PROCESSES FOR THE IDENTIFICATION OF COMPOUNDS WHICH CONTROL CELL BEHAVIOUR, THE COMPOUNDS IDENTIFIED AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE IN THE CONTROL OF CELL BEHAVIOUR

Abstract: UNC-53 protein of <u>C. elegans</u> or its functional equivalent is identified as a signal transducer/integrator involved in controlling the rate and directionality of cell migration and/or cell shape. Nucleic acid sequences encoding UNC-53 protein or its functional equivalent, such as genomic or cDNA are used to transfect <u>C. elegans</u> or mammalian cell lines useful for identifying inhibitors or enhancers of the UNC-53 protein. Any of the inhibitors or enhancers identified or the UNC-53 protein itself or sequences encoding UNC-53 protein can be used in the preparation of medicament for treatment of neurological conditions such as Alzheimer's or Huntingdon's disease, peripheral neuropathies for inhibition of metastasis.

Description: PROCESSES FOR THE IDENTIFICATION OF COMPOUNDS WHICH CONTROL CELL BEHAVIOUR. THE COMPOUNDS IDENTIFIED •μ AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND „ THEIR USE IN THE CONTROL OF CELL BEHAVIOUR 5 The present invention relates to processes for the identification of compounds which inhibit or enhance the rate and direction of cell migration or the control of cell shape, the compounds identified 10 and pharmaceutical formulations containing such compounds together with their use in the regulation of cell behaviour. The invention also relates to an UNC- 53 protein encoded by nucleic acid in the cells of the nematode worm C. elegans and cDNA seguences encoding 15 an UNC-53 protein or functional equivalents thereof. The control of cell otility, cell shape and the outgrowth of axones or other cell outgrowths is an essential feature in the morphogenesis and function of both unicellular and ulticellular organisms. The 20 control of this process is disturbed in a variety of disease states in which for example the Receptor Tyrosine Kinase (RTK) signal transduction pathways or the like or their downstream intra-cellular pathways (which are shared with other extra-cellular receptors, 25 including cell adhesion molecules like N-CAMS and integrins) are overstimulated. Some cell surface proteins and extracellular molecules controlling the directionality and potential of cell migration have been identified. However the 30 processes in which these proteins or molecules are involved to effect cell migration, shape or rate of cell differentiation are not understood. ^ It is generally considered that a long-range , migration of a cell process (which may also be known 35 as a growth cone spike) is a stepwise event, whereby prior to and after each extension there is the formation of a structure at the leading edge of the cell which senses signals in the environment instructing the cell to either stabilize a cell process extending in a preferred direction, or to cause a cell process lamellipodium to extend a process in a given direction. Localized stabilization of the actin cytoskeleton, is a general cell biological process underlying this choice of directional extension. A gene from the free-living ne atode Caenorhabditis elegans. designated "unc-53" has been previously identified and cloned (Abstract, International C. elegans meeting; June 1-5 1991, Madison, Wisconsin, 58, Bogaert and Goh) . However, to date no known biological function has been attributed to the unc-53 gene or its corresponding UNC-53 protein. The present inventors have surprisingly identified, through biochemical, genetic, phenotypic and transgenic evidence which is presented herewith, UNC-53 as a signal transducer or signal integrator controlling the rate and directionality of cell migration, and/or cell shape. Key experiments leading to this conclusion were the molecular identification of its domain structure, its biochemical interaction with GRB-2, actin cytoskeleton sequence information and the presence of a potential signal integrating domain in the UNC-53 protein. An additional key observation is that increased UNC-53 protein activity is proportional to increased cell process extension in the correct direction of cell migration. Reduction of UNC-53 function has previously been shown to lead to a reduction of cell process extension, identifying it as a general component required for cell migration. However, it had not been identified as a component whose level of activity has a determining role in the specification of the quantum and directionality of migration. The work of the present inventors suggests that UNC-53 plays a central role in quantitatively transducing extracellular signals to the machinery controlling directional cell migration. The importance of UNC-53 in a variety of cell types in C. elegans has been demonstrated. The gene encodes a signal transduction molecule that transduces a signal from a Receptor Tyrosine Kinase such as for example via the adaptor protein SEM-5/GRB-2, to the machinery controlling directional