ACCCTGAGAG AGCCACACAC AGTGGGCTTG GGCTGAGGAT GGAGCTACTG GGCTGTGAAG 2100 TGGAAGCACC TACAGCTGGA CCAACCACAC CCAATGGGAA CCCAGTGCAT GAGTGTGACG 2160 ACGACCAGGC CAACTGCCAC AGTGGCACAG GTGATGACTT CCAGCTCACA GGAGGCACCA 2220 CTGTCCTGGC CACAGAGAAG CCAACCATTA TAGACAGCAC CATCCAATCA GAGTTCCCGA 2280 CATACGGTTT TAACTGCGAG TTTGGCTGGG GCTCTCACAA GACATTCTGC CACTGGGAGC 2340. ATGACAGCCA TGCACAGCTC AGGTGGAGTG TGCTGACCAG CAAGACAGGG CCGATTCAGG 2400 ACCATACAGG AGATGGCAAC TTCATCTATT CCCAAGCTGA TGAAAATCAG AAAGGCAAAG 2460 TAGCCCGCCT GGTGAGCCCT GTGGTCTATT CCCAGAGCTC TGCCCACTGT ATGACCTTCT 2520 GGTATCACAT GTCCGGCTCT CATGTGGGTA CACTGAGGGT CAAACTACGC TACCAGAAGC 2580 CAGAGGAATA TGATCAACTG GTCTGGATGG TGGTTGGGCA CCAAGGAGAC CACTGGAAAG 2640 AAGGACGTGT CTTGCTGCAC AAATCTCTGA AACTATATCA GGTTATTTTT GAAGGTGAAA 2700 TCGGAAAAGG AAACCTTGGT GGAATTGCTG TGGATGATAT CAGTATTAAC AACCATATTT 2760 CTCAGGAAGA CTGTGCAAAA CCAACAGACC TAGATAAAAA GAACACAGAA ATTAAAATTG 2820 ATGAAACAGG GAGCACTCCA GGATATGAAG GAGAAGGGGA AGGTGACAAG AACATCTCCA 2880 GGAAGCCAGG CAATGTGCTT AAGACCCTGG ATCCCATCCT GATCACCATC ATAGCCATGA 2940 GTGCCCTGGG AGTACTCCTG GGTGCAGTCT GTGGAGTTGT GCTGTACTGT GCCTGTTGGC 3000 ACAATGGGAT GTCAGAAAGG AACCTATCTG CCCTGGAGAA CTATAACTTT GAACTTGTGG 3060 ATGGTGTAAA GTTGAAAAAA GATAAACTGA ACCCACAGAG T.AATTACTCA GAGGCGTGAA 3120 GGCACGGAGC TGGAGGGAAC AAGGGAGGAG CACGGCAGGA GAACAGGTGG AGGCATGGGG 3180 ACTCTGTTAC TCTGCTTTCA CTGTAAGCTG GGAAGGGCGG GGACTCTGTT ACTCCGCTTT 3240 CACTGTAAGC TCGGAAGGGC ATCCACGATG CCATGCCAGG CTTTTCTCAG GAGCTTCAAT 3300 GAGCGTCACC TACAGACACA AGCAGGTGAC TGCGGTAACA ACAGGAATCA TGTACAAGCC 3360 TGCTTTCTTC TCTTGGTTTC ATTTGGGTAA TCAGAAGCCA TTTGAGACCA AGTGTGACTG 3420 ACTTCATGGT TCATCCTACT AGCCCCCTTT TTTCCTCTCT TTCTCCTTAC CCTGTGGTGG 3480 ATTCTTCTCG GAAACTGCAA AATCCAAGAT GCTGGCACTA GGCGTTATTC AGTGGGCCCT 3540 TTTGATGGAC ATGTGACCTG TAGCCCAGTG CCCAGAGCAT ATTATCATAA CCACATTTCA 3600 GGGGACGCCA ACGTCCATCC ACCTTTGCAT CGCTACCTGC AGCGAGCACA GG 3652 (2) INFORMATION FOR SEQ ID NO : 6 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 923 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 6 : Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Thr Leu Ala Leu Ala Leu 1 5 10 15 Ala Leu Ala Gly Ala Phe Arg Ser Asp Lys Cys Gly Gly Thr He Lys 20 25 30 He Glu Asn Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr 35 40 45 His Pro Ser Glu Lys Cys Glu Trp Leu He Gin Ala Pro Glu Pro Tyr 50 55 60 Gin Arg He He He Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg 65 70 75 80 Asp Cys Lys Tyr Asp Tyr Val Glu Val He Asp Gly Glu Asn Glu Gly 85 90 95 Gly Arg Leu Trp Gly Lys Phe Cys Gly Lys He Ala Pro Ser Pro Val 100 105 110 Val Ser Ser Gly Pro Phe Leu Phe He Lys Phe Val Ser Asp Tyr Glu 115 120 125 Thr His Gly Ala Gly Phe Ser He Arg Tyr Glu He Phe Lys Arg Gly 130 135 140 Pro Glu Cys Ser Gin Asn Tyr Thr Ala Pro Thr Gly Val He Lys Ser 145 150 155 160 Pro Gly Phe Pro Glu Lys Tyr Pro Asn Cys Leu Glu Cys Thr Tyr He 165 170 175 He Phe Ala Pro Lys Met Ser Glu He He Leu Glu Phe Glu Ser Phe 180 185 190 Asp Leu Glu Gin Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr 195 200 205 Asp Arg Leu Glu He Trp Asp Gly Phe Pro Glu Val Gly Pro His He 210 215 220 Gly Arg Tyr Cys Gly Gin Lys Thr Pro Gly Arg He Arg Ser Ser Ser 225 230 235 240 Gly Val Leu Ser Met Val Phe Tyr Thr Asp Ser Ala He Ala Lys Glu 245 250 255 Gly Phe Ser Ala Asn Tyr Ser Val Leu Gin Ser Ser He Ser Glu Asp 260 265 270 Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu He His Ser 275 280 285 Asp Gin He Thr Ala Ser Ser Gin Tyr Gly Thr Asn Trp Ser Val Glu 290 295 300 Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp 305 310 315 320 Ser Tyr Lys Glu Trp He Gin Val Asp Leu Gly Leu Leu Arg Phe Val 325 330 335 Thr Ala Val Gly Thr Gin Gly Ala He Ser Lys Glu Thr Lys Lys Lys 340 345 350 Tyr Tyr Val Lys Thr Tyr Arg Val Asp He Ser Ser Asn Gly Glu Asp 355 360 365 Trp He Ser Leu Lys Glu Gly Asn Lys Ala He He Phe Gin Gly Asn 370 375 380 Thr Asn Pro Thr Asp Val Val Leu Gly Val Phe Ser Lys Pro Leu He 385 390 395 400 Thr Arg Phe Val Arg He Lys Pro Val Ser Trp Glu Thr Gly He Ser 405 410 415 Met Arg Phe Glu Val Tyr Gly Cys Lys He Thr Asp Tyr Pro Cys Ser 420 425 430 Gly Met Leu Gly Met Val Ser Gly Leu He Ser Asp Ser Gin He Thr 435 440 445 Ala Ser Asn Gin Ala Asp Arg Asn Trp Met Pro Glu Asn He Arg Leu 450 455 460 Val Thr Ser Arg Thr Gly Trp Ala Leu Pro Pro Ser Pro His Pro Tyr 465 470 475 480 Thr Asn Glu Trp Leu Gin Val Asp Leu Gly Asp Glu Lys He Val Arg 485 490 495 Gly Val He He Gin Gly Gly Lys His Arg Glu Asn Lys Val Phe Met 500 505 510 Arg Lys Phe Lys He Ala Tyr Ser Asn Asn Gly Ser Asp Trp Lys Thr 515 520 525 He Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn 530 535 540 Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Ser Pro Leu Ser Thr Arg 545 550 555 560 Phe He Arg He Tyr Pro Glu Arg Ala Thr His Ser Gly Leu Gly Leu 565 570 575 Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro 580 585 590 Thr Thr Pro Asn Gly Asn Pro Val His Glu Cys Asp Asp Asp Gin Ala 595 600 605 Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gin Leu Thr Gly Gly Thr 610 615 620 Thr Val Leu Ala Thr Glu Lys Pro Thr He He Asp Ser Thr He Gin 625 630 635 640 Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser 645 650 655 His Lys Thr Phe Cys His Trp Glu His Asp Ser His Ala Gin Leu Arg 660 665 670 Trp Ser Val Leu Thr Ser Lys Thr Gly Pro He Gin Asp His Thr Gly 675 680 685 Asp Gly Asn Phe He Tyr Ser Gin Ala Asp Glu Asn Gin Lys Gly Lys 690 695 700 Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gin Ser Ser Ala His 705 710 715 720 Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu 725 730 735 Arg Val Lys Leu Arg Tyr Gin Lys Pro Glu Glu Tyr Asp Gin Leu Val 740 745 750 Trp Met Val Val Gly His Gin Gly Asp His Trp Lys Glu Gly Arg Val 755 760 765 Leu Leu His Lys Ser Leu Lys Leu Tyr Gin Val He Phe Glu Gly Glu 770 775 780 He Gly Lys Gly Asn Leu Gly Gly He Ala Val Asp Asp He Ser He 785 790 795 800 Asn Asn His He Ser Gin Glu Asp Cys Ala Lys Pro Thr Asp Leu Asp 805 810 815 Lys Lys Asn Thr Glu He Lys He Asp Glu Thr Gly Ser Thr Pro Gly 820 825 830 Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn He Ser Arg Lys Pro Gly 835 840 845 Asn Val Leu Lys Thr Leu Asp Pro He Leu He Thr He He Ala Met 850 855 860 Ser Ala Leu Gly Val Leu Leu Gly Ala Val Cys Gly Val Val Leu Tyr 865 870 875 880 Cys Ala Cys Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu 885 890 895 Glu Asn Tyr Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp 900 905 910 Lys Leu Asn Pro Gin Ser Asn Tyr Ser Glu Ala 915 920 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3539 base pairs (B) TYPE: nucleic acid (C) STRJMJDEDNESS : single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: AAACTGGAGC TCCACCGCGG TGGCGGCCGC CCGGGCAGGT CTAGAATTCA GCGGCCGCTG 60 AATTCTATCC AGCGGTCGGT GCCTCTGCCC GCGTGTGTGT CCCGGGTGCC GGGGGACCTG 120 TGTCAGTTAG CGCTTCTGAG ATCACACAGC TGCCTAGGGG CCGTGTGATG CCCAGGGCAA 180 TTCTTGGCTT TGATTTTTAT TATTATTACT ATTATTTTGC GTTCAGCTTT CGGGAAACCC 240 TCGTGATGTT GTAGGATAAA GGAAATGACA CTTTGAGGAA CTGGAGAGAA CATACACGCG 300 TTTGGGTTTG AAGAGGAAAC CGGTCTCCGC TTCCTTAGCT TGCTCCCTCT TTGCTGATTT 360 CAAGAGCTAT CTCCTATGAG GTGGAGATAT TCCAGCAAGA ATAAAGGTGA AGACAGACTG 420 ACTGCCAGGA CCCAGGAGGA AAACGTTGAT CGTTAGAGAC CTTTGCAGAA GACACCACCA 480 GGAGGAAAAT TAGAGAGGAA AAACACAAAG ACATAATTAT ATGGAGATCC CACAAACTTA 540 GCCCGGGAGA GAGCTTCTCT GTCAAAAATG GATATGTTTC CTCTTACCTG GGTTTTCTTA 600 GCTCTGTACT TTTCAGGACA CGAAGTGAGA AGCCAGCAAG ATCCACCTTG CGGAGGTCGG 660 CCGAATTCCA AGGATGCTGG CTACATCACT TCCCCAGGCT ACCCCCAGGA CTATCCCTCC 720 CACCAGAACT GTGAGTGGAT TGTCTACGCC CCCGAACCCA ACCAGAAGAT TGTTCTCAAC 780 TTCAACCCTC ACTTTGAAAT CGAGAAACAC GACTGCAAGT ATGACTTCAT TGAGATTCGG 840 GATGGGGACA GTGAGTCAGC TGACCTCCTG GGCAAGCACT GTGGGAACAT CGCCCCGCCC 900 ACCATCATCT CCTCAGGCTC CGTGTTATAC ATCAAGTTCA CCTCAGACTA CGCCCGGCAG 960 GGGGCAGGTT TCTCTCTACG CTATGAGATC TTCAAAACAG GCTCTGAAGA TTGTTCCAAG 1020 AACTTTACAA GCCCCAATGG GACCATTGAA TCTCCAGGGT TTCCAGAGAA GTATCCACAC 1080 AATCTGGACT GTACCTTCAC CATCCTGGCC AAACCCAGGA TGGAGATCAT CCTACAGTTC 1140 CTGACCTTTG ACCTGGAGCA TGACCCTCTA CAAGTGGGGG AAGGAGACTG TAAATATGAC 1200 TGGCTGGACA TCTGGGATGG CATTCCACAT GTTGGACCTC TGATTGGCAA GTACTGTGGG 1260 ACGAAAACAC CCTCCAAACT CCGCTCGTCC ACGGGGATCC TCTCCTTGAC CTTTCACACG 1320 GACATGGCAG TGGCCAAGGA TGGCTTCTCC GCACGTTACT ATTTGATCCA CCAGGAGCCA 1380 CCTGAGAATT TTCAGTGCAA TGTCCCTTTG GGAATGGAGT CTGGCCGGAT TGCTAATGAA 1440 CAGATCAGTG CCTCCTCCAC CTTCTCTGAT GGGAGGTGGA CTCCTCAACA GAGCCGGCTC 1500 CATGGTGATG ACAATGGCTG GACACCCAAT TTGGATTCCA ACAAGGAGTA TCTCCAGGTG 1560 GACCTGCGCT TCCTAACCAT GCTCACAGCC ATTGCAACAC AGGGAGCCAT TTCCAGGGAA 1620 ACCCAGAAAG GCTACTACGT CAAATCGTAC AAGCTGGAAG TCAGCACAAA TGGTGAAGAT 1680 TGGATGGTCT ACCGGCATGG CAAAAACCAC AAGATATTCC AAGCGAACAA TGATGCGACC 1740 GAGGTGGTGC TAAACAAGCT CCACATGCCA CTGCTGACTC GGTTCATCAG GATCCGCCCG 1800 CAGACGTGGC ATTTGGGCAT TGCCCTTCGC CTGGAGCTCT TTGGCTGCCG GGTCACAGAT 1860 GCACCCTGCT CCAACATGCT GGGGATGCTC TCGGGCCTCA TTGCTGATAC CCAGATCTCT 1920 GCCTCCTCCA CCCGAGAGTA CCTCTGGAGC CCCAGTGCTG CCCGCCTGGT TAGTAGCCGC 1980 TCTGGCTGGT TTCCTCGGAA CCCTCAAGCC CAGCCAGGTG AAGAATGGCT TCAGGTTGAC 2040 CTGGGGACAC CCAAGACAGT GAAAGGGGTC ATCATCCAGG GAGCCCGAGG AGGAGACAGC 2100 ATCACTGCCG TGGAAGCCAG GGCGTTTGTA CGCAAGTTCA AAGTCTCCTA CAGCCTAAAT 2160 GGCAAGGACT GGGAATATAT CCAGGACCCC AGGACTCAGC AGACAAAGCT GTTTGAAGGG 2220 AACATGCACT ATGACACCCC TGACATCCGA AGGTTCGATC CTGTTCCAGC GCAGTATGTG 2280 CGGGTGTACC CAGAGAGGTG GTCGCCAGCA GGCATCGGGA TGAGGCTGGA GGTGCTGGGC 2340 TGTGACTGGA CAGACTCAAA GCCCACAGTG GAGACGCTGG GACCCACCGT GAAGAGTGAA 2400 GAGACTACCA CCCCATATCC CATGGATGAG GATGCCACCG AGTGTGGGGA AAACTGCAGC 2460 TTTGAGGATG ACAAAGATTT GCAACTTCCT TCAGGATTCA ACTGCAACTT TGATTTTCCG 2520 GAAGAGACCT GTGGTTGGGT GTACGACCAT GCCAAGTGGC TCCGGAGCAC GTGGATCAGC 2580 AGCGCTAACC CCAATGACAG AACATTTCCA GATGACAAGA ACTTCTTGAA ACTGCAGAGT 2640 GATGGCCGAC GAGAGGGCCA GTACGGGCGG CTCATCAGCC CACCGGTGCA CCTGCCCCGA 2700 AGCCCTGTGT GCATGGAGTT CCAGTACCAA GCCATGGGCG GCCACGGGGT GGCACTGCAG 2760 GTGGTTCGGG AAGCCAGCCA GGAAAGCAAA CTCCTTTGGG TCATCCGTGA GGACCAGGGC 2820 AGCGAGTGGA AGCACGGGCG CATTATCCTG CCCAGCTATG ACATGGAGTA TCAGATCGTG 2880 TTCGAGGGAG TGATAGGGAA GGGACGATCG GGAGAGATTT CCATCGATGA CATTCGGATA 2940 AGCACTGATG TCCCACTGGA GAACTGCATG GAACCCATAT CAGCTTTTGC AGATGAATAT 3000 GAAGGAGATT GGAGCAACTC TTCTTCCTCT ACCTCAGGGG CTGGTGACCC CTCATCTGGC 3060 AAAGAAAAGA GCTGGCTGTA CACCCTAGAT CCCATTCTGA TCACCATCAT CGCCATGAGC 3120 TCGCTGGGGG TCCTGCTGGG GGCCACCTGT GCGGGCCTCC TCCTTTACTG CACCTGCTCC 3180 TATTCGGGTC TGAGTTCGAG GAGCTGCACC ACACTGGAGA ACTACAACTT TGAGCTCTAC 3240 GATGGCCTCA AGCACAAGGT CAAGATCAAT CATCAGAAGT GCTGCTCGGA GGCATGACCG 3300 ATTGTGTCTG GATCGCTTCT GGCGTTTCAT TCCAGTGAGA GGGGCTAGCG AAGATTACAG 3360 TTTTGTTTTG TTTTGTTTTG TTTTCCCTTT GGAAACTGAA TGCCATAATC TGGATCAAAG 3420 TGTTCCAGAA TACTGAAGGT ATGGACAGGA CAGACAGGCC AGTCTAGGGA GAAAGGGAGA 3480 TGCAGCTGTG AAGGGGATCG TTGCCCACCA GGACTGTGGT GGCCAAGTGA ATGCAGGAA 3539 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 909 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Gly His Glu Val Arg Ser Gin Gin Asp Pro Pro Cys Gly Gly Arg Pro 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Val Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Arg Met Glu He He Leu Gin Phe Leu 180 185 190 Thr Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Lys Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu He His Gin Glu Pro Pro 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Phe Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Lys Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys He Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Met 385 390 395 400 Pro Leu Leu Thr Arg Phe He Arg He Arg Pro Gin Thr Trp His Leu 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Thr 435 440 445 Gin He Ser Ala Ser Ser Thr Arg Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg Asn Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Thr Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro Val Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Glu Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Met Asp Glu Asp Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Pro Glu Glu Thr Cys Gly 645 650 655 Trp Val Tyr Asp His Ala Lys Trp Leu Arg Ser Thr Trp He Ser Ser 660 665 670 Ala Asn Pro Asn Asp Arg Thr Phe Pro Asp Asp Lys Asn Phe Leu Lys 675 680 685 Leu Gin Ser Asp Gly Arg Arg Glu Gly Gin Tyr Gly Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Met Gly Gly His Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Ser 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ser He Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Asp Glu Tyr Glu Gly Asp Trp Ser 805 810 815 Asn Ser Ser Ser Ser Thr Ser Gly Ala Gly Asp Pro Ser Ser Gly Lys 820 825 830 Glu Lys Ser Trp Leu Tyr Thr Leu Asp Pro He Leu He Thr He He 835 840 845 Ala Met Ser Ser Leu Gly Val Leu Leu Gly Ala Thr Cys Ala Gly Leu 850 855 860 Leu Leu Tyr Cys Thr Cys Ser Tyr Ser Gly Leu Ser Ser Arg Ser Cys 865 870 875 880 Thr Thr Leu Glu Asn Tyr Asn Phe Glu Leu Tyr Asp Gly Leu Lys His 885 890 895 Lys Val Lys He Asn His Gin Lys Cys Cys Ser Glu Ala 900 905 (2) INFORMATION FOR SEQ ID NO : 9 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4718 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: AAACTGGAGC TCCACCGCGG TGGCGGCCGC CCGGGCAGGT CTAGAATTCA GCGGCCGCTG 60 AATTCTATCC AGCGGTCGGT GCCTCTGCCC GCGTGTGTGT CCCGGGTGCC GGGGGACCTG 120 TGTCAGTTAG CGCTTCTGAG ATCACACAGC TGCCTAGGGG CCGTGTGATG CCCAGGGCAA 180 TTCTTGGCTT TGATTTTTAT TATTATTACT ATTATTTTGC GTTCAGCTTT CGGGAAACCC 240 TCGTGATGTT GTAGGATAAA GGAAATGACA CTTTGAGGAA CTGGAGAGAA CATACACGCG 300 TTTGGGTTTG AAGAGGAAAC CGGTCTCCGC TTCCTTAGCT TGCTCCCTCT TTGCTGATTT 360 CAAGAGCTAT CTCCTATGAG GTGGAGATAT TCCAGCAAGA ATAAAGGTGA AGACAGACTG 420 ACTGCCAGGA CCCAGGAGGA AAACGTTGAT CGTTAGAGAC CTTTGCAGAA GACACCACCA 480 GGAGGAAAAT TAGAGAGGAA AAACACAAAG ACATAATTAT AGGAGATCCC ACAAACCTAG 540 CCCGGGAGAG AGCCTCTCTG TCAAAAATGG ATATGTTTCC TCTTACCTGG GTTTTCTTAG 600 CTCTGTACTT TTCAGGACAC GAAGTGAGAA GCCAGCAAGA TCCACCCTGC GGAGGTCGGC 660 CGAATTCCAA AGATGCTGGC TACATCACTT CCCCAGGCTA CCCCCAGGAC TATCCCTCCC 720 ACCAGAACTG TGAGTGGATT GTCTACGCCC CCGAACCCAA CCAGAAGATT GTTCTCAACT 780 TCAACCCTCA CTTTGAAATC GAGAAACACG ACTGCAAGTA TGACTTCATT GAGATTCGGG 840 ATGGGGACAG TGAGTCAGCT GACCTCCTGG GCAAGCACTG TGGGAACATC GCCCCGCCCA 900 CCATCATCTC CTCAGGCTCC GTGTTATACA TCAAGTTCAC CTCAGACTAC GCCCGGCAGG 960 GGGCAGGTTT CTCTCTACGC TATGAGATCT TCAAAACAGG CTCTGAAGAT TGTTCCAAGA 1020 ACTTTACAAG CCCCAATGGG ACCATTGAAT CTCCAGGGTT TCCAGAGAAG TATCCACACA 1080 ATCTGGACTG TACCTTCACC ATCCTGGCCA AACCCAGGAT GGAGATCATC CTACAGTTCC 1140 TGACCTTTGA CCTGGAGCAT GACCCTCTAC AAGTGGGGGA AGGAGACTGT AAATATGACT 1200 GGCTGGACAT CTGGGATGGC ATTCCACATG TTGGACCTCT GATTGGCAAG TACTGTGGGA 1260 CGAAAACACC CTCCAAACTC CGCTCGTCCA CGGGGATCCT CTCCTTGACC TTTCACACGG 1320 ACATGGCAGT GGCCAAGGAT GGCTTCTCCG CACGTTACTA TTTGATCCAC CAGGAGCCAC 1380 CTGAGAATTT TCAGTGCAAT GTCCCTTTGG GAATGGAGTC TGGCCGGATT GCTAATGAAC 1440 AGATCAGTGC CTCCTCCACC TTCTCTGATG GGAGGTGGAC TCCTCAACAG AGCCGGCTCC 1500 ATGGTGATGA CAATGGCTGG ACACCCAATT TGGATTCCAA CAAGGAGTAT CTCCAGGTGG 1560 ACCTGCGCTT CCTAACCATG CTCACAGCCA TTGCAACACA GGGAGCCATT TCCAGGGAAA 1620 CCCAG.AAAGG CTACTACGTC AAATCGTACA AGCTGGAAGT CAGCACAAAT GGTGAAGATT 1680 GGATGGTCTA CCGGCATGGC AAAAACCACA AGATATTCCA AGCGAACAAT GATGCGACCG 1740 AGGTGGTGCT AAACAAGCTC CACATGCCAC TGCTGACTCG GTTCATCAGG ATCCGCCCGC 1800 AGACGTGGCA TTTGGGCATT GCCCTTCGCC TGGAGCTCTT TGGCTGCCGG GTCACAGATG 1860 CACCCTGCTC CAACATGCTG GGGATGCTCT CGGGCCTCAT TGCTGATACC CAGATCTCTG 1920 CCTCCTCCAC CCGAGAGTAC CTCTGGAGCC CCAGTGCTGC CCGCCTGGTT AGTAGCCGCT 1980 CTGGCTGGTT TCCTCGGAAC CCTCAAGCCC AGCCAGGTGA AGAATGGCTT CAGGTAGACC 2040 TGGGGACACC CAAGACAGTG AAAGGGGTCA TCATCCAGGG AGCCCGAGGA GGAGACAGCA 2100 TCACTGCCGT GGAAGCCAGG GCGTTTGTAC GCAAGTTCAA AGTCTCCTAC AGCCTAAATG 2160 GCAAGGACTG GGAATATATC CAGGACCCCA GGACTCAGCA GACAAAGCTG TTTGAAGGGA 2220 ACATGCACTA TGACACCCCT GACATCCGAA GGTTCGATCC TGTTCCAGCG CAGTATGTGC 2280 GGGTGTACCC AGAGAGGTGG TCGCCAGCAG GCATCGGGAT GAGGCTGGAG GTGCTGGGCT 2340 GTGACTGGAC AGACTCAAAG CCCACAGTGG AGACGCTGGG ACCCACCGTG AAGAGTGAAG 2400 AGACTACCAC CCCATATCCC ATGGATGAGG ATGCCACCGA GTGTGGGGAA AACTGCAGCT 2460 TTGAGGATGA CAAAGATTTG CAACTTCCTT CAGGATTCAA CTGCAACTTT GATTTTCCGG 2520 AAGAGACCTG TGGTTGGGTG TACGACCATG CCAAGTGGCT CCGGAGCACG TGGATCAGCA 2580 GCGCTAACCC CAATGACAGA ACATTTCCAG ATGACAAGAA CTTCTTGAAA CTGCAGAGTG 2640 ATGGCCGACG AGAGGGCCAG TACGGGCGGC TCATCAGCCC ACCGGTGCAC CTGCCCCGAA 2700 GCCCTGTGTG CATGGAGTTC CAGTACCAAG CCATGGGCGG CCACGGGGTG GCACTGCAGG 2760 TGGTTCGGGA AGCCAGCCAG GAAAGCAAAC TCCTTTGGGT CATCCGTGAG GACCAGGGCA 2820 GCGAGTGGAA GCACGGGCGC ATTATCCTGC CCAGCTATGA CATGGAGTAT CAGATCGTGT 2880 TCGAGGGAGT GATAGGGAAG GGACGATCGG GAGAGATTTC CGGCGATGAC ATTCGGATAA 2940 GCACTGATGT CCCACTGGAG AACTGCATGG AACCCATATC AGCTTTTGCA GATGAATATG 3000 AAGGAGATTG GAGCAACTCT TCTTCCTCTA CCTCAGGGGC TGGTGACCCC TCATCTGGCA 3060 AAGAAAAGAG CTGGCTGTAC ACCCTAGATC CCATTCTGAT CACCATCATC GCCATGAGCT 3120 CGCTGGGGGT CCTGCTGGGG GCCACCTGTG CGGGCCTCCT CCTTTACTGC ACCTGCTCCT 3180 ATTCGGGTCT GAGTTCGAGG AGCTGCACCA CACTGGAGAA CTACAACTTT GAGCTCTACG 3240 ATGGCCTCAA GCACAAGGTC AAGATCAATC ATCAGAAGTG CTGCTCGGAG GCATGACCGA 3300 TTGTGTCTGG ATCGCTTCTG GCGTTTCATT CCAGTGAGAG GGGCTAGCGA AGATTACAGT 3360 TTTGTTTTGT TTTGTTTTGT TTTCCCTTTG G.AAACTGAAT GCCATAATCT GGATCAAAGT 3420 GTTCCAGAAT ACTGAAGGTA TGGACAGGAC AGACAGGCCA GTCTAGGGAG AAAGGGAGAT 3480 GCAGCTGTGA AGGGGATCGT TGCCCACCAG GACTGTGGTG GCCAAGTGAA TGCAGGAACC 3540 GGGCCCGGAA TTCCGGCTCT CGGCTAAAAT CTCAGCTGCC TCTGGAAAGG CTCAACCATA 3600 CTCAGTGCCA ACTCAGACTC TGTTGCTGTG GTGTCAACAT GGATGGATCA TCTGTACCTT 3660 GTATTTTTAG CAGAATTCAT GCTCAGATTT CTTTGTTCTG AATCCTTGCT TTGTGCTAGA 3720 CACAAAGCAT ACATGTCCTT CTAAAATTAA TATGATCACT ATAATCTCCT GTGTGCAGAA 3780 TTCAGAAATA GACCTTTGAA ACCATTTGCA TTGTGAGTGC AGATCCATGA CTGGGGCTAG 3840 TGCAGCAATG AAACAGAATT CCAGAAACAG TGTGTTCTTT TTATTATGGG AAAATACAGA 3900 TAAAAATGGC CACTGATGAA CATGAAAGTT AGCACTTTCC CAACACAGTG TACACTTGCA 3960 ACCTTGTTTT GGATTTCTCA TACACCAAGA CTGTGAAACA CAAATTTCAA GAATGTGTTC 4020 AAATGTGTGT GTGTGTGTGT GTGTGTGTGT GTGTGTGTGT GTATGTGTGT GTGTGTGTGT 4080 GTGCTTGTGT GTTTCTGTCA GTGGTATGAG TGATATGTAT GCATGTGTGT ATGTATATGT 4140 ATGTATGTAT GTATGTATGT ACGTACATAT GTATGTATGT ATGTATGTAT GTATGTATGT 4200 ATATGTGTGT GTGTGTTTGT GTGTGTGTGT GTTTGTGTGT GTGTGTGTGG TAAGTGTGGT 4260 ATGTGTGTAT GCATTTGTCT ATATGTGTAT CTGTGTGTCT ATGTGTTTCT GTCAGTGGAA 4320 TGAGTGGCAT GTGTGCATGT GTATGTATGT GGATATGTGT GTTGTGTTTA TGTGCTTGTG 4380 TATAAGAGGT AAGTGTGGTG TGTGTGCATG TGTCTCTGTG TGTGTTTGTC TGTGTACCTC 4440 TTTGTATAAG TACCTGTGTT TGTATGTGGG AATATGTATA TTGAGGCATT GCTGTGTTAG 4500 TATGTTTATA GAAAAGAAGA CAGTCTGAGA TGTCTTCCTC AATACCTCTC CACTTATATC 4560 TTGGATAGAC AAAAGTAATG ACAAAAAATT GCTGGTGTGT ATATGGAAAA GGGGGACACA 4620 TATCCATGGA TGGTAGAAGT GTAAACTGTG CAGTCACTGT GGACATCAAT ATGCAGGTTC 4680 TTCACAAATG TAGATATAAA GCTACTATAG TTATACCC 4718 (2) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 909 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Gly His Glu Val Arg Ser Gin Gin Asp Pro Pro Cys Gly Gly Arg Pro 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Val Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Arg Met Glu He He Leu Gin Phe Leu 180 185 190 Thr Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Lys Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu He His Gin Glu Pro Pro 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Phe Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Lys Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys He Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Met 385 390 395 400 Pro Leu Leu Thr Arg Phe He Arg He Arg Pro Gin Thr Trp His Leu 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Thr 435 440 445 Gin He Ser Ala Ser Ser Thr Arg Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg Asn Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Thr Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro Val Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Glu Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Met Asp Glu Asp Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Pro Glu Glu Thr Cys Gly 645 650 655 Trp Val Tyr Asp His Ala Lys Trp Leu Arg Ser Thr Trp He Ser Ser 660 665 670 Ala Asn Pro Asn Asp Arg Thr Phe Pro Asp Asp Lys Asn Phe Leu Lys 675 680 685 Leu Gin Ser Asp Gly Arg Arg Glu Gly Gin Tyr Gly Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Met Gly Gly His Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Ser 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ser Gly Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Asp Glu Tyr Glu Gly Asp Trp Ser 805 810 815 Asn Ser Ser Ser Ser Thr Ser Gly Ala Gly Asp Pro Ser Ser Gly Lys 820 825 830 Glu Lys Ser Trp Leu Tyr Thr Leu Asp Pro He Leu He Thr He He 835 840 845 Ala Met Ser Ser Leu Gly Val Leu Leu Gly Ala Thr Cys Ala Gly Leu 850 855 860 Leu Leu Tyr Cys Thr Cys Ser Tyr Ser Gly Leu Ser Ser Arg Ser Cys 865 870 875 880 Thr Thr Leu Glu Asn Tyr Asn Phe Glu Leu Tyr Asp Gly Leu Lys His 885 890 895 Lys Val Lys He Asn His Gin Lys Cys Cys Ser Glu Ala 900 905 (2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4733 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: AAACTGGAGC TCCACCGCGG TGGCGGCCGC CCGGGCAGGT CTAGAATTCA GCGGCCGCTG 60 AATTCTATCC AGCGGTCGGT GCCTCTGCCC GCGTGTGTGT CCCGGGTGCC GGGGGACCTG 120 TGTCAGTTAG CGCTTCTGAG ATCACACAGC TGCCTAGGGG CCGTGTGATG CCCAGGGCAA 180 TTCTTGGCTT TGATTTTTAT TATTATTACT ATTATTTTGC GTTCAGCTTT CGGGAAACCC 240 TCGTGATGTT GTAGGATAAA GGAAATGACA CTTTGAGGAA CTGGAGAGAA CATACACGCG 300 TTTGGGTTTG AAGAGGAAAC CGGTCTCCGC TTCCTTAGCT TGCTCCCTCT TTGCTGATTT 360 CAAGAGCTAT CTCCTATGAG GTGGAGATAT TCCAGCAAGA ATAAAGGTGA AGACAGACTG 420 ACTGCCAGGA CCCAGGAGGA AAACGTTGAT CGTTAGAGAC CTTTGCAGAA GACACCACCA 480 GGAGGAAAAT TAGAGAGGAA AAACACAAAG ACATAATTAT AGGAGATCCC ACAAACCTAG 540 CCCGGGAGAG AGCCTCTCTG TCAAAAATGG ATATGTTTCC TCTTACCTGG GTTTTCTTAG 600 CTCTGTACTT TTCAGGACAC GAAGTGAGAA GCCAGCAAGA TCCACCCTGC GGAGGTCGGC 660 CGAATTCCAA AGATGCTGGC TACATCACTT CCCCAGGCTA CCCCCAGGAC TATCCCTCCC 720 ACCAGAACTG TGAGTGGATT GTCTACGCCC CCGAACCCAA CCAGAAGATT GTTCTCAACT 780 TCAACCCTCA CTTTGAAATC GAGAAACACG ACTGCAAGTA TGACTTCATT GAGATTCGGG 840 ATGGGGACAG TGAGTCAGCT GACCTCCTGG GCAAGCACTG TGGGAACATC GCCCCGCCCA 900 CCATCATCTC CTCAGGCTCC GTGTTATACA TCAAGTTCAC CTCAGACTAC GCCCGGCAGG 960 GGGCAGGTTT CTCTCTACGC TATGAGATCT TCAAAACAGG CTCTGAAGAT TGTTCCAAGA 1020 ACTTTACAAG CCCCAATGGG ACCATTGAAT CTCCAGGGTT TCCAGAGAAG TATCCACACA 1080 ATCTGGACTG TACCTTCACC ATCCTGGCCA AACCCAGGAT GGAGATCATC CTACAGTTCC 1140 TGACCTTTGA CCTGGAGCAT GACCCTCTAC AAGTGGGGGA AGGAGACTGT AAATATGACT 1200 GGCTGGACAT CTGGGATGGC ATTCCACATG TTGGACCTCT GATTGGCAAG TACTGTGGGA 1260 CGAAAACACC CTCCAAACTC CGCTCGTCCA CGGGGATCCT CTCCTTGACC TTTCACACGG 1320 ACATGGCAGT GGCCAAGGAT GGCTTCTCCG CACGTTACTA TTTGATCCAC CAGGAGCCAC 1380 CTGAGAATTT TCAGTGCAAT GTCCCTTTGG GAATGGAGTC TGGCCGGATT GCTAATGAAC 1440 AGATCAGTGC CTCCTCCACC TTCTCTGATG GGAGGTGGAC TCCTCAACAG AGCCGGCTCC 1500 ATGGTGATGA CAATGGCTGG ACACCCAATT TGGATTCCAA CAAGGAGTAT CTCCAGGTGG 1560 ACCTGCGCTT CCTAACCATG CTCACAGCCA TTGCAACACA GGGAGCCATT TCCAGGGAAA 1620 CCCAGAAAGG CTACTACGTC AAATCGTACA AGCTGGAAGT CAGCACAAAT GGTGAAGATT 1680 GGATGGTCTA CCGGCATGGC AAAAACCACA AGATATTCCA AGCGAACAAT GATGCGACCG 1740 AGGTGGTGCT AAACAAGCTC CACATGCCAC TGCTGACTCG GTTCATCAGG ATCCGCCCGC 1800 AGACGTGGCA TTTGGGCATT GCCCTTCGCC TGGAGCTCTT TGGCTGCCGG GTCACAGATG 1860 CACCCTGCTC CAACATGCTG GGGATGCTCT CGGGCCTCAT TGCTGATACC CAGATCTCTG 1920 CCTCCTCCAC CCGAGAGTAC CTCTGGAGCC CCAGTGCTGC CCGCCTGGTT AGTAGCCGCT 1980 CTGGCTGGTT TCCTCGGAAC CCTCAAGCCC AGCCAGGTGA AGAATGGCTT CAGGTAGACC 2040 TGGGGACACC CAAGACAGTG AAAGGGGTCA TCATCCAGGG AGCCCGAGGA GGAGACAGCA 2100 TCACTGCCGT GGAAGCCAGG GCGTTTGTAC GCAAGTTCAA AGTCTCCTAC AGCCTAAATG 2160 GCAAGGACTG GGAATATATC CAGGACCCCA GGACTCAGCA GACAAAGCTG TTTGAAGGGA 2220 ACATGCACTA TGACACCCCT GACATCCGAA GGTTCGATCC TGTTCCAGCG CAGTATGTGC 2280 GGGTGTACCC AGAGAGGTGG TCGCCAGCAG GCATCGGGAT GAGGCTGGAG GTGCTGGGCT 2340 GTGACTGGAC AGACTCAAAG CCCACAGTGG AGACGCTGGG ACCCACCGTG AAGAGTGAAG 2400 AGACTACCAC CCCATATCCC ATGGATGAGG ATGCCACCGA GTGTGGGGAA AACTGCAGCT 2460 TTGAGGATGA CAAAGATTTG CAACTTCCTT CAGGATTCAA CTGCAACTTT GATTTTCCGG 2520 AAGAGACCTG TGGTTGGGTG TACGACCATG CCAAGTGGCT CCGGAGCACG TGGATCAGCA 2580 GCGCTAACCC CAATGACAGA ACATTTCCAG ATGACAAGAA CTTCTTGAAA CTGCAGAGTG 2640 ATGGCCGACG AGAGGGCCAG TACGGGCGGC TCATCAGCCC ACCGGTGCAC CTGCCCCGAA 2700 GCCCTGTGTG CATGGAGTTC CAGTACCAAG CCATGGGCGG CCACGGGGTG GCACTGCAGG 2760 TGGTTCGGGA AGCCAGCCAG GAAAGCAAAC TCCTTTGGGT CATCCGTGAG GACCAGGGCA 2820 GCGAGTGGAA GCACGGGCGC ATTATCCTGC CCAGCTATGA CATGGAGTAT CAGATCGTGT 2880 TCGAGGGAGT GATAGGGAAG GGACGATCGG GAGAGATTTC CGGCGATGAC ATTCGGATAA 2940 GCACTGATGT CCCACTGGAG AACTGCATGG AACCCATATC AGCTTTTGCA GGTGAGGATT 3000 TTAAAGATGA ATATGAAGGA GATTGGAGCA ACTCTTCTTC CTCTACCTCA GGGGCTGGTG 3060 ACCCCTCATC TGGCAAAGAA AAGAGCTGGC TGTACACCCT AGATCCCATT CTGATCACCA 3120 TCATCGCCAT GAGCTCGCTG GGGGTCCTGC TGGGGGCCAC CTGTGCGGGC CTCCTCCTTT 3180 ACTGCACCTG CTCCTATTCG GGTCTGAGTT CGAGGAGCTG CACCACACTG GAGAACTACA 3240 ACTTTGAGCT CTACGATGGC CTCAAGCACA AGGTCAAGAT CAATCATCAG AAGTGCTGCT 3300 CGGAGGCATG ACCGATTGTG TCTGGATCGC TTCTGGCGTT TCATTCCAGT GAGAGGGGCT 3360 AGCGAAGATT ACAGTTTTGT TTTGTTTTGT TTTGTTTTCC CTTTGGAAAC TGAATGCCAT 3420 AATCTGGATC AAAGTGTTCC AGAATACTGA AGGTATGGAC AGGACAGACA GGCCAGTCTA 3480 GGGAGAAAGG GAGATGCAGC TGTGAAGGGG ATCGTTGCCC ACCAGGACTG TGGTGGCCAA 3540 GTGAATGCAG GAACCGGGCC CGGAATTCCG GCTCTCGGCT AAAATCTCAG CTGCCTCTGG 3600 AAAGGCTCAA CCATACTCAG TGCCAACTCA GACTCTGTTG CTGTGGTGTC AACATGGATG 3660 GATCATCTGT ACCTTGTATT TTTAGCAGAA TTCATGCTCA GATTTCTTTG TTCTGAATCC 3720 TTGCTTTGTG CTAGACACAA AGCATACATG TCCTTCTAAA ATTAATATGA TCACTATAAT 3780 CTCCTGTGTG CAGAATTCAG AAATAGACCT TTGAAACCAT TTGCATTGTG AGTGCAGATC 3840 CATGACTGGG GCTAGTGCAG CAATGAAACA GAATTCCAGA AACAGTGTGT TCTTTTTATT 3900 ATGGGAAAAT ACAGATAAAA ATGGCCACTG ATGAACATGA AAGTTAGCAC TTTCCCAACA 3960 CAGTGTACAC TTGCAACCTT GTTTTGGATT TCTCATACAC CAAGACTGTG AAACACAAAT 4020 TTCAAGAATG TGTTCAAATG TGTGTGTGTG TGTGTGTGTG TGTGTGTGTG TGTGTGTATG 4080 TGTGTGTGTG TGTGTGTGCT TGTGTGTTTC TGTCAGTGGT ATGAGTGATA TGTATGCATG 4140 TGTGTATGTA TATGTATGTA TGTATGTATG TATGTACGTA CATATGTATG TATGTATGTA 4200 TGTATGTATG TATGTATATG TGTGTGTGTG TTTGTGTGTG TGTGTGTTTG TGTGTGTGTG 4260 TOTGGTAAGT GTGGTATGTG TGTATGCATT TGTCTATATG TGTATCTGTG TGTCTATGTG 4320 TTTCTGTCAG TGGAATGAGT GGCATGTGTG CATGTGTATG TATGTGGATA TGTGTGTTGT 4380 GTTTATGTGC TTGTGTATAA GAGGTAAGTG TGGTGTGTGT GCATGTGTCT CTGTGTGTGT 4440 TTGTCTGTGT ACCTCTTTGT ATAAGTACCT GTGTTTGTAT GTGGGAATAT GTATATTGAG 4500 GCATTGCTGT GTTAGTATGT TTATAGAAAA GAAGACAGTC TGAGATGTCT TCCTCAATAC 4560 CTCTCCACTT ATATCTTGGA TAGACAAAAG TAATGACAAA AAATTGCTGG TGTGTATATG 4620 GAAAAGGGGG ACACATATCC ATGGATGGTA GAAGTGTAAA CTGTGCAGTC ACTGTGGACA 4680 TCAATATGCA GGTTCTTCAC AAATGTAGAT ATAAAGCTAC TATAGTTATA CCC 4733 (2) INFORMATION FOR SEQ ID NO : 12 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 914 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO : 12 : Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Gly His Glu Val Arg Ser Gin Gin Asp Pro Pro Cys Gly Gly Arg Pro 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Val Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Arg Met Glu He He Leu Gin Phe Leu 180 185 190 Thr Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Lys Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu He His Gin Glu Pro Pro 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Phe Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Lys Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys He Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Met 385 390 395 400 Pro Leu Leu Thr Arg Phe He Arg He Arg Pro Gin Thr Trp His Leu 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Thr 435 440 445 Gin He Ser Ala Ser Ser Thr Arg Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg Asn Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Thr Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro Val Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Glu Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Met Asp Glu Asp Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Pro Glu Glu Thr Cys Gly 645 650 655 Trp Val Tyr Asp His Ala Lys Trp Leu Arg Ser Thr Trp He Ser Ser 660 665 670 Ala Asn Pro Asn Asp Arg Thr Phe Pro Asp Asp Lys Asn Phe Leu Lys 675 680 685 Leu Gin Ser Asp Gly Arg Arg Glu Gly Gin Tyr Gly Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Met Gly Gly His Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Ser 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ser Gly Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Gly Glu Asp Phe Lys Asp Glu Tyr 805 810 815 Glu Gly Asp Trp Ser Asn Ser Ser Ser Ser Thr Ser Gly Ala Gly Asp 820 825 830 Pro Ser Ser Gly Lys Glu Lys Ser Trp Leu Tyr Thr Leu Asp Pro He 835 840 845 Leu He Thr He He Ala Met Ser Ser Leu Gly Val Leu Leu Gly Ala 850 855 860 Thr Cys Ala Gly Leu Leu Leu Tyr Cys Thr Cys Ser Tyr Ser Gly Leu 865 870 875 880 Ser Ser Arg Ser Cys Thr Thr Leu Glu Asn Tyr Asn Phe Glu Leu Tyr 885 890 895 Asp Gly Leu Lys His Lys Val Lys He Asn His Gin Lys Cys Cys Ser 900 905 910 Glu Ala (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4769 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: AAACTGGAGC TCCACCGCGG TGGCGGCCGC CCGGGCAGGT CTAGAATTCA GCGGCCGCTG 60 AATTCTATCC AGCGGTCGGT GCCTCTGCCC GCGTGTGTGT CCCGGGTGCC GGGGGACCTG 120 TGTCAGTTAG CGCTTCTGAG ATCACACAGC TGCCTAGGGG CCGTGTGATG CCCAGGGCAA 180 TTCTTGGCTT TGATTTTTAT TATTATTACT ATTATTTTGC GTTCAGCTTT CGGGAAACCC 240 TCGTGATGTT GTAGGATAAA GGAAATGACA CTTTGAGGAA CTGGAGAGAA CATACACGCG 300 TTTGGGTTTG AAGAGGAAAC CGGTCTCCGC TTCCTTAGCT TGCTCCCTCT TTGCTGATTT 360 CAAGAGCTAT CTCCTATGAG GTGGAGATAT TCCAGCAAGA ATAAAGGTGA AGACAGACTG 420 