growth cone extension or stabilization. The UNC-53 protein does this in a highly dosage-dependent fashion whereby reduction of protein activity such as reduction in expression of protein or in the reduction in its activity leads to proportional reduction of cell process extension (cell migration) . This is believed to be either by regulated cross-linking of the actin cytoskeleton or by transferring the received signal downstream within the transduction pathway. Higher than wild type UNC-53 expression leads to higher than wild type growth cone extension in the anterior- posterior axis. Both the observed SEM-5/GRB-2 binding to UNC-53 and the predicted ATP/GTP-ase activity of UNC-53 demonstrate a signal transduction role for UNC-53 involved in cell process or growth cone guidance. UNC-53 is a protein working at the intracellular level. It is so far believed to be the only intracellular protein identified which is involved in the control of directionality and rate of cell migration in response to a specific signal and which integrates different directional signals in defining direction of migration. Based on the present inventors accumulated knowledge of the unc-53 gene function in C. elegans it is understood that inhibitors or enhancers of the unc- 53 gene or the UNC-53 protein will affect the cell motility including (metastasis) via an RTK pathway or the like, or may lead to changes in the shape of the cells (which has been demonstrated in C. elegans body muscle) . Applications for such inhibitors and/or enhancers are envisaged in a wide variety of pathologies in which the RTK pathways play a central role, including oncogenesis, psoriasis, cell migration (metastasis) , neuronal regeneration/degeneration and immunological disorders among others. The identification of the biochemical function of the unc-53 gene (and UNC-53 pathway) in the RTK signal transduction pathway is novel and unexpected. No biological function has previously been linked to the unc-53 gene or UNC-53 protein, nor has any homology with any other nucleic acid sequence or gene been recognised. An analysis of the predicted protein sequence of UNC-53 from the gene sequence thereof has revealed the following: (a) an N-terminal domain with homology to cortical actin binding proteins of the α-actinin and β-spectrin families (designated ABPII in Figure 11) . Alignment of UNC-53 with the α-actinin and β-spectrin family of proteins is shown in Fig. 15.). (b) two putative actin binding sites of the LKK class (ABS1 and ABS2) . (c) two polyproline rich sequences similar to the SH3 binding domains of the SOS family of signal transduction molecules (SH3 binding site) (Fig. 16) . (d) a putative ATP/GTP nucleotide binding site having some of the additional features of the GTP binding domain of RAS-like proteins (Dynamin, NBD) . (e) besides the N-terminal region of the protein, which is similar to actin binding proteins, the predicted protein sequence of UNC-53 identified two putative actin binding sites. The first borders on the 3' end of the region of α-actinin/β-spectrin homology and the second lies in the 3' end of the cDNA sequence. This suggests that UNC-53 could potentially bind two actin molecules and via actin cross linking, could stabilize a particular cell process to promote directional extension. In addition, genetic evidence shows that alleles of unc-53 enhance the sex myoblast migration defect of sem-5 mutants. Sem-5 represents the C. elegans homologue of GRB2, the function of these proteins being assigned/attributed to their SH2 and SH3 domains (Clark et al., (1992) Nature 3J56, 340-344; Stern et al., (1993), Molec. Biol. Cell, 1, 1175-1188). The current model regarding sem-5 function in the migration of sex myoblasts is that sem-5 transduces a signal received at the cell surface by egl-15, a receptor kinase of the fibroblast growth factor family. Together, the genetic and molecular data suggest a role for UNC-53 in both signal transduction and actin binding. We have been able to demonstrate how UNC-53 might act to direct both growth cone rate and directionality. By binding directly to the actin cytoskeleton, UNC-53 may stabilize and cross-link actin molecules (assuming a two actin binding site model) to promote directional growth cone extension. Alternatively, by binding actin, UNC-53 may convey a signal to the cytoskeleton and then via an ATP/GTPase activity transduce the signal to downstream targets. To test these models, biochemical experiments were conducted to determine if any of the sequence similarities observed represented functional domains (see examples 2 to 5) . Transgenic analysis as described in examples 6 to 8 support this proposed model. As described above, the unc-53 gene from C. elegans has been previously identified. However, cDNA sequences substantially corresponding to unc-53 genomic exon sequences of C. elegans or fragments or derivatives thereof have never been previously disclosed. The present inventors have advantageously identified two unc-53 cDNA clones which have been designated as the 7A and 8A clones. The two clones differ in the number of Adenosine(A) residues (7 or 8) in a poly A stretch of the 3' coding region. Therefore, the two clones have different reading frames in the carboxyterminal coding region. Therefore according to one aspect of the present invention there is provided a cDNA encoding an UNC-53 protein of C. elegans or a functional equivalent derivative or bioprecursor of said protein which cDNA comprises at least from nucleotide position 431 to nucleotide position 4647 or alternatively to the 3' poly-A region of the sequence shown in Figure 1. More preferably the cDNA comprises at least from nucleotide position 64 to nucleotide position 4647 or to the 3' poly-A region of the sequence as shown in Figure 1. This cDNA is comprised in the 8A clone having 8A residues in a poly A stretch of the 3' coding region as shown in Figure 1. In an alternative embodiment of this aspect of the invention the cDNA comprises at least from nucleotide position 431 to nucleotide position 4812 or alternatively to the 3' poly-A region of the sequence shown in Figure 2 and more preferably at least from position 64 to nucleotide position 4812 or the 3' poly-A region of the sequence shown in Figure 2. This cDNA according to the invention comprises the 7A clone, having only 7 Adenine residues in the poly A stretch of the 3 ' coding region as shown in the nucleotide sequence of Figure 2 page 8. Each of the cDNA clones according to the invention, may be included in an expression vector which vector may itself be used to transform or transfect a host cell which may be bacterial, animal or plant in origin. Thus, advantageously, once the cDNA corresponding to the unc-53 genome is synthesised using for example reverse transcriptase or the like, a range of cells, tissues or organisms may be transfected following incorporation of the selected cDNA clone into an appropriate expression vector. The present invention therefore, also further comprises a transgenic cell, tissue or organism comprising a transgene capable of expressing UNC-53 protein of C. elegans or a functional equivalent, fragment, derivative or bioprecursor thereof. The term "transgene capable of expressing UNC-53 protein" as used herein means a suitable nucleic acid sequence which leads to the expression of an UNC-53 protein having the same function and/or activity. The transgene may include for example genomic nucleic acid isolated from C. elegans or synthetic nucleic acid or alternatively any of the cDNA clones as described above. The term "transgenic organism, tissue or cell" as used herein means any suitable organism and/or part of an organism, tissue or cell that contains exogenous nucleic acid either stably integrated in the genome or in an extra chromosomal state. Preferably, the transgenic cell comprises either a C. elegans cell, an N4 neuroblastoma cell or an MCF- 7 breast carcinoma cell. The transgenic organism may be C. elegans itself, or alternatively may be an insect, a non-human animal or a plant. Preferably the unc-53 transgene comprises the unc-53 gene or a functional fragment thereof. The term "functional fragment" as used herein should be taken to mean a fragment of an UNC-53 gene which encodes an UNC-53 protein or a functional equivalent or bioprecursor of the protein. For example the gene may comprise deletions or mutations but may still encode a functional UNC-53 protein. Reference to "tissue or tissue culture" for the purpose of the present invention should be taken to mean such a mutant cell which has been grown in such a culture. Further provided by the present invention is a mutant C. elegans organism which comprises an induced mutation, such as a point mutation in the wild-type unc-53 gene and which mutation affects the regulation of cell motility or shape or the direction of cell migration. Such mutations may be introduced using changes in the cDNA corresponding to qualitative, quantitative direct and indirect changes in the genomic make up. The term "mutant organism" used herein means any suitable organism that contains genetic information which has been induced to mutate and is thus altered from the wild-type. Therefore naturally occurring mutations in the wild-type organism are not within the scope of this term. The present invention further comprises an UNC-53 protein or a functional equivalent or fragment thereof, which protein may be encoded by a cDNA according to the invention, and which protein has the amino acid sequence shown in Figure 4 from amino acid position 135 to amino acid position 1528; this corresponds to the 8A clone. More preferably the UNC- 53 protein, when encoded by a cDNA according to the invention, comprises the amino acid sequence shown in Figure 4. In another aspect of the invention the protein comprises an UNC-53 protein or a functional equivalent, fragment or bioprecursor of the protein which comprises the sequence of from amino acid position 135 to