ACTGCCAGGA CCCAGGAGGA AAACGTTGAT CGTTAGAGAC CTTTGCAGAA GACACCACCA 480 GGAGGAAAAT TAGAGAGGAA AAACACAAAG ACATAATTAT AGGAGATCCC ACAAACCTAG 540 CCCGGGAGAG AGCCTCTCTG TCAAAAATGG ATATGTTTCC TCTTACCTGG GTTTTCTTAG 600 CTCTGTACTT TTCAGGACAC GAAGTGAGAA GCCAGCAAGA TCCACCCTGC GGAGGTCGGC 660 CGAATTCCAA AGATGCTGGC TACATCACTT CCCCAGGCTA CCCCCAGGAC TATCCCTCCC 720 ACCAGAACTG TGAGTGGATT GTCTACGCCC CCGAACCCAA CCAGAAGATT GTTCTCAACT 780 TCAACCCTCA CTTTGAAATC GAGAAACACG ACTGCAAGTA TGACTTCATT GAGATTCGGG 840 ATGGGGACAG TGAGTCAGCT GACCTCCTGG GCAAGCACTG TGGGAACATC GCCCCGCCCA 900 CCATCATCTC CTCAGGCTCC GTGTTATACA TCAAGTTCAC CTCAGACTAC GCCCGGCAGG 960 GGGCAGGTTT CTCTCTACGC TATGAGATCT TCAAAACAGG CTCTGAAGAT TGTTCCAAGA 1020 ACTTTACAAG CCCCAATGGG ACCATTGAAT CTCCAGGGTT TCCAGAGAAG TATCCACACA 1080 ATCTGGACTG TACCTTCACC ATCCTGGCCA AACCCAGGAT GGAGATCATC CTACAGTTCC 1140 TGACCTTTGA CCTGGAGCAT GACCCTCTAC AAGTGGGGGA AGGAGACTGT AAATATGACT 1200 GGCTGGACAT CTGGGATGGC ATTCCACATG TTGGACCTCT GATTGGCAAG TACTGTGGGA 1260 CGAAAACACC CTCCAAACTC CGCTCGTCCA CGGGGATCCT CTCCTTGACC TTTCACACGG 1320 ACATGGCAGT GGCCAAGGAT GGCTTCTCCG CACGTTACTA TTTGATCCAC CAGGAGCCAC 1380 CTGAGAATTT TCAGTGCAAT GTCCCTTTGG GAATGGAGTC TGGCCGGATT GCTAATGAAC 1440 AGATCAGTGC CTCCTCCACC TTCTCTGATG GGAGGTGGAC TCCTCAACAG AGCCGGCTCC 1500 ATGGTGATGA CAATGGCTGG ACACCCAATT TGGATTCCAA CAAGGAGTAT CTCCAGGTGG 1560 ACCTGCGCTT CCTAACCATG CTCACAGCCA TTGCAACACA GGGAGCCATT TCCAGGGAAA 1620 CCCAGAAAGG CTACTACGTC AAATCGTACA AGCTGGAAGT CAGCACAAAT GGTGAAGATT 1680 GGATGGTCTA CCGGCATGGC AAAAACCACA AGATATTCCA AGCGAACAAT GATGCGACCG 1740 AGGTGGTGCT AAACAAGCTC CACATGCCAC TGCTGACTCG GTTCATCAGG ATCCGCCCGC 1800 AGACGTGGCA TTTGGGCATT GCCCTTCGCC TGGAGCTCTT TGGCTGCCGG GTCACAGATG 1860 CACCCTGCTC CAACATGCTG GGGATGCTCT CGGGCCTCAT TGCTGATACC CAGATCTCTG 1920 CCTCCTCCAC CCGAGAGTAC CTCTGGAGCC CCAGTGCTGC CCGCCTGGTT AGTAGCCGCT 1980 CTGGCTGGTT TCCTCGGAAC CCTCAAGCCC AGCCAGGTGA AGAATGGCTT CAGGTAGACC 2040 TGGGGACACC CAAGACAGTG AAAGGGGTCA TCATCCAGGG AGCCCGAGGA GGAGACAGCA 2100 TCACTGCCGT GGAAGCCAGG GCGTTTGTAC GCAAGTTCAA AGTCTCCTAC AGCCTAAATG 2160 GCAAGGACTG GGAATATATC CAGGACCCCA GGACTCAGCA GACAAAGCTG TTTGAAGGGA 2220 ACATGCACTA TGACACCCCT GACATCCGAA GGTTCGATCC TGTTCCAGCG CAGTATGTGC 2280 GGGTGTACCC AGAGAGGTGG TCGCCAGCAG GCATCGGGAT GAGGCTGGAG GTGCTGGGCT 2340 GTGACTGGAC AGACTCAAAG CCCACAGTGG AGACGCTGGG ACCCACCGTG AAGAGTGAAG 2400 AGACTACCAC CCCATATCCC ATGGATGAGG ATGCCACCGA GTGTGGGGAA AACTGCAGCT 2460 TTGAGGATGA CAAAGATTTG CAACTTCCTT CAGGATTCAA CTGCAACTTT GATTTTCCGG 2520 AAGAGACCTG TGGTTGGGTG TACGACCATG CCAAGTGGCT CCGGAGCACG TGGATCAGCA 2580 GCGCTAACCC CAATGACAGA ACATTTCCAG ATGACAAGAA CTTCTTGAAA CTGCAGAGTG 2640 ATGGCCGACG AGAGGGCCAG TACGGGCGGC TCATCAGCCC ACCGGTGCAC CTGCCCCGAA 2700 GCCCTGTGTG CATGGAGTTC CAGTACCAAG CCATGGGCGG CCACGGGGTG GCACTGCAGG 2760 TGGTTCGGGA AGCCAGCCAG GAAAGCAAAC TCCTTTGGGT CATCCGTGAG GACCAGGGCA 2820 GCGAGTGGAA GCACGGGCGC ATTATCCTGC CCAGCTATGA CATGGAGTAT CAGATCGTGT 2880 TCGAGGGAGT GATAGGGAAG GGACGATCGG GAGAGATTTC CGGCGATGAC ATTCGGATAA 2940 GCACTGATGT CCCACTGGAG AACTGCATGG AACCCATATC AGCTTTTGCA GTGGACATCC 3000 CAGAAACCCA TGGGGGAGAG GGCTATGAAG ATGAGATTGA TGATGAATAT GAAGGAGATT 3060 GGAGCAACTC TTCTTCCTCT ACCTCAGGGG CTGGTGACCC CTCATCTGGC AAAGAAAAGA 3120 GCTGGCTGTA CACCCTAGAT CCCATTCTGA TCACCATCAT CGCCATGAGC TCGCTGGGGG 3180 TCCTGCTGGG GGCCACCTGT GCGGGCCTCC TCCTTTACTG CACCTGCTCC TATTCGGGTC 3240 TGAGTTCGAG GAGCTGCACC ACACTGGAGA ACTACAACTT TGAGCTCTAC GATGGCCTCA 3300 AGCACAAGGT CAAGATCAAT CATCAGAAGT GCTGCTCGGA GGCATGACCG ATTGTGTCTG 3360 GATCGCTTCT GGCGTTTCAT TCCAGTGAGA GGGGCTAGCG AAGATTACAG TTTTGTTTTG 3420 TTTTGTTTTG TTTTCCCTTT GGAAACTGAA TGCCATAATC TGGATCAAAG TGTTCCAGAA 3480 TACTGAAGGT ATGGACAGGA CAGACAGGCC AGTCTAGGGA GAAAGGGAGA TGCAGCTGTG 3540 AAGGGGATCG TTGCCCACCA GGACTGTGGT GGCCAAGTGA ATGCAGGAAC CGGGCCCGGA 3600 ATTCCGGCTC TCGGCTAAAA TCTCAGCTGC CTCTGGAAAG GCTCAACCAT ACTCAGTGCC 3660 AACTCAGACT CTGTTGCTGT GGTGTCAACA TGGATGGATC ATCTGTACCT TGTATTTTTA 3720 GCAGAATTCA TGCTCAGATT TCTTTGTTCT GAATCCTTGC TTTGTGCTAG ACACAAAGCA 3780 TACATGTCCT TCTAAAATTA ATATGATCAC TATAATCTCC TGTGTGCAGA ATTCAGAAAT 3840 AGACCTTTGA AACCATTTGC ATTGTGAGTG CAGATCCATG ACTGGGGCTA GTGCAGCAAT 3900 GAAACAGAAT TCCAGAAACA GTGTGTTCTT TTTATTATGG GAAAATACAG ATAAAAATGG 3960 CCACTGATGA ACATGAAAGT TAGCACTTTC CCAACACAGT GTACACTTGC AACCTTGTTT 4020 TGGATTTCTC ATACACCAAG ACTGTGAAAC ACAAATTTCA AGAATGTGTT CAAATGTGTG 4080 TGTGTGTGTG TGTGTGTGTG TGTGTGTGTG TGTATGTGTG TGTGTGTGTG TGTGCTTGTG 4140 TGTTTCTGTC AGTGGTATGA GTGATATGTA TGCATGTGTG TATGTATATG TATGTATGTA 4200 TGTATGTATG TACGTACATA TGTATGTATG TATGTATGTA TGTATGTATG TATATGTGTG 4260 TGTGTGTTTG TGTGTGTGTG TGTTTGTGTG TGTGTGTGTG GTAAGTGTGG TATGTGTGTA 4320 TGCATTTGTC TATATGTGTA TCTGTGTGTC TATGTGTTTC TGTCAGTGGA ATGAGTGGCA 4380 TGTGTGCATG TGTATGTATG TGGATATGTG TGTTGTGTTT ATGTGCTTGT GTATAAGAGG 4440 TAAGTGTGGT GTGTGTGCAT GTGTCTCTGT GTGTGTTTGT CTGTGTACCT CTTTGTATAA 4500 GTACCTGTGT TTGTATGTGG GAATATGTAT ATTGAGGCAT TGCTGTGTTA GTATGTTTAT 4560 AGAAAAGAAG ACAGTCTGAG ATGTCTTCCT CAATACCTCT CCACTTATAT CTTGGATAGA 4620 CAAAAGTAAT GACAAAAAAT TGCTGGTGTG TATATGGAAA AGGGGGACAC ATATCCATGG 4680 ATGGTAGAAG TGTAAACTGT GCAGTCACTG TGGACATCAA TATGCAGGTT CTTCACAAAT 4740 GTAGATATAA AGCTACTATA GTTATACCC 4769 (2) INFORMATION FOR SEQ ID NO : 14 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 926 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Gly His Glu Val Arg Ser Gin Gin Asp Pro Pro Cys Gly Gly Arg Pro 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Val Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Arg Met Glu He He Leu Gin Phe Leu 180 185 190 Thr Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Lys Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu He His Gin Glu Pro Pro 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Phe Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Lys Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys He Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Met 385 390 395 400 Pro Leu Leu Thr Arg Phe He Arg He Arg Pro Gin Thr Trp His Leu 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Thr 435 440 445 Gin He Ser Ala Ser Ser Thr Arg Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg Asn Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Thr Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro Val Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Glu Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Met Asp Glu Asp Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Pro Glu Glu Thr Cys Gly 645 650 655 Trp Val Tyr Asp His Ala Lys Trp Leu Arg Ser Thr Trp He Ser Ser 660 665 670 Ala Asn Pro Asn Asp Arg Thr Phe Pro Asp Asp Lys Asn Phe Leu Lys 675 680 685 Leu Gin Ser Asp Gly Arg Arg Glu Gly Gin Tyr Gly Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Met Gly Gly His Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Ser 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ser Gly Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Val Asp He Pro Glu Thr His Gly 805 810 815 Gly Glu Gly Tyr Glu Asp Glu He Asp Asp Glu Tyr Glu Gly Asp Trp 820 825 830 Ser Asn Ser Ser Ser Ser Thr Ser Gly Ala Gly Asp Pro Ser Ser Gly 835 840 845 Lys Glu Lys Ser Trp Leu Tyr Thr Leu Asp Pro He Leu He Thr He 850 855 860 He Ala Met Ser Ser Leu Gly Val Leu Leu Gly Ala Thr Cys Ala Gly 865 870 875 880 Leu Leu Leu Tyr Cys Thr Cys Ser Tyr Ser Gly Leu Ser Ser Arg Ser 885 890 895 Cys Thr Thr Leu Glu Asn Tyr Asn Phe Glu Leu Tyr Asp Gly Leu Lys 900 905 910 His Lys Val Lys He Asn His Gin Lys Cys Cys Ser Glu Ala 915 920 925 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4784 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: AAACTGGAGC TCCACCGCGG TGGCGGCCGC CCGGGCAGGT CTAGAATTCA GCGGCCGCTG 60 AATTCTATCC AGCGGTCGGT GCCTCTGCCC GCGTGTGTGT CCCGGGTGCC GGGGGACCTG 120 TGTCAGTTAG CGCTTCTGAG ATCACACAGC TGCCTAGGGG CCGTGTGATG CCCAGGGCAA 180 TTCTTGGCTT TGATTTTTAT TATTATTACT ATTATTTTGC GTTCAGCTTT CGGGAAACCC 240 TCGTGATGTT GTAGGATAAA GGAAATGACA CTTTGAGGAA CTGGAGAGAA CATACACGCG 300 TTTGGGTTTG AAGAGGAAAC CGGTCTCCGC TTCCTTAGCT TGCTCCCTCT TTGCTGATTT 360 CAAGAGCTAT CTCCTATGAG GTGGAGATAT TCCAGCAAGA ATAAAGGTGA AGACAGACTG 420 ACTGCCAGGA CCCAGGAGGA AAACGTTGAT CGTTAGAGAC CTTTGCAGAA GACACCACCA 480 GGAGGAAAAT TAGAGAGGAA AAACACAAAG ACATAATTAT AGGAGATCCC ACAAACCTAG 540 CCCGGGAGAG AGCCTCTCTG TCAAAAATGG ATATGTTTCC TCTTACCTGG GTTTTCTTAG 600 CTCTGTACTT TTCAGGACAC GAAGTGAGAA GCCAGCAAGA TCCACCCTGC GGAGGTCGGC 660 CGAATTCCAA AGATGCTGGC TACATCACTT CCCCAGGCTA CCCCCAGGAC TATCCCTCCC 720 ACCAGAACTG TGAGTGGATT GTCTACGCCC CCGAACCCAA CCAGAAGATT GTTCTCAACT 780 TCAACCCTCA CTTTGAAATC GAGJ&AACACG ACTGCAAGTA TGACTTCATT GAGATTCGGG 840 ATGGGGACAG TGAGTCAGCT GACCTCCTGG GCAAGCACTG TGGGAACATC GCCCCGCCCA 900 CCATCATCTC CTCAGGCTCC GTGTTATACA TCAAGTTCAC CTCAGACTAC GCCCGGCAGG 960 GGGCAGGTTT CTCTCTACGC TATGAGATCT TCAAAACAGG CTCTGAAGAT TGTTCCAAGA 1020 ACTTTACAAG CCCCAATGGG ACCATTGAAT CTCCAGGGTT TCCAGAGAAG TATCCACACA 1080 ATCTGGACTG TACCTTCACC ATCCTGGCCA AACCCAGGAT GGAGATCATC CTACAGTTCC 1140 TGACCTTTGA CCTGGAGCAT GACCCTCTAC AAGTGGGGGA AGGAGACTGT AAATATGACT 1200 GGCTGGACAT CTGGGATGGC ATTCCACATG TTGGACCTCT GATTGGCAAG TACTGTGGGA 1260 CGAAAACACC CTCCAAACTC CGCTCGTCCA CGGGGATCCT CTCCTTGACC TTTCACACGG 1320 ACATGGCAGT GGCCAAGGAT GGCTTCTCCG CACGTTACTA TTTGATCCAC CAGGAGCCAC 1380 CTGAGAATTT TCAGTGCAAT GTCCCTTTGG GAATGGAGTC TGGCCGGATT GCTAATGAAC 1440 AGATCAGTGC CTCCTCCACC TTCTCTGATG GGAGGTGGAC TCCTCAACAG AGCCGGCTCC 1500 ATGGTGATGA CAATGGCTGG ACACCCAATT TGGATTCCAA CAAGGAGTAT CTCCAGGTGG 1560 ACCTGCGCTT CCTAACCATG CTCACAGCCA TTGCAACACA GGGAGCCATT TCCAGGGAAA 1620 CCCAGAAAGG CTACTACGTC AAATCGTACA AGCTGGAAGT CAGCACAAAT GGTGAAGATT 1680 GGATGGTCTA CCGGCATGGC AAAAACCACA AGATATTCCA AGCGAACAAT GATGCGACCG 1740 AGGTGGTGCT AAACAAGCTC CACATGCCAC TGCTGACTCG GTTCATCAGG ATCCGCCCGC 1800 AGACGTGGCA TTTGGGCATT GCCCTTCGCC TGGAGCTCTT TGGCTGCCGG GTCACAGATG 1860 CACCCTGCTC CAACATGCTG GGGATGCTCT CGGGCCTCAT TGCTGATACC CAGATCTCTG 1920 CCTCCTCCAC CCGAGAGTAC