amino acid position 1583 of the amino acid sequence shown in Figure 6. Preferably, the UNC- 53 protein when encoded by a cDNA in accordance with the invention has the amino acid sequence shown in Figure 6. The UNC-53 protein of C. elegans or a functional equivalent, fragment or bioprecursor of the UNC-53 protein, may advantageously be used as a medicament to promote neuronal regeneration, revascularisation or wound healing or the treatment of chronic neuro- degenerative disorders or acute traumatic injuries. Similarly, the UNC-53 protein produced by the transgenic cells, tissue or organisms according to the invention may also be used in the preparation of a medicament for treatment of the conditions as described above. Furthermore, in an alternative embodiment of the invention the nucleic acid sequence itself encoding an UNC-53 protein of C. elegans or a functional equivalent, fragment or bioprecursor of the protein may also be used as a medicament or, alternatively in the preparation of a medicament, to promote neuronal regeneration, vascularisation or wound healing or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. Typically neurological conditions which may be treated by either an UNC-53 protein or a functional equivalent thereof, or a nucleic acid according to the invention, comprise peripheral nerve regeneration after trauma; recovery of function of the spinal cord after spinal cord trauma or peripheral neuropathies. Similarly neuro- degeneration diseases which may be treated include Alzheimers disease or Huntingdons disease. Acute traumatic injuries such as stroke, head trauma or haemorrhages may also advantageously be treated. The nucleic acid sequence according to the invention may comprise a cDNA sequence according to the invention as described above or alternatively may be genomic DNA derived from C. elegans. The UNC-53 protein of C. elegans. or a functional equivalent, fragment or bioprecursor of said protein may be incorporated into a pharmaceutically acceptable composition together with a suitable carrier, diluent or an excipient therefor. The pharmaceutical composition may advantageously comprise, additionally or alternatively to the UNC-53 protein according to the invention, the nucleic acid sequence according to the invention as defined above. The present invention also provides for a method of determining whether a compound is an inhibitor or an enhancer of the regulation of cell shape or otility or the direction of cell migration in a transgenic cell, tissue or organism according to the invention as described herein. The method preferably comprises contacting the compound with a transgenic cell, tissue or organism according to the invention as described above, and screening for a phenotypic change in the cell, tissue or organism. Preferably the compound comprises an inhibitor or enhancer of a protein of the signal transduction pathway of the cell, tissue or organism of which UNC-53 is a component or is an inhibitor or enhancer of a parallel or redundant signal transduction pathway. Such enhancers or inhibitors are defined by particular phenotypic changes in the transgenic cell, tissue or organism, for example changes in cell shape or mobility or the direction of cell migration. Preferably the compound is an inhibitor or an enhancer of the activity of UNC-53 protein of C. elegans or a functional equivalent, derivative or bioprecursor thereof, which protein is expressed in the transgenic cell, tissue or organism as defined herein. Preferably the phenotypic change to be screened comprises a change in cell shape or a change in cell motility. Where a transgenic cell is used in accordance with one embodiment of the method of the invention, an N4 neuroblastoma cell may be used and in such an embodiment the phenotypic change to be screened may be the length of neurite growth or changes in filipodia outgrowth or alternatively changes in ruffling behaviour or cell adhesion. In an alternative embodiment of the method of the invention, the transgenic cell may comprise an MCF-7 breast carcinoma cell. Typically in such an embodiment the phenotypic change to be screened comprises the extent of phagokinesis. The method according to the invention, may also utilise a mutant cell or mutant organism according to the invention as described above, where the mutant cell is capable of growing in tissue culture and either of which cell or organism has a mutation in the wild-type unc-53 gene. In accordance with the present invention, a "phenotypic change", may be any phenotype resulting from changes at any suitable point in the life cycle of the cell, tissue or organism defined above, which change can be attributed to the expression of the transgene such as for example, growth, viability, morphology, behaviour, movement, cell migration or cell process or growth cone extension of cells and includes changes in body shape, locomotion, chemotaxis, mating behaviour or the like. The phenotypic change may preferably be monitored directly by visual inspection or alternatively by for example measuring indicators of viability including endogenous or transgenically introduced histochemical markers or other reporter genes, such as for example β- galactosidase. A compound which is identifiable by the method according to the invention as described above, as an enhancer of the regulation of cell shape or motility or the direction of cell migration in C. elegans may be used as a medicament, or alternatively in the preparation of a medicament, for promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. Examples of promoting neuronal regeneration include for example peripheral nerve regeneration after trauma and spinal cord trauma. Where a compound is identified in accordance with the method described above as being an inhibitor of the regulation of cell shape, the compound may be used as a medicament, or in the preparation of a medicament, for substantially alleviating spread of disease inducing cells, such as in spread of cancers, or the like in metastasis. Advantageously, any of the compounds which may have been identified as an inhibitor or an enhancer in accordance with the method as described above, may also be included in a pharmaceutically acceptable formulation comprising the respective compound and an acceptable carrier, diluent or excipient therefor. The particular mechanism of action of a compound identified as either an inhibitor or an enhancer of the cell motility or direction of cell migration is not limiting preferably the compound acts as an inhibitor or enhancer of a signal transduction pathway downstream. The compound may also act on parallel pathway or on the UNC-53 protein of C. elegans. For example, the method of action of the compound may include direct interaction with UNC-53 protein, interaction with processes for regulating phosphorylation of UNC-53 or for processes regulating activity of an unc-53 gene or for processes for post- transcriptional or post-translational modification or the like. Preferably the compound is identified by the method according to the invention as an inhibitor or an enhancer, by utilising differences of phenotype of the cell, tissue or organism, which are visible to the eye. Alternatively indicators of viability including endogenous or transgenically introduced histochemical markers or a reporter gene may be used. According to a further aspect of the invention there is also provided a transgenic cell or tissue culture which has been constructed to comprise a promoter sequence of an unc-53 gene of C. elegans or a functional fragment thereof, fused to a nucleic acid sequence encoding a reporter molecule. Preferably, the reporter sequence encoding the reporter molecule encodes for a detectable protein, for example one which may be monitored by eye inspection such as antibiotic resistance, β-galactosidase or a molecule detectable by spectrophotometric, spectrofluorometric, luminescent or radioactive assays. Preferably the reporter molecule is green fluorescent protein (GFP) , which advantageously allows inhibition or enhancement of the UNC-53 protein according to the invention to be monitored visually. The present invention also provides a method of determining whether a compound is an inhibitor or an enhancer of transcription of a an unc-53 gene in C. elegans. or a functional fragment thereof, which method comprises the steps of: (a) contacting said compound with a transgenic cell according to the further aspect of the invention as described above, (b) monitoring the reporter molecule and comparing results obtained from this monitoring step with a control comprising a transgenic cell having the promoter sequence of an unc-53 gene, or a functional fragment thereof and the reporter molecule, in the absence of the compound. In one embodiment of the method according to the invention the reporter molecule may comprise messenger RNA. Alternatively the reporter molecule may be green fluorescent protein (GFP) . A compound identified as an inhibitor or enhancer of transcription of the unc-53 gene or a fragment thereof may also be used as a medicament, or in the preparation of a medicament, for promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. Furthermore, such compounds may be included in a pharmaceutical formulation including a carrier, diluent or excipient therefor. The present invention also provides a kit for determining whether a compound is an enhancer or an inhibitor of the regulation of cell motility or shape or the direction of cell migration, which kit comprises at least a plurality of transgenic or mutant cells according to the invention as described above and a plurality of wild-type cells of the same cell type or cell line or tissue culture. Also provided by the present invention is a kit for determining whether a compound is an inhibitor or an enhancer of transcription of an unc-53 gene of C. elegans or a functional fragment thereof, which comprises at least a plurality of transgenic cells as described