CTCTGGAGCC CCAGTGCTGC CCGCCTGGTT AGTAGCCGCT 1980 CTGGCTGGTT TCCTCGGAAC CCTCAAGCCC AGCCAGGTGA AGAATGGCTT CAGGTAGACC 2040 TGGGGACACC CAAGACAGTG AAAGGGGTCA TCATCCAGGG AGCCCGAGGA GGAGACAGCA 2100 TCACTGCCGT GGAAGCCAGG GCGTTTGTAC GCAAGTTCAA AGTCTCCTAC AGCCTAAATG 2160 GCAAGGACTG GGAATATATC CAGGACCCCA GGACTCAGCA GACAAAGCTG TTTGAAGGGA 2220 ACATGCACTA TGACACCCCT GACATCCGAA GGTTCGATCC TGTTCCAGCG CAGTATGTGC 2280 GGGTGTACCC AGAGAGGTGG TCGCCAGCAG GCATCGGGAT GAGGCTGGAG GTGCTGGGCT 2340 GTGACTGGAC AGACTCAAAG CCCACAGTGG AGACGCTGGG ACCCACCGTG AAGAGTGAAG 2400 AGACTACCAC CCCATATCCC ATGGATGAGG ATGCCACCGA GTGTGGGGAA AACTGCAGCT 2460 TTGAGGATGA CAAAGATTTG CAACTTCCTT CAGGATTCAA CTGCAACTTT GATTTTCCGG 2520 AAGAGACCTG TGGTTGGGTG TACGACCATG CCAAGTGGCT CCGGAGCACG TGGATCAGCA 2580 GCGCTAACCC CAATGACAGA ACATTTCCAG ATGACAAGAA CTTCTTGAAA CTGCAGAGTG 2640 ATGGCCGACG AGAGGGCCAG TACGGGCGGC TCATCAGCCC ACCGGTGCAC CTGCCCCGAA 2700 GCCCTGTGTG CATGGAGTTC CAGTACCAAG CCATGGGCGG CCACGGGGTG GCACTGCAGG 2760 TGGTTCGGGA AGCCAGCCAG GAAAGCAAAC TCCTTTGGGT CATCCGTGAG GACCAGGGCA 2820 GCGAGTGGAA GCACGGGCGC ATTATCCTGC CCAGCTATGA CATGGAGTAT CAGATCGTGT 2880 TCGAGGGAGT GATAGGGAAG GGACGATCGG GAGAGATTTC CGGCGATGAC ATTCGGATAA 2940 GCACTGATGT CCCACTGGAG AACTGCATGG AACCCATATC AGCTTTTGCA GGTGAGGATT 3000 TTAAAGTGGA CATCCCAGAA ACCCATGGGG GAGAGGGCTA TGAAGATGAG ATTGATGATG 3060 AATATGAAGG AGATTGGAGC AACTCTTCTT CCTCTACCTC AGGGGCTGGT GACCCCTCAT 3120 CTGGCAAAGA AAAGAGCTGG CTGTACACCC TAGATCCCAT TCTGATCACC ATCATCGCCA 3180 TGAGCTCGCT GGGGGTCCTG CTGGGGGCCA CCTGTGCGGG CCTCCTCCTT TACTGCACCT 3240 GCTCCTATTC GGGTCTGAGT TCGAGGAGCT GCACCACACT GGAGAACTAC AACTTTGAGC 3300 TCTACGATGG CCTCAAGCAC AAGGTCAAGA TCAATCATCA GAAGTGCTGC TCGGAGGCAT 3360 GACCGATTGT GTCTGGATCG CTTCTGGCGT TTCATTCCAG TGAGAGGGGC TAGCGAAGAT 3420 TACAGTTTTG TTTTGTTTTG TTTTGTTTTC CCTTTGGAAA CTGAATGCCA TAATCTGGAT 3480 CAAAGTGTTC CAGAATACTG AAGGTATGGA CAGGACAGAC AGGCCAGTCT AGGGAGAAAG 3540 GGAGATGCAG CTGTGAAGGG GATCGTTGCC CACCAGGACT GTGGTGGCCA AGTGAATGCA 3600 GGAACCGGGC CCGGAATTCC GGCTCTCGGC TAAAATCTCA GCTGCCTCTG GAAAGGCTCA 3660 ACCATACTCA GTGCCAACTC AGACTCTGTT GCTGTGGTGT CAACATGGAT GGATCATCTG 3720 TACCTTGTAT TTTTAGCAGA ATTCATGCTC AGATTTCTTT GTTCTGAATC CTTGCTTTGT 3780 GCTAGACACA AAGCATACAT GTCCTTCTAA AATTAATATG ATCACTATAA TCTCCTGTGT 3840 GCAGAATTCA GAAATAGACC TTTGAAACCA TTTGCATTGT GAGTGCAGAT CCATGACTGG 3900 GGCTAGTGCA GCAATGAAAC AGAATTCCAG AAACAGTGTG TTCTTTTTAT TATGGGAAAA 3960 TACAGATAAA AATGGCCACT GATGAACATG AAAGTTAGCA CTTTCCCAAC ACAGTGTACA 4020 CTTGCAACCT TGTTTTGGAT TTCTCATACA CCAAGACTGT GAAACACAAA TTTCAAGAAT 4080 GTGTTCAAAT GTGTGTGTGT GTGTGTGTGT GTGTGTGTGT GTGTGTGTAT GTGTGTGTGT 4140 GTGTGTGTGC TTGTGTGTTT CTGTCAGTGG TATGAGTGAT ATGTATGCAT GTGTGTATGT 4200 ATATGTATGT ATGTATGTAT GTATGTACGT ACATATGTAT GTATGTATGT ATGTATGTAT 4260 GTATGTATAT GTGTGTGTGT GTTTGTGTGT GTGTGTGTTT GTGTGTGTGT GTGTGGTAAG 4320 TGTGGTATGT GTGTATGCAT TTGTCTATAT GTGTATCTGT GTGTCTATGT GTTTCTGTCA 4380 GTGGAATGAG TGGCATGTGT GCATGTGTAT GTATGTGGAT ATGTGTGTTG TGTTTATGTG 4440 CTTGTGTATA AGAGGTAAGT GTGGTGTGTG TGCATGTGTC TCTGTGTGTG TTTGTCTGTG 4500 TACCTCTTTG TATAAGTACC TGTGTTTGTA TGTGGGAATA TGTATATTGA GGCATTGCTG 4560 TGTTAGTATG TTTATAGAAA AGAAGACAGT CTGAGATGTC TTCCTCAATA CCTCTCCACT 4620 TATATCTTGG ATAGACAAAA GTAATGACAA AAAATTGCTG GTGTGTATAT GGAAAAGGGG 4680 GACACATATC CATGGATGGT AGAAGTGTAA ACTGTGCAGT CACTGTGGAC ATCAATATGC 4740 AGGTTCTTCA CAAATGTAGA TATAAAGCTA CTATAGTTAT ACCC 4784 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 931 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Gly His Glu Val Arg Ser Gin Gin Asp Pro Pro Cys Gly Gly Arg Pro 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Val Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Arg Met Glu He He Leu Gin Phe Leu 180 185 190 Thr Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Lys Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu He His Gin Glu Pro Pro 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Phe Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Lys Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys He Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Met 385 390 395 400 Pro Leu Leu Thr Arg Phe He Arg He Arg Pro Gin Thr Trp His Leu 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Thr 435 440 445 Gin He Ser Ala Ser Ser Thr Arg Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg Asn Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Thr Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro Val Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Glu Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Met Asp Glu Asp Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Pro Glu Glu Thr Cys Gly 645 650 655 Trp Val Tyr Asp His Ala Lys Trp Leu Arg Ser Thr Trp He Ser Ser 660 665 670 Ala Asn Pro Asn Asp Arg Thr Phe Pro Asp Asp Lys Asn Phe Leu Lys 675 680 685 Leu Gin Ser Asp Gly Arg Arg Glu Gly Gin Tyr Gly Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Met Gly Gly His Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Ser 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ser Gly Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Gly Glu Asp Phe Lys Val Asp He 805 810 815 Pro Glu Thr His Gly Gly Glu Gly Tyr Glu Asp Glu He Asp Asp Glu 820 825 830 Tyr Glu Gly Asp Trp Ser Asn Ser Ser Ser Ser Thr Ser Gly Ala Gly 835 840 845 Asp Pro Ser Ser Gly Lys Glu Lys Ser Trp Leu Tyr Thr Leu Asp Pro 850 855 860 He Leu He Thr He He Ala Met Ser Ser Leu Gly Val Leu Leu Gly 865 870 875 880 Ala Thr Cys Ala Gly Leu Leu Leu Tyr Cys Thr Cys Ser Tyr Ser Gly 885 890 895 Leu Ser Ser Arg Ser Cys Thr Thr Leu Glu Asn Tyr Asn Phe Glu Leu 900 905 910 Tyr Asp Gly Leu Lys His Lys Val Lys He Asn His Gin Lys Cys Cys 915 920 925 Ser Glu Ala 930 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2730 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: ATGGATATGT TTCCTCTCAC CTGGGTTTTC TTAGCCCTCT ACTTTTCAAG ACACCAAGTG 60 AGAGGCCAAC CAGACCCACC GTGCGGAGGT CGTTTGAATT CCAAAGATGC TGGCTATATC 120 ACCTCTCCCG GTTACCCCCA GGACTACCCC TCCCACCAGA ACTGCGAGTG GATTGTTTAC 180 GCCCCCGAAC CCAACCAGAA GATTGTCCTC AACTTCAACC CTCACTTTGA AATCGAGAAG 240 CACGACTGCA AGTATGACTT TATCGAGATT CGGGATGGGG ACAGTGAATC CGCAGACCTC 300 CTGGGCAAAC ACTGTGGGAA CATCGCCCCG CCCACCATCA TCTCCTCGGG CTCCATGCTC 360 TACATCAAGT TCACCTCCGA CTACGCCCGG CAGGGGGCAG GCTTCTCTCT GCGCTACGAG 420 ATCTTCAAGA CAGGCTCTGA AGATTGCTCA AAAAACTTCA CAAGCCCCAA CGGGACCATC 480 GAATCTCCTG GGTTTCCTGA GAAGTATCCA CACJAACTTGG ACTGCACCTT TACCATCCTG 540 GCCAAACCCA AGATGGAGAT CATCCTGCAG TTCCTGATCT TTGACCTGGA GCATGACCCT 600 TTGCAGGTGG GAGAGGGGGA CTGCAAGTAC GATTGGCTGG ACATCTGGGA TGGCATTCCA 660 CATGTTGGCC CCCTGATTGG CAAGTACTGT GGGACCAAAA CACCCTCTGA ACTTCGTTCA 720 TCGACGGGGA TCCTCTCCCT GACCTTTCAC ACGGACATGG CGGTGGCCAA GGATGGCTTC 780 TCTGCGCGTT ACTACCTGGT CCACCAAGAG CCACTAGAGA ACTTTCAGTG CAATGTTCCT 840 CTGGGCATGG AGTCTGGCCG GATTGCTAAT GAACAGATCA GTGCCTCATC TACCTACTCT 900 GATGGGAGGT GGACCCCTCA ACAAAGCCGG CTCCATGGTG ATGACAATGG CTGGACCCCC 960 AACTTGGATT CCAACAAGGA GTATCTCCAG GTGGACCTGC GCTTTTTAAC CATGCTCACG 1020 GCCATCGCAA CACAGGGAGC GATTTCCAGG GAAACACAGA ATGGCTACTA CGTCAAATCC 1080 TACAAGCTGG AAGTCAGCAC TAATGGAGAG GACTGGATGG TGTACCGGCA TGGCAAAAAC 1140 CACAAGGTAT TTCAAGCCAA CAACGATGCA ACTGAGGTGG TTCTGAACAA GCTCCACGCT 1200 CCACTGCTGA CAAGGTTTGT TAGAATCCGC CCTCAGACCT GGCACTCAGG TATCGCCCTC 1260 CGGCTGGAGC TCTTCGGCTG CCGGGTCACA GATGCTCCCT GCTCCAACAT GCTGGGGATG 1320 CTCTCAGGCC TCATTGCAGA CTCCCAGATC TCCGCCTCTT CCACCCAGGA ATACCTCTGG 1380 AGCCCCAGTG CAGCCCGCCT GGTCAGCAGC CGCTCGGGCT GGTTCCCTCG AATCCCTCAG 1440 GCCCAGCCCG GTGAGGAGTG GCTTCAGGTA GATCTGGGAA CACCCAAGAC AGTGAAAGGT 1500 GTCATCATCC AGGGAGCCCG CGGAGGAGAC AGTATCACTG CTGTGGAAGC CAGAGCATTT 1560 GTGCGCAAGT TCAAAGTCTC CTACAGCCTA AACGGCAAGG ACTGGGAATA CATTCAGGAC 1620 CCCAGGACCC AGCAGCCAAA GCTGTTCGAA GGGAACATGC ACTATGACAC CCCTGACATC 1680 CGAAGGTTTG ACCCCATTCC GGCACAGTAT GTGCGGGTAT ACCCGGAGAG GTGGTCGCCG 1740 GCGGGGATTG GGATGCGGCT GGAGGTGCTG GGCTGTGACT GGACAGACTC CAAGCCCACG 1800 GTAAAAACGC TGGGACCCAC TGTGAAGAGC GAAGAGACAA CCACCCCCTA CCCCACCGAA 1860 GAGGAGGCCA CAGAGTGTGG GGAGAACTGC AGCTTTGAGG ATGACAAAGA TTTGCAGCTC 1920 CCTTCGGGAT TCAATTGCAA CTTCGATTTC CTCGAGGAGC CCTGTGGTTG GATGTATGAC 1980 CATGCCAAGT GGCTCCGGAC CACCTGGGCC AGCAGCTCCA GCCCAAACGA CCGGACGTTT 2040 CCAGATGACA GGAATTTCTT GCGGCTGCAG AGTGACAGCC AGAGAGAGGG CCAGTATGCC 2100 CGGCTCATCA GCCCCCCTGT CCACCTGCCC CGAAGCCCGG TGTGCATGGA GTTCCAGTAC 2160 CAGGCCACGG GCGGCCGCGG GGTGGCGCTG CAGGTGGTGC GGGAAGCCAG CCAGGAGAGC 2220 AAGTTGCTGT GGGTCATCCG TGAGGACCAG GGCGGCGAGT GGAAGCACGG GCGGATCATC 2280 CTGCCCAGCT ACGACATGGA GTACCAGATT GTGTTCGAGG GAGTGATAGG GAAAGGACGT 2340 TCCGGAGAGA TTGCCATTGA TGACATTCGG ATAAGCACTG ATGTCCCACT GGAGAACTGC 2400 ATGGAACCCA TCTCGGCTTT TGCAGATGAA TACGAGGTGG ACTGGAGCAA TTCTTCTTCT 2460 GCAACCTCAG GGTCTGGCGC CCCCTCGACC GACAAAGAAA AGAGCTGGCT GTACACCCTG 2520 GATCCCATCC TCATCACCAT CATCGCCATG AGCTCACTGG GCGTCCTCCT GGGGGCCACC 2580 TGTGCAGGCC TCCTGCTCTA CTGCACCTGT TCCTACTCGG GCCTGAGCTC CCGAAGCTGC 2640 ACCACACTGG AGAACTACAA CTTCGAGCTC TACGATGGCC TTAAGCACAA GGTCAAGATG 2700 AACCACCAAA AGTGCTGCTC CGAGGCATGA 2730 (2) INFORMATION FOR SEQ ID NO: 18: ( i ) SEQUENCE CHARACTERISTICS : (A) LENGTH: 909 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Arg His Gin Val Arg Gly Gin Pro Asp Pro Pro Cys Gly Gly Arg Leu 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Met Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Lys Met Glu He He Leu Gin Phe Leu 180 185 190 He Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Glu Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu Val His Gin Glu Pro Leu 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Tyr Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Asn Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys Val Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Ala 385 390 395 400 Pro Leu Leu Thr Arg Phe Val Arg He Arg Pro Gin Thr Trp His Ser 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Ser 