above and means for monitoring the reporter molecule . For the purposes of the present invention, the term "unc-53 gene or a functional fragment thereof" includes the nucleic acid sequence shown in Figure 1 or a fragment thereof, including the differentially spliced isoforms and transcriptional start of the unc- 53 gene sequence and which sequence encodes an UNC-53 protein or a functional equivalent, derivative, fragment or bioprecursor of the protein. The present invention also provides an oligonucleotide probe which comprises the carboxy- terminal 1.5 kb of the coding nucleic acid sequence shown in Figure 1 or a fragment thereof comprising not less than 15 base pairs. In addition, the present invention provides a further oligonucleotide probe comprising a nucleic acid sequence encoding the amino acid sequence as numbered 1 to 10 and 14 to 133, 487 to 495, 537 to 545, 1032 to 1037, 1097 to 1116 or 1300 to 1307, as shown in Figure 3 or a fragment thereof comprising between 18 and 24 base pairs. The oligonucleotide probes described above may also be advantageously be labelled for detection. The present invention also provides methods of identifying C. elegans genes or fragments thereof, which encode proteins which are active in the signal transduction pathway of which UNC-53 is a component and which are homologues of UNC-53. A preferred method comprises hybridizing to a C. elegans cDNA library an oligonucleotide probe according to the invention as described above, under appropriate conditions or stringency in order to identify genes having statistically significant homology with the cDNA clones of any one of the cDNA sequences according to the invention described above. Furthermore, there is also provided by the present invention a method of identifying a protein which is active in the signal transduction pathway of a cell. According to this aspect of the invention, the method comprises; (a) contacting an extract of said cell with an antibody to the UNC-53 protein or a functional equivalent, fragment or bioprecursor thereof, (b) identifying the antibody/UNC-53 complex, and (c) analysing the complex to identify any protein bound to the UNC-53 protein other than the antibody. The UNC-53 protein, therefore may bind regions of other proteins involved in the signal transduction pathway. It is also possible to sequentially identify a whole range of proteins involved in the signal transduction pathway. This aspect of the invention, further comprises a method of identifying a further protein or proteins which are active in the signal transduction pathway of a cell which method comprises: (a) forming an antibody to the identified protein bound to the UNC-53 protein in the method as described above, (b) contacting a cell extract of C. elegans with the antibody, (c) identifying the antibody/protein complex, (d) analysing the complex to identify any further protein bound to the first protein other than the antibody, and (e) optionally repeating steps (a) to (d) to identify further proteins in the pathway. According to this aspect of the present invention, the antibody, which is preferably a monoclonal antibody, such as for example monoclonal antibody designated as 16-48-2, starts the process by binding to the UNC-53 protein or a functional equivalent thereof in the signal transduction pathway. Any other proteins found complexed to the bound antibody or UNC-53 protein can then be used to identify further interacting proteins involved in the pathway. It may also be possible to identify proteins involved in the signal transduction of a cell by using UNC-53 protein of C. elegans. According to this aspect of the invention the method comprises: (a) contacting an extract of the cell with the UNC-53 protein of C. elegans or a functional equivalent, fragment or bioprecursor of said UNC-53 protein (b) identifying the UNC-53 protein/protein complex and (c) analysing the complex to identify any protein bound to the UNC-53 protein other than another UNC-53 protein This method can also advantageously be used to identify further proteins in a signal transduction pathway of a cell by contacting an extract of the cell used as described above, with any protein identified from step (c) above not being an UNC-53 protein and repeating steps (b) and (c) . Other methods which may be used for identifying proteins in a signal transduction pathway of a cell may comprise for example a western blot overlay method which method is well known to those skilled in the art. Cell extracts are run on SDS-gels to separate out protein and subsequently blotted onto a nylon membrane. These membranes may then be incubated, for example in a medium containing UNC-53 with a biotin label thereon and any protein conjugates visualised with a streptavidin-alkaline phosphatase conjugated antibody. The present invention also advantageously provides a process for the preparation of binding antibodies which recognise proteins or fragments thereof involved in the rate and direction of cell migration or the control of cell shape, for the above methods. Preferably the antibody is monoclonal antibody and more preferably monoclonal antibody 16- 48-2. The monoclonal antibody for binding to UNC-53 (or its functional equivalent) may be prepared by known techniques as described by Kohler R. and Milstein C. , (1975) Nature 256, 495 to 497. Another method which may be used to identify proteins involved in the signal transduction pathway involves investigating protein-protein interactions using the two-hybrid vector method. This method, which is well known to those skilled in the art, utilises the properties of the GAL4 protein in yeast. GAL4 is a transcriptional activator of galactose metabolism in yeast and has a separate domain for binding to activators upstream of the galactose metabolising genes as well as a protein binding domain. Nucleotide vectors may be constructed, one of which comprises the nucleotide residues encoding the DNA binding domain of GAL4. These binding domain residues may be fused to a known protein encoding sequence, such as for example unc-53. The other vector comprises the residues encoding the protein binding domain of GAL4. These residues are fused to residues encoding a test protein, preferably from the signal transduction pathway of C. elegans. Any interaction between the UNC-53 protein and the protein to be tested leads to transcriptional activation of a reporter molecule in a GAL-4 transcription deficient yeast cell into which the vectors have been transformed. Preferably, a reporter molecule such as β-galactosidase is activated upon restoration of transcription of the yeast galactose metabolism genes. This method enables any interactions between proteins involved in the signal transduction pathway to be investigated. Any proteins identified in the signal transduction pathway of the cell, which may be for example a mammalian cell, may also be included in a pharmaceutical composition together with a carrier, diluent or excipient therefor. The present invention also provides a process for producing an UNC-53 protein of C. elegans or a functional equivalent, fragment, or derivative of the protein, which process comprises culturing the cells transformed or transfected with a cDNA expression vector having any of the cDNA sequences according to the invention as described above, and recovering the expressed UNC-53 protein. The cell may advantageously be a bacterial, animal, insect or plant cell. A particularly preferred process for producing UNC-53 protein comprises using insect cells. Accordingly, the invention provides a process for producing an UNC-53 protein of C. elegans or a functional equivalent, fragment, derivative or bioprecursor of the UNC-53 protein, which process comprises culturing an insect cell transfected with a recombinant Baculovirus vector, said vector comprising a nucleotide vector encoding the UNC-53 protein or a functional equivalent, fragment or bioprecursor thereof downstream of the Baculovirus polyhedrin promoter and recovering the expressed UNC-53 protein. Advantageously, this method produces large amounts of protein for recovery. The insect cell may be from for example Spodoptera frugiperda or Drosophila Melanogester. In accordance with the present invention, a defined nucleic acid sequence includes not only the identical nucleic acid but also any minor base variations from the natural nucleic acid sequence including in particular, substitutions in bases which result in a synonymous codon (a different codon specifying the same amino acid) , due to the degenerate code in conservative amino acid substitution. The term "nucleic acid sequence" also includes the complimentary sequence to any single stranded sequence given which includes the definition above regarding base variations. Furthermore, a defined protein, polypeptide or amino acid sequence according to the invention, includes not only the identical amino acid sequence but also minor amino acid variations from the natural amino acid sequence including conservative amino acid replacements (a replacement by an amino acid that is related in its side chains) . Also included are amino acid sequences which vary from the natural amino acid but result in a polypeptide which is immunologically identical or similar to the polypeptide encoded by the naturally occurring sequence. Such polypeptides may be encoded by a corresponding nucleic acid sequence. The invention may be more clearly understood from the following description with reference to the accompanying drawings and photographs, in which Fig. 1 shows one strand of the C. elegans unc-53 mRNA translated into DNA (U to T) (5073 bases) which corresponds to the 8A clone variant encoding the corresponding 8A protein shown in Figure 3. Designations "TB" are positions onto which SL1 transplices have been identified at the 5' end of the sequence. Different mRNAs which differ in their 5' end therefore exist. Potential start methionines are double underlined (M) . Restriction