435 440 445 Gin He Ser Ala Ser Ser Thr Gin Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg He Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Pro Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro He Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Lys Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Thr Glu Glu Glu Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Leu Glu Glu Pro Cys Gly 645 650 655 Trp Met Tyr Asp His Ala Lys Trp Leu Arg Thr Thr Trp Ala Ser Ser 660 665 670 Ser Ser Pro Asn Asp Arg Thr Phe Pro Asp Asp Arg Asn Phe Leu Arg 675 680 685 Leu Gin Ser Asp Ser Gin Arg Glu Gly Gin Tyr Ala Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Thr Gly Gly Arg Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Gly 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ala He Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Asp Glu Tyr Glu Val Asp Trp Ser 805 810 815 Asn Ser Ser Ser Ala Thr Ser Gly Ser Gly Ala Pro Ser Thr Asp Lys 820 825 830 Glu Lys Ser Trp Leu Tyr Thr Leu Asp Pro He Leu He Thr He He 835 840 845 Ala Met Ser Ser Leu Gly Val Leu Leu Gly Ala Thr Cys Ala Gly Leu 850 855 860 Leu Leu Tyr Cys Thr Cys Ser Tyr Ser Gly Leu Ser Ser Arg Ser Cys 865 870 875 880 Thr Thr Leu Glu Asn Tyr Asn Phe Glu Leu Tyr Asp Gly Leu Lys His 885 890 895 Lys Val Lys Met Asn His Gin Lys Cys Cys Ser Glu Ala 900 905 (2) INFORMATION FOR SEQ ID NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2781 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: ATGGATATGT TTCCTCTCAC CTGGGTTTTC TTAGCCCTCT ACTTTTCAAG ACACCAAGTG 60 AGAGGCCAAC CAGACCCACC GTGCGGAGGT CGTTTGAATT CCAAAGATGC TGGCTATATC 120 ACCTCTCCCG GTTACCCCCA GGACTACCCC TCCCACCAGA ACTGCGAGTG GATTGTTTAC 180 GCCCCCGAAC CCAACCAGAA GATTGTCCTC AACTTCAACC CTCACTTTGA AATCGAGAAG 240 CACGACTGCA AGTATGACTT TATCGAGATT CGGGATGGGG ACAGTGAATC CGCAGACCTC 300 CTGGGCAAAC ACTGTGGGAA CATCGCCCCG CCCACCATCA TCTCCTCGGG CTCCATGCTC 360 TACATCAAGT TCACCTCCGA CTACGCCCGG CAGGGGGCAG GCTTCTCTCT GCGCTACGAG 420 ATCTTCAAGA CAGGCTCTGA AGATTGCTCA AAAAACTTCA CAAGCCCCAA CGGGACCATC 480 GAATCTCCTG GGTTTCCTGA GAAGTATCCA CACAACTTGG ACTGCACCTT TACCATCCTG 540 GCCAAACCCA AGATGGAGAT CATCCTGCAG TTCCTGATCT TTGACCTGGA GCATGACCCT 600 TTGCAGGTGG GAGAGGGGGA CTGCAAGTAC GATTGGCTGG ACATCTGGGA TGGCATTCCA 660 CATGTTGGCC CCCTGATTGG CAAGTACTGT GGGACCAAAA CACCCTCTGA ACTTCGTTCA 720 TCGACGGGGA TCCTCTCCCT GACCTTTCAC ACGGACATGG CGGTGGCCAA GGATGGCTTC 780 TCTGCGCGTT ACTACCTGGT CCACCAAGAG CCACTAGAGA ACTTTCAGTG CAATGTTCCT 840 CTGGGCATGG AGTCTGGCCG GATTGCTAAT GAACAGATCA GTGCCTCATC TACCTACTCT 900 GATGGGAGGT GGACCCCTCA ACAAAGCCGG CTCCATGGTG ATGACAATGG CTGGACCCCC 960 AACTTGGATT CCAACAAGGA GTATCTCCAG GTGGACCTGC GCTTTTTAAC CATGCTCACG 1020 GCCATCGCAA CACAGGGAGC GATTTCCAGG GAAACACAGA ATGGCTACTA CGTCAAATCC 1080 TACAAGCTGG AAGTCAGCAC TAATGGAGAG GACTGGATGG TGTACCGGCA TGGCAAAAAC 1140 CACAAGGTAT TTCAAGCCAA CAACGATGCA ACTGAGGTGG TTCTGAACAA GCTCCACGCT 1200 CCACTGCTGA CAAGGTTTGT TAGAATCCGC CCTCAGACCT GGCACTCAGG TATCGCCCTC 1260 CGGCTGGAGC TCTTCGGCTG CCGGGTCACA GATGCTCCCT GCTCCAACAT GCTGGGGATG 1320 CTCTCAGGCC TCATTGCAGA CTCCCAGATC TCCGCCTCTT CCACCCAGGA ATACCTCTGG 1380 AGCCCCAGTG CAGCCCGCCT GGTCAGCAGC CGCTCGGGCT GGTTCCCTCG AATCCCTCAG 1440 GCCCAGCCCG GTGAGGAGTG GCTTCAGGTA GATCTGGGAA CACCCAAGAC AGTGAAAGGT 1500 GTCATCATCC AGGGAGCCCG CGGAGGAGAC AGTATCACTG CTGTGGAAGC CAGAGCATTT 1560 GTGCGCAAGT TCAAAGTCTC CTACAGCCTA AACGGCAAGG ACTGGGAATA CATTCAGGAC 1620 CCCAGGACCC AGCAGCCAAA GCTGTTCGAA GGGAACATGC ACTATGACAC CCCTGACATC 1680 CGAAGGTTTG ACCCCATTCC GGCACAGTAT GTGCGGGTAT ACCCGGAGAG GTGGTCGCCG 1740 GCGGGGATTG GGATGCGGCT GGAGGTGCTG GGCTGTGACT GGACAGACTC CAAGCCCACG 1800 GTAAAAACGC TGGGACCCAC TGTGAAGAGC GAAGAGACAA CCACCCCCTA CCCCACCGAA 1860 GAGGAGGCCA CAGAGTGTGG GGAGAACTGC AGCTTTGAGG ATGACAAAGA TTTGCAGCTC 1920 CCTTCGGGAT TCAATTGCAA CTTCGATTTC CTCGAGGAGC CCTGTGGTTG GATGTATGAC 1980 CATGCCAAGT GGCTCCGGAC CACCTGGGCC AGCAGCTCCA GCCCAAACGA CCGGACGTTT 2040 CCAGATGACA GGAATTTCTT GCGGCTGCAG AGTGACAGCC AGAGAGAGGG CCAGTATGCC 2100 CGGCTCATCA GCCCCCCTGT CCACCTGCCC CGAAGCCCGG TGTGCATGGA GTTCCAGTAC 2160 CAGGCCACGG GCGGCCGCGG GGTGGCGCTG CAGGTGGTGC GGGAAGCCAG CCAGGAGAGC 2220 AAGTTGCTGT GGGTCATCCG TGAGGACCAG GGCGGCGAGT GGAAGCACGG GCGGATCATC 2280 CTGCCCAGCT ACGACATGGA GTACCAGATT GTGTTCGAGG GAGTGATAGG GAAAGGACGT 2340 TCCGGAGAGA TTGCCATTGA TGACATTCGG ATAAGCACTG ATGTCCCACT GGAGAACTGC 2400 ATGGAACCCA TCTCGGCTTT TGCAGTGGAC ATCCCAGAAA TACATGAGAG AGAAGGATAT 2460 GAAGATGAAA TTGATGATGA ATACGAGGTG GACTGGAGCA ATTCTTCTTC TGCAACCTCA 2520 GGGTCTGGCG CCCCCTCGAC CGACAAAGAA AAGAGCTGGC TGTACACCCT GGATCCCATC 2580 CTCATCACCA TCATCGCCAT GAGCTCACTG GGCGTCCTCC TGGGGGCCAC CTGTGCAGGC 2640 CTCCTGCTCT ACTGCACCTG TTCCTACTCG GGCCTGAGCT CCCGAAGCTG CACCACACTG 2700 GAGAACTACA ACTTCGAGCT CTACGATGGC CTTAAGCACA AGGTCAAGAT GAACCACCAA 2760 AAGTGCTGCT CCGAGGCATG A 2781 (2) INFORMATION FOR SEQ ID NO: 20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 926 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Arg His Gin Val Arg Gly Gin Pro Asp Pro Pro Cys Gly Gly Arg Leu 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Met Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Lys Met Glu He He Leu Gin Phe Leu 180 185 190 He Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Glu Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu Val His Gin Glu Pro Leu 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Tyr Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Asn Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys Val Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Ala 385 390 395 400 Pro Leu Leu Thr Arg Phe Val Arg He Arg Pro Gin Thr Trp His Ser 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Ser 435 440 445 Gin He Ser Ala Ser Ser Thr Gin Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg He Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Pro Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro He Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Lys Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Thr Glu Glu Glu Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Leu Glu Glu Pro Cys Gly 645 650 655 Trp Met Tyr Asp His Ala Lys Trp Leu Arg Thr Thr Trp Ala Ser Ser 660 665 670 Ser Ser Pro Asn Asp Arg Thr Phe Pro Asp Asp Arg Asn Phe Leu Arg 675 680 685 Leu Gin Ser Asp Ser Gin Arg Glu Gly Gin Tyr Ala Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Thr Gly Gly Arg Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Gly 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ala He Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Val Asp He Pro Glu He His Glu 805 810 815 Arg Glu Gly Tyr Glu Asp Glu He Asp Asp Glu Tyr Glu Val Asp Trp 820 825 830 Ser Asn Ser Ser Ser Ala Thr Ser Gly Ser Gly Ala Pro Ser Thr Asp 835 840 845 Lys Glu Lys Ser Trp Leu Tyr Thr Leu Asp Pro He Leu He Thr He 850 855 860 He Ala Met Ser Ser Leu Gly Val Leu Leu Gly Ala Thr Cys Ala Gly 865 870 875 880 Leu Leu Leu Tyr Cys Thr Cys Ser Tyr Ser Gly Leu Ser Ser Arg Ser 885 890 895 Cys Thr Thr Leu Glu Asn Tyr Asn Phe Glu Leu Tyr Asp Gly Leu Lys 900 905 910 His Lys Val Lys Met Asn His Gin Lys Cys Cys Ser Glu Ala 915 920 925 (2) INFORMATION FOR SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4765 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21: AAACTGGAGC TCCACCGCGG TGGCGGCCGC CCGGGCAGGT CTAGAATTCA GCGGCCGCTG 60 AATTCTATCC AGCGGTCGGT GCCTCTGCCC GCGTGTGTGT CCCGGGTGCC GGGGGACCTG 120 TGTCAGTTAG CGCTTCTGAG ATCACACAGC TGCCTAGGGG CCGTGTGATG CCCAGGGCAA 180 TTCTTGGCTT TGATTTTTAT TATTATTACT ATTATTTTGC GTTCAGCTTT CGGGAAACCC 240 TCGTGATGTT GTAGGATAAA GGAAATGACA CTTTGAGGAA CTGGAGAGAA CATACACGCG 300 TTTGGGTTTG AAGAGGAAAC CGGTCTCCGC TTCCTTAGCT TGCTCCCTCT TTGCTGATTT 360 CAAGAGCTAT CTCCTATGAG GTGGAGATAT TCCAGCAAGA ATAAAGGTGA AGACAGACTG 420 ACTGCCAGGA CCCAGGAGGA AAACGTTGAT CGTTAGAGAC CTTTGCAGAA GACACCACCA 480 GGAGGAAAAT TAGAGAGGAA AAACACAAAG ACATAATTAT AGGAGATCCC ACAAACCTAG 540 CCCGGGAGAG AGCCTCTCTG TCAAAAATGG ATATGTTTCC TCTTACCTGG GTTTTCTTAG 600 CTCTGTACTT TTCAGGACAC GAAGTGAGAA GCCAGCAAGA TCCACCCTGC GGAGGTCGGC 660 CGAATTCCAA AGATGCTGGC TACATCACTT CCCCAGGCTA CCCCCAGGAC TATCCCTCCC 720 ACCAGAACTG TGAGTGGATT GTCTACGCCC CCGAACCCAA CCAGAAGATT GTTCTCAACT 780 TCAACCCTCA CTTTGAAATC GAGAAACACG ACTGCAAGTA TGACTTCATT GAGATTCGGG 840 ATGGGGACAG TGAGTCAGCT GACCTCCTGG GCAAGCACTG TGGGAACATC GCCCCGCCCA 900 CCATCATCTC CTCAGGCTCC GTGTTATACA TCAAGTTCAC CTCAGACTAC GCCCGGCAGG 960 GGGCAGGTTT CTCTCTACGC TATGAGATCT TCAAAACAGG CTCTGAAGAT TGTTCCAAGA 1020 ACTTTACAAG CCCCAATGGG ACCATTGAAT CTCCAGGGTT TCCAGAGAAG TATCCACACA 1080 ATCTGGACTG TACCTTCACC ATCCTGGCCA AACCCAGGAT GGAGATCATC CTACAGTTCC 1140 TGACCTTTGA CCTGGAGCAT GACCCTCTAC AAGTGGGGGA AGGAGACTGT AAATATGACT 1200 GGCTGGACAT CTGGGATGGC ATTCCACATG TTGGACCTCT GATTGGCAAG TACTGTGGGA 1260 CGAAAACACC CTCCAAACTC CGCTCGTCCA CGGGGATCCT CTCCTTGACC TTTCACACGG 1320 ACATGGCAGT GGCCAAGGAT GGCTTCTCCG CACGTTACTA TTTGATCCAC CAGGAGCCAC 1380 CTGAGAATTT TCAGTGCAAT GTCCCTTTGG GAATGGAGTC TGGCCGGATT GCTAATGAAC 1440 AGATCAGTGC CTCCTCCACC TTCTCTGATG GGAGGTGGAC TCCTCAACAG AGCCGGCTCC 1500 ATGGTGATGA CAATGGCTGG ACACCCAATT TGGATTCCAA CAAGGAGTAT CTCCAGGTGG 1560 ACCTGCGCTT CCTAACCATG CTCACAGCCA TTGCAACACA GGGAGCCATT TCCAGGGAAA 1620 CCCAGAAAGG CTACTACGTC AAATCGTACA AGCTGGAAGT CAGCACAAAT GGTGAAGATT 1680 GGATGGTCTA CCGGCATGGC AAAAACCACA AGATATTCCA AGCGAACAAT GATGCGACCG 1740 AGGTGGTGCT AAACAAGCTC CACATGCCAC TGCTGACTCG GTTCATCAGG ATCCGCCCGC 1800 AGACGTGGCA TTTGGGCATT GCCCTTCGCC TGGAGCTCTT TGGCTGCCGG GTCACAGATG 1860 CACCCTGCTC CAACATGCTG GGGATGCTCT CGGGCCTCAT TGCTGATACC CAGATCTCTG 1920 CCTCCTCCAC CCGAGAGTAC CTCTGGAGCC CCAGTGCTGC CCGCCTGGTT AGTAGCCGCT 1980 CTGGCTGGTT TCCTCGGAAC CCTCAAGCCC AGCCAGGTGA AG.AATGGCTT CAGGTAGACC 2040 TGGGGACACC CAAGACAGTG AAAGGGGTCA TCATCCAGGG AGCCCGAGGA GGAGACAGCA 2100 TCACTGCCGT GGAAGCCAGG GCGTTTGTAC GCAAGTTCAA AGTCTCCTAC AGCCTAAATG 2160 GCAAGGACTG GGAATATATC CAGGACCCCA GGACTCAGCA GACAAAGCTG TTTGAAGGGA 2220 ACATGCACTA TGACACCCCT GACATCCGAA GGTTCGATCC TGTTCCAGCG CAGTATGTGC 2280 GGGTGTACCC AGAGAGGTGG TCGCCAGCAG GCATCGGGAT GAGGCTGGAG GTGCTGGGCT 2340 GTGACTGGAC AGACTCAAAG CCCACAGTGG AGACGCTGGG ACCCACCGTG AAGAGTGAAG 2400 AGACTACCAC CCCATATCCC ATGGATGAGG ATGCCACCGA GTGTGGGGAA AACTGCAGCT 2460 TTGAGGATGA CAAAGATTTG CAACTTCCTT CAGGATTCAA CTGCAACTTT GATTTTCCGG 2520 AAGAGACCTG TGGTTGGGTG TACGACCATG CCAAGTGGCT CCGGAGCACG TGGATCAGCA 2580 GCGCTAACCC CAATGACAGA ACATTTCCAG ATGACAAGAA CTTCTTGAAA CTGCAGAGTG 2640 ATGGCCGACG AGAGGGCCAG TACGGGCGGC TCATCAGCCC ACCGGTGCAC CTGCCCCGAA 2700 GCCCTGTGTG CATGGAGTTC CAGTACCAAG CCATGGGCGG CCACGGGGTG GCACTGCAGG 2760 TGGTTCGGGA AGCCAGCCAG GAAAGCAAAC TCCTTTGGGT CATCCGTGAG GACCAGGGCA 2820 GCGAGTGGAA GCACGGGCGC ATTATCCTGC CCAGCTATGA CATGGAGTAT CAGATCGTGT 2880 TCGAGGGAGT GATAGGGAAG GGACGATCGG GAGAGATTTC CATCGATGAC ATTCGGATAA 2940 GCACTGATGT CCCACTGGAG AACTGCATGG AACCCATATC AGCTTTTGCA GGGGGCACCC 3000 TCCCGCCAGG GACCGAGCCC ACAGTGGACA CGGTGCCCGT GCAGCCCATC CCAGCCTACT 3060 GGTATTACGT TATGGCGGCC GGGGGCGCCG TGCTGGTGCT GGCCTCCGTC GTCCTGGCCC 3120 TGGTGCTCCA CTACCACCGG TTCCGCTATG CGGCCAAGAA GACCGATCAC TCCATCACCT 3180 ACAAAACCTC CCACTACACC AACGGGGCCC CTCTGGCGGT CGAGCCCACC CTAACCATTA 3240 AGCTAGAGCA AGAGCGGGGC TCGCACTGCT GAGGGCCGAA GCAGGAACAG CGCCCCCCCA 3300 AAAAAAACCC AAGAAAGACT GCAAACACGT TGCCTCGATT TTGCACTTTT TTTCTCCTCG 3360 CCTAGTCTCT GTGTGAACCC TCAGACATCT CTCTCCAGGG TCCCCAACCC TGAGCGCTCT 3420 CATGTACCCC ACACCATTCT CTGTGGTTCT TGGTTCCGGT TTCTCTTTGC TCTGATATTG 3480 TTTGTTTTTA ATCATTATTT TTTTTCCTTT TCTTCTTTCC TTTTAATCTT CTCTCTTTTA 3540 TTCCTTTCTC CCCTCCCCGC CCCGCCTTTT TCTAATGATT TTAAACCAAC TCTAATGCTG 3600 CATCTGGAAT CCCAGAAGAG ACCCGCCCCT AAGCACTTCA CAACCCAAGG CTCTGTTGGT 3660 TTTGTTCCAG AGACAGGCCC TGTTGTTTTC TCCCCTTGCC TTATCCCATC CCTCCTCTCC 3720 TGGGCAGGCT GCCAGGTGTC TTGAGGGGAG CCTGGTCCTG TATGTATGTA CACAGTACAC 3780 TCCCATGTGA AGAGGTGTGT GTGTGTGTGT GTGTGTGTGT GTATTTTCGA GGGAGAGACT 3840 GATTCACTGT GGAAGGGGGG GAGTGTGGGT GTGTGTAGAG AGGGGCCCCT TCCCTCTTAT 3900 GTTGCTTCTT CTGGGGTACT TTTCAAGAAA ATAATATACT GTACACATTT TGTTTACTTG 3960 GAGAAGAGAT TGGAGCTTTT TTGTTGCCTT ATCTAGCTCT GGCTGGGTTT CTGTTGGCTG 4020 TCATTGTCAT CTCCAGGTAC CTAGACAAAT AGAGACCATT GGGAATGCAA TGTGGCTTCA 4080 CCCATCCTTA TCCCCATCCC AAGCCACCCA AGACTATGGT TCCTCCAGTG CACTCAGACA 4140 TGACCCCTTT TGTTATGTTT CCTGGTGTCT TTGAAGTCAC AAGATAACAG CCATTGGGTG 4200 CATGGAGTCA TTTCTACTTC CAGCCCTGAA GCAAATGTGT CTCATGTTGC CTTATAAAAA 4260 AAACCGGAAT TCCTGTAGTT GAAGAGTAAG ATTTTGTACG GTACATTTTT AATGACAGCT 4320 TGGATATTGG AATACTCAAC TTTTGTTGTA GCCAATGAGA GGGATATGCC ACTAATGGTA 4380 TCTAAATCAT ACAGTACGTA CTTTAGGATG GGGACAAAAA TCACAACGAT TTATTTATTT 4440 ATTTACTTAG TGTATGTGAG TGCACTGTTG GTGTCTTCAG ACACACCAGA AGATGACTTC 4500 AGATCCGATT ACATATGGGT TGTGAGCCAC CATGTGGTTG CTGGGATTTG AACTCTGGAC 4560 CTCTGGAAGA GCAGTCAGTG CTTGTAACTC TGAGCCATCT TTCTAGCCCC CCCCCCCCCC 4620 CCGCTATCTT TTAGAAATGT AATTTGCCAT ACTTTGAGCA ATGTTCTTGA TGTCATTAGG 4680 ATATTTCACA GATAACTTCA CTTAAGATAA TTAGAGCAAA AAAAAAAAAA AAAAAAAAAA 4740 AAAJAAAAAAA AAAAAAAAAA AAAAA 4765 (2) INFORMATION FOR SEQ ID NO: 22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 901 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Gly His Glu Val Arg Ser Gin Gin Asp Pro Pro Cys Gly Gly Arg Pro 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Val Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Arg Met Glu He He Leu Gin Phe Leu 180 185 190 Thr Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Lys Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu He His Gin Glu Pro Pro 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Phe Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Lys Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys He Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Met 385 390 395 400 Pro Leu Leu Thr Arg Phe He Arg He Arg Pro Gin Thr Trp His Leu 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Thr 435 440 445 Gin He Ser Ala Ser Ser Thr Arg Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg Asn Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Thr Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro Val Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Glu Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Met Asp Glu Asp Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Pro Glu Glu Thr Cys Gly 645 650 655 Trp Val Tyr Asp His Ala Lys Trp Leu Arg Ser Thr Trp He Ser Ser 660 665 670 Ala Asn Pro Asn Asp Arg Thr Phe Pro Asp Asp Lys Asn Phe Leu Lys 675 680 685 Leu Gin Ser Asp Gly Arg Arg Glu Gly Gin Tyr Gly Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Met Gly Gly His Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Ser 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ser He Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Gly Gly Thr Leu Pro Pro Gly Thr 805 810 815 Glu Pro Thr Val Asp Thr Val Pro Val Gin Pro He Pro Ala Tyr Trp 820 825 830 Tyr Tyr Val Met Ala Ala Gly Gly Ala Val Leu Val Leu Ala Ser Val 835 840 845 Val Leu Ala Leu Val Leu His Tyr His Arg Phe Arg Tyr Ala Ala Lys 850 855 860 Lys Thr Asp His Ser He Thr Tyr Lys Thr Ser His Tyr Thr Asn Gly 865 870 875 880 Ala Pro Leu Ala Val Glu Pro Thr Leu Thr He Lys Leu Glu Gin Glu 885 890 895 Arg Gly Ser His Cys 900 (2) INFORMATION FOR SEQ ID NO: 23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4780 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: AAACTGGAGC TCCACCGCGG TGGCGGCCGC CCGGGCAGGT CTAGAATTCA GCGGCCGCTG 60 AATTCTATCC AGCGGTCGGT GCCTCTGCCC GCGTGTGTGT CCCGGGTGCC GGGGGACCTG 120 TGTCAGTTAG CGCTTCTGAG ATCACACAGC TGCCTAGGGG CCGTGTGATG CCCAGGGCAA 180 TTCTTGGCTT TGATTTTTAT TATTATTACT ATTATTTTGC GTTCAGCTTT CGGGAAACCC 240 TCGTGATGTT GTAGGATAAA GGAAATGACA CTTTGAGGAA CTGGAGAGAA CATACACGCG 300 TTTGGGTTTG AAGAGGAAAC CGGTCTCCGC TTCCTTAGCT TGCTCCCTCT TTGCTGATTT 360 CAAGAGCTAT CTCCTATGAG GTGGAGATAT TCCAGCAAGA ATAAAGGTGA AGACAGACTG 420 ACTGCCAGGA CCCAGGAGGA AAACGTTGAT CGTTAGAGAC CTTTGCAGAA GACACCACCA 480 GGAGGAAAAT TAGAGAGGAA AAACACAAAG ACATAATTAT AGGAGATCCC ACAAACCTAG 540 CCCGGGAGAG AGCCTCTCTG TCAAAAATGG ATATGTTTCC TCTTACCTGG GTTTTCTTAG 600 CTCTGTACTT TTCAGGACAC GAAGTGAGAA GCCAGCAAGA TCCACCCTGC GGAGGTCGGC 660 CGAATTCCAA AGATGCTGGC TACATCACTT CCCCAGGCTA CCCCCAGGAC TATCCCTCCC 720 ACCAGAACTG TGAGTGGATT GTCTACGCCC CCGAACCCAA CCAGAAGATT GTTCTCAACT 780 TCAACCCTCA CTTTGAAATC GAGAAACACG ACTGCAAGTA TGACTTCATT GAGATTCGGG 840 ATGGGGACAG TGAGTCAGCT GACCTCCTGG GCAAGCACTG TGGGAACATC GCCCCGCCCA 900 CCATCATCTC CTCAGGCTCC GTGTTATACA TCAAGTTCAC CTCAGACTAC GCCCGGCAGG 960 GGGCAGGTTT CTCTCTACGC TATGAGATCT TCAAAACAGG CTCTGAAGAT TGTTCCAAGA 1020 ACTTTACAAG CCCCAATGGG ACCATTGAAT CTCCAGGGTT TCCAGAGAAG TATCCACACA 1080 ATCTGGACTG TACCTTCACC ATCCTGGCCA AACCCAGGAT GGAGATCATC CTACAGTTCC 1140 TGACCTTTGA CCTGGAGCAT GACCCTCTAC AAGTGGGGGA AGGAGACTGT AAATATGACT 1200 GGCTGGACAT CTGGGATGGC ATTCCACATG TTGGACCTCT GATTGGCAAG TACTGTGGGA 1260 CGAAAACACC CTCCAAACTC CGCTCGTCCA CGGGGATCCT CTCCTTGACC TTTCACACGG 1320 ACATGGCAGT GGCCAAGGAT GGCTTCTCCG CACGTTACTA TTTGATCCAC CAGGAGCCAC 1380 CTGAGAATTT TCAGTGCAAT GTCCCTTTGG GAATGGAGTC TGGCCGGATT GCTAATGAAC 1440 AGATCAGTGC CTCCTCCACC TTCTCTGATG GGAGGTGGAC TCCTCAACAG AGCCGGCTCC 1500 ATGGTGATGA CAATGGCTGG ACACCCAATT TGGATTCCAA CAAGGAGTAT CTCCAGGTGG 1560 ACCTGCGCTT CCTAACCATG CTCACAGCCA TTGCAACACA GGGAGCCATT TCCAGGGAAA 1620 CCCAGAAAGG CTACTACGTC AAATCGTACA AGCTGGAAGT CAGCACAAAT GGTGAAGATT 1680 GGATGGTCTA CCGGCATGGC AAAAACCACA AGATATTCCA AGCGAACAAT GATGCGACCG 1740 AGGTGGTGCT AAACAAGCTC CACATGCCAC TGCTGACTCG GTTCATCAGG ATCCGCCCGC 1800 AGACGTGGCA TTTGGGCATT GCCCTTCGCC TGGAGCTCTT TGGCTGCCGG GTCACAGATG 1860 CACCCTGCTC CAACATGCTG GGGATGCTCT CGGGCCTCAT TGCTGATACC CAGATCTCTG 1920 CCTCCTCCAC CCGAGAGTAC CTCTGGAGCC CCAGTGCTGC CCGCCTGGTT AGTAGCCGCT 1980 CTGGCTGGTT TCCTCGGAAC CCTCAAGCCC AGCCAGGTGA AGAATGGCTT CAGGTAGACC 2040 TGGGGACACC CAAGACAGTG AAAGGGGTCA TCATCCAGGG AGCCCGAGGA GGAGACAGCA 2100 TCACTGCCGT GGAAGCCAGG GCGTTTGTAC GCAAGTTCAA AGTCTCCTAC AGCCTAAATG 2160 GCAAGGACTG GGAATATATC CAGGACCCCA GGACTCAGCA GACAAAGCTG TTTGAAGGGA 2220 ACATGCACTA TGACACCCCT GACATCCGAA GGTTCGATCC TGTTCCAGCG CAGTATGTGC 2280 GGGTGTACCC AGAGAGGTGG TCGCCAGCAG GCATCGGGAT GAGGCTGGAG GTGCTGGGCT 2340 GTGACTGGAC AGACTCAAAG CCCACAGTGG AGACGCTGGG ACCCACCGTG AAGAGTGAAG 2400 AGACTACCAC CCCATATCCC ATGGATGAGG ATGCCACCGA GTGTGGGGAA AACTGCAGCT 2460 TTGAGGATGA CAAAGATTTG CAACTTCCTT CAGGATTCAA CTGCAACTTT GATTTTCCGG 2520 AAGAGACCTG TGGTTGGGTG TACGACCATG CCAAGTGGCT CCGGAGCACG TGGATCAGCA 2580 GCGCTAACCC CAATGACAGA ACATTTCCAG ATGACAAGAA CTTCTTGAAA CTGCAGAGTG 2640 ATGGCCGACG AGAGGGCCAG TACGGGCGGC TCATCAGCCC ACCGGTGCAC CTGCCCCGAA 2700 GCCCTGTGTG CATGGAGTTC CAGTACCAAG CCATGGGCGG CCACGGGGTG GCACTGCAGG 2760 TGGTTCGGGA AGCCAGCCAG GAAAGCAAAC TCCTTTGGGT CATCCGTGAG GACCAGGGCA 2820 GCGAGTGGAA GCACGGGCGC ATTATCCTGC CCAGCTATGA CATGGAGTAT CAGATCGTGT 2880 TCGAGGGAGT GATAGGGAAG GGACGATCGG GAGAGATTTC CATCGATGAC ATTCGGATAA 2940 GCACTGATGT CCCACTGGAG AACTGCATGG AACCCATATC AGCTTTTGCA GGTGAGGATT 3000 TTAAAGGGGG CACCCTCCCG CCAGGGACCG AGCCCACAGT GGACACGGTG CCCGTGCAGC 3060 CCATCCCAGC CTACTGGTAT TACGTTATGG CGGCCGGGGG CGCCGTGCTG GTGCTGGCCT 3120 CCGTCGTCCT GGCCCTGGTG CTCCACTACC ACCGGTTCCG CTATGCGGCC AAGAAGACCG 3180 ATCACTCCAT CACCTACAAA ACCTCCCACT ACACCAACGG GGCCCCTCTG GCGGTCGAGC 3240 CCACCCTAAC CATTAAGCTA GAGCAAGAGC GGGGCTCGCA CTGCTGAGGG CCGAAGCAGG 3300 AACAGCGCCC CCCCAAAAAA AACCCAAGAA AGACTGCAAA CACGTTGCCT CGATTTTGCA 3360 CTTTTTTTCT CCTCGCCTAG TCTCTGTGTG AACCCTCAGA CATCTCTCTC CAGGGTCCCC 3420 AACCCTGAGC GCTCTCATGT ACCCCACACC ATTCTCTGTG GTTCTTGGTT CCGGTTTCTC 3480 TTTGCTCTGA TATTGTTTGT TTTTAATCAT TATTTTTTTT CCTTTTCTTC TTTCCTTTTA 3540 ATCTTCTCTC TTTTATTCCT TTCTCCCCTC CCCGCCCCGC CTTTTTCTAA TGATTTTAAA 3600 CCAACTCTAA TGCTGCATCT GG.AATCCCAG AAGAGACCCG CCCCTAAGCA CTTCACAACC 3660 CAAGGCTCTG TTGGTTTTGT TCCAGAGACA GGCCCTGTTG TTTTCTCCCC TTGCCTTATC 3720 CCATCCCTCC TCTCCTGGGC AGGCTGCCAG GTGTCTTGAG GGGAGCCTGG TCCTGTATGT 3780 ATGTACACAG TACACTCCCA TGTGAAGAGG TGTGTGTGTG TGTGTGTGTG TGTGTGTATT 3840 TTCGAGGGAG AGACTGATTC ACTGTGGAAG GGGGGGAGTG TGGGTGTGTG TAGAGAGGGG 3900 CCCCTTCCCT CTTATGTTGC TTCTTCTGGG GTACTTTTCA AGAAAATAAT ATACTGTACA 3960 CATTTTGTTT ACTTGGAGAA GAGATTGGAG CTTTTTTGTT GCCTTATCTA GCTCTGGCTG 4020 GGTTTCTGTT GGCTGTCATT GTCATCTCCA GGTACCTAGA CAAATAGAGA CCATTGGGAA 4080 TGCAATGTGG CTTCACCCAT CCTTATCCCC ATCCCAAGCC ACCCAAGACT ATGGTTCCTC 4140 CAGTGCACTC AGACATGACC CCTTTTGTTA TGTTTCCTGG TGTCTTTGAA GTCACAAGAT 4200 AACAGCCATT GGGTGCATGG AGTCATTTCT ACTTCCAGCC CTGAAGCAAA TGTGTCTCAT 4260 GTTGCCTTAT AAAAAAAACC GGAATTCCTG TAGTTGAAGA GTAAGATTTT GTACGGTACA 4320 TTTTTAATGA CAGCTTGGAT ATTGGAATAC TCAACTTTTG TTGTAGCCAA TGAGAGGGAT 4380 ATGCCACTAA TGGTATCTAA ATCATACAGT ACGTACTTTA GGATGGGGAC AAAAATCACA 4440 ACGATTTATT TATTTATTTA CTTAGTGTAT GTGAGTGCAC TGTTGGTGTC TTCAGACACA 4500 CCAGAAGATG ACTTCAGATC CGATTACATA TGGGTTGTGA GCCACCATGT GGTTGCTGGG 4560 ATTTGAACTC TGGACCTCTG GAAGAGCAGT CAGTGCTTGT AACTCTGAGC CATCTTTCTA 4620 GCCCCCCCCC CCCCCCCGCT ATCTTTTAGA AATGTAATTT GCCATACTTT GAGCAATGTT 4680 CTTGATGTCA TTAGGATATT TCACAGATAA CTTCACTTAA GATAATTAGA GCAAAAAAAA 4740 AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA 4780 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 906 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: Met Asp Met Phe Pro Leu Thr Trp Val Phe Leu Ala Leu Tyr Phe Ser 1 5 10 15 Gly His Glu Val Arg Ser Gin Gin Asp Pro Pro Cys Gly Gly Arg Pro 20 25 30 Asn Ser Lys Asp Ala Gly Tyr He Thr Ser Pro Gly Tyr Pro Gin Asp 35 40 45 Tyr Pro Ser His Gin Asn Cys Glu Trp He Val Tyr Ala Pro Glu Pro 50 55 60 Asn Gin Lys He Val Leu Asn Phe Asn Pro His Phe Glu He Glu Lys 65 70 75 80 His Asp Cys Lys Tyr Asp Phe He Glu He Arg Asp Gly Asp Ser Glu 85 90 95 Ser Ala Asp Leu Leu Gly Lys His Cys Gly Asn He Ala Pro Pro Thr 100 105 110 He He Ser Ser Gly Ser Val Leu Tyr He Lys Phe Thr Ser Asp Tyr 115 120 125 Ala Arg Gin Gly Ala Gly Phe Ser Leu Arg Tyr Glu He Phe Lys Thr 130 135 140 Gly Ser Glu Asp Cys Ser Lys Asn Phe Thr Ser Pro Asn Gly Thr He 145 150 155 160 Glu Ser Pro Gly Phe Pro Glu Lys Tyr Pro His Asn Leu Asp Cys Thr 165 170 175 Phe Thr He Leu Ala Lys Pro Arg Met Glu He He Leu Gin Phe Leu 180 185 190 Thr Phe Asp Leu Glu His Asp Pro Leu Gin Val Gly Glu Gly Asp Cys 195 200 205 Lys Tyr Asp Trp Leu Asp He Trp Asp Gly He Pro His Val Gly Pro 210 215 220 Leu He Gly Lys Tyr Cys Gly Thr Lys Thr Pro Ser Lys Leu Arg Ser 225 230 235 240 Ser Thr Gly He Leu Ser Leu Thr Phe His Thr Asp Met Ala Val Ala 245 250 255 Lys Asp Gly Phe Ser Ala Arg Tyr Tyr Leu He His Gin Glu Pro Pro 260 265 270 Glu Asn Phe Gin Cys Asn Val Pro Leu Gly Met Glu Ser Gly Arg He 275 280 285 Ala Asn Glu Gin He Ser Ala Ser Ser Thr Phe Ser Asp Gly Arg Trp 290 295 300 Thr Pro Gin Gin Ser Arg Leu His Gly Asp Asp Asn Gly Trp Thr Pro 305 310 315 320 Asn Leu Asp Ser Asn Lys Glu Tyr Leu Gin Val Asp Leu Arg Phe Leu 325 330 335 Thr Met Leu Thr Ala He Ala Thr Gin Gly Ala He Ser Arg Glu Thr 340 345 350 Gin Lys Gly Tyr Tyr Val Lys Ser Tyr Lys Leu Glu Val Ser Thr Asn 355 360 365 Gly Glu Asp Trp Met Val Tyr Arg His Gly Lys Asn His Lys He Phe 370 375 380 Gin Ala Asn Asn Asp Ala Thr Glu Val Val Leu Asn Lys Leu His Met 385 390 395 400 Pro Leu Leu Thr Arg Phe He Arg He Arg Pro Gin Thr Trp His Leu 405 410 415 Gly He Ala Leu Arg Leu Glu Leu Phe Gly Cys Arg Val Thr Asp Ala 420 425 430 Pro Cys Ser Asn Met Leu Gly Met Leu Ser Gly Leu He Ala Asp Thr 435 440 445 Gin He Ser Ala Ser Ser Thr Arg Glu Tyr Leu Trp Ser Pro Ser Ala 450 455 460 Ala Arg Leu Val Ser Ser Arg Ser Gly Trp Phe Pro Arg Asn Pro Gin 465 470 475 480 Ala Gin Pro Gly Glu Glu Trp Leu Gin Val Asp Leu Gly Thr Pro Lys 485 490 495 Thr Val Lys Gly Val He He Gin Gly Ala Arg Gly Gly Asp Ser He 500 505 510 Thr Ala Val Glu Ala Arg Ala Phe Val Arg Lys Phe Lys Val Ser Tyr 515 520 525 Ser Leu Asn Gly Lys Asp Trp Glu Tyr He Gin Asp Pro Arg Thr Gin 530 535 540 Gin Thr Lys Leu Phe Glu Gly Asn Met His Tyr Asp Thr Pro Asp He 545 550 555 560 Arg Arg Phe Asp Pro Val Pro Ala Gin Tyr Val Arg Val Tyr Pro Glu 565 570 575 Arg Trp Ser Pro Ala Gly He Gly Met Arg Leu Glu Val Leu Gly Cys 580 585 590 Asp Trp Thr Asp Ser Lys Pro Thr Val Glu Thr Leu Gly Pro Thr Val 595 600 605 Lys Ser Glu Glu Thr Thr Thr Pro Tyr Pro Met Asp Glu Asp Ala Thr 610 615 620 Glu Cys Gly Glu Asn Cys Ser Phe Glu Asp Asp Lys Asp Leu Gin Leu 625 630 635 640 Pro Ser Gly Phe Asn Cys Asn Phe Asp Phe Pro Glu Glu Thr Cys Gly 645 650 655 Trp Val Tyr Asp His Ala Lys Trp Leu Arg Ser Thr Trp He Ser Ser 660 665 670 Ala Asn Pro Asn Asp Arg Thr Phe Pro Asp Asp Lys Asn Phe Leu Lys 675 680 685 Leu Gin Ser Asp Gly Arg Arg Glu Gly Gin Tyr Gly Arg Leu He Ser 690 695 700 Pro Pro Val His Leu Pro Arg Ser Pro Val Cys Met Glu Phe Gin Tyr 705 710 715 720 Gin Ala Met Gly Gly His Gly Val Ala Leu Gin Val Val Arg Glu Ala 725 730 735 Ser Gin Glu Ser Lys Leu Leu Trp Val He Arg Glu Asp Gin Gly Ser 740 745 750 Glu Trp Lys His Gly Arg He He Leu Pro Ser Tyr Asp Met Glu Tyr 755 760 765 Gin He Val Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He 770 775 780 Ser He Asp Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys 785 790 795 800 Met Glu Pro He Ser Ala Phe Ala Gly Glu Asp Phe Lys Gly Gly Thr 805 810 815 Leu Pro Pro Gly Thr Glu Pro Thr Val Asp Thr Val Pro Val Gin Pro 820 825 830 He Pro Ala Tyr Trp Tyr Tyr Val Met Ala Ala Gly Gly Ala Val Leu 835 840 845 Val Leu Ala Ser Val Val Leu Ala Leu Val Leu His Tyr His Arg Phe 850 855 860 Arg Tyr Ala Ala Lys Lys Thr Asp His Ser He Thr Tyr Lys Thr Ser 865 870 875 880 His Tyr Thr Asn Gly Ala Pro Leu Ala Val Glu Pro Thr Leu Thr He 885 890 895 Lys Leu Glu Gin Glu Arg Gly Ser His Cys 900 905 (2) INFORMATION FOR SEQ ID NO: 25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 195 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID N0:25: TTCGAGGGAG TGATAGGGAA AGGACGTTCC GGAGAGATTG CCATTGATGA CATTCGGATA 60 AGCACTGATG TCCCACTGGA GAACTGCATG GAACCCATCT CGGCTTTTGC AGGGGGCACC 120 CTCCTGCCAG GGACCGAGCC CACAGTGGAC ACGGTGCCCA TGCAGCCCAT CCCAGCCTAC 180 TGGTATTACG TAATG 195 (2) INFORMATION FOR SEQ ID NO: 26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 65 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear

Claims: (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26: Phe Glu Gly Val He Gly Lys Gly Arg Ser Gly Glu He Ala He Asp 1 5 10 15 Asp He Arg He Ser Thr Asp Val Pro Leu Glu Asn Cys Met Glu Pro 20 25 30 He Ser Ala Phe Ala Gly Gly Thr Leu Leu Pro Gly Thr Glu Pro Thr 35 40 45 Val Asp Thr Val Pro Met Gin Pro He Pro Ala Tyr Trp Tyr Tyr Val 50 55 60 Met 65 WHAT IS CLAIMED IS: 1. An isolated polypeptide comprising the amino acid sequence of SEQ ID NO:2, 4, 8, 10, 12, 14, 16, 18, 20, 22 or 24, or a deletion mutant thereof comprising at least an 8 residue domain thereof found in neither mouse, chick nor drosphila neuropilin- 1 cDNA nor SEQ ID NO:26, wherein said polypeptide has an activity selected from at least one of: a semaphorin binding or binding inhibitory activity, a neuron modulating or modulting inhibitory activity and a semaphorin receptor specific antigenicity or immunogenicity. 2. The isolated polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:2, 18 or 20 or a deletion mutant thereof, wherein said domain comprises a human specific SR sequence. 3. An isolated or recombinant first nucleic acid comprising a strand of SEQ ID NO:l, 3, 7, 9, 11, 13, 15, 17, 19, 21 or 23 or at least 24 consecutive bases of SEQ ID NO:l, 3, 7, 9, 11, 13, 15, 17, 19, 21 or 23 and sufficient to specifically hybridize with a second nucleic acid comprising SEQ ID NO: 1, 3, 7, 9, 11, 13, 15, 17, 19, 21 or 23, respectively, in the presence of mouse, chick and drosophilia neuropilin- 1 cDNA. 4. A recombinant nucleic acid encoding a polypeptide according to claim 1. 5. A cell comprising a nucleic acid according to claim 4. 6. An antibody which specifically binds a polypeptide according to claim 1. 7. A method of making an SR polypeptide said method comprising steps: introducing a nucleic acid according to claim 4 into a host cell or cellular extract, incubating said host cell or extract under conditions whereby said nucleic acid is expressed as a transcript and said transcript is expressed as a translation product comprising said polypeptide, and isolating said translation product. 8. A method of modulating a cell comprising at least one of a SR polypeptide and a semaphorin, said method comprising the step of modulating the interaction of the SR polypeptide and the semaphorin by contacting the cell with an effective amount of a composition comprising an inhibitor of the interaction, where by a characteristic of the cell is modulated, wherein said cell is a neuron, said characteristic is axon outgrowth and or guidance and said inhibitor is a polypeptide according to claim 1. 9. A method of screening for an agent which modulates the interaction of a SR polypeptide to a binding target, said method comprising the steps of: incubating a mixture comprising: an isolated polypeptide according to claim 1, a binding target of said polypeptide, and a candidate agent; under conditions whereby, but for the presence of said agent, said polypeptide specifically binds said binding target at a reference affinity; detecting the binding affinity of said polypeptide to said binding target to determine an agent-biased affinity, wherein a difference between the agent-biased affinity and the reference affinity indicates that said agent modulates the binding of said polypeptide to said binding target. 10. A method according to claim 9, wherein said binding target is a semaphorin polypeptide.

Inventors: CHEN HANG, HE ZHIGANG, TESSIER-LAVIGNE MARC, CHEN, HANG, HE, ZHIGANG, TESSIER-LAVIGNE, MARC
Applicants: UNIV CALIFORNIA, THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Application year: 1998
Main classification: C07K14
IPC codes: A61K38, A61P25, A61P43, C07K14, C07K16, C12N1, C12N5, C12N15, C12P21, G01N33