endonuclease sites are indicated. A region of 8 sequential A bases at positions 4594 to 4601 is underlined. This region differs from the corresponding region of the known sequence in the database (F45E10.1) by having 8 rather than 7 A^denine (A) bases resulting in a frame shift (see Fig 15) and corresponds to the 7A form of the protein. The nucleic acid sequence from the database is also included in the nucleic acid sequences of the present application for reference only. Fig. 2 shows a comparison of the sequences of the 7A and 8A clones of Figure 1. Fig. 3 shows the predicted C. elegans amino acid UNC-53 sequence corresponding to the nucleic acid sequence of the 8A clone shown numbered from 1 to 1528. Again, potential start methionines are double underlined (M) . Designations "tb" are regions for PCR clones to identify PCR products. Other regions of interest are identified. The region indicated as S4 is part of a lambda clone - 16.8 kb of the UNC-53 nucleic acid. This sequence, when translated is part only of the UNC-53 protein. Yet, injection of this part gives transformation rescue in organisms, i.e. providing additional evidence for the existence of shorter forms of the protein. Fig. 4 shows the predicted C. elegans amino acid sequences of Figure 3 in the three letter code for indicating amino acids. Fig. 5 shows the predicted C. elegans amino acid sequence UNC-53 sequence corresponding to the nucleic acid sequence of the 7A clone of Figure 2 shown numbered from 1 to 1583. Fig. 6 shows the amino acid sequence of Figure 5 in the corresponding three letter code format for indicating amino acids. 311 - 22 - Fig. 7 shows sequences of low complexity of the amino acid sequence of the corresponding nucleic acid sequence of the 8A clone of Fig. 3 identified with the filter and SEG algorithms of the BLAST sequence homology package. Regions of low complexity are indicated by "X" for the first copy of the sequence and by underlined amino acids for the second copy. Fig. 8 shows, schematically, the known branches of the highly conserved Receptor Tyrosine Kinase/GRB2 signal transduction pathway including UNC-53. Fig. 9 shows, schematically, the differences in cells with increased and decreased UNC-53 expression from the wild type. Fig. 10 is a graph of the effect of anterior- posterior signal strength on growth cone extension rate of C. elegans organisms, with increased and decreased UNC-53 expression from the wild type. This graph translates the observation that UNC-53 acts in a dosage-dependent way to direct the rate of extension in the anterior/posterior axis into a model. The signal received e.g. (egl-15) is an RTK mediated signal which is postulated to be received by UNC-53 and which results in extension in the anterior/posterior axis. The graph shows an allelic series of organisms with a graded reduction in extension from increased UNC-53 expression down through wild type to a reduced UNC-53 expression. The prediction is thus: for the same level of RTK mediated signal the increased/decreased growth in the anterior/posterior axis depends on the level of expression of UNC-53 in any organism. The graph also reflects the prediction that for organisms with a particular level of UNC-53 overexpression there is no requirement for a signal before growth cone extension occurs. This extension is likely to be in a random direction or influenced by alternative factors. Fig. 11 shows constructs of unc-53 nucleic acid including identified functional domains . Fig. 12 shows 5' amino terminus of the cDNA encoding from the first methionine amino acid through the actin binding protein homology domain (amino acids 1-133 from Fig. 1) and oligonucleotides designated oligo BGOl, BG02 and BG03 (amplification strategies of amino terminus of the unc-53 cDNA) . Combinations of oligo BG02 with either oligo BG02 or BG03 were used to amplify the 5' terminus of the cDNA from the first methionine through the actin binding protein homology domain (amino acids 1-133) . All of the oligonucleotides are underlined and sequences identical to the cDNA are shown in upper-case. In addition to unc-53 sequence, oligo BG02 contains a stop codon and the recognition sequence for BamHI endonuclease. Oligo BGOl has engineered EcoRI and Ndel recognition sites for inclusion in bacterial expression vectors. Both constructs remove the 5' untranslated region of unc-53 and oligo BG03 contains a NotI cleavage site. Oligo BG03 has an improved riboso e binding site similar to mammalian ribosome binding sites. Use of BG03 in PCR thus results in constructs optimised for mammalian expression. Figure 13 shows, schematically, constructs of the plasmids pTB109, pTBHO, pTBlll and pTB112. Fig. 14(a) shows a summary of transcript starts at the 5' end of the unc-53 gene. Different identified transcript starts and corresponding in- frame ATG-codons are marked. Tab2 is the oligo from within cDNA M5 which was used in RT PCR experiment to identify/isolate the 5' ends of different UNC-53 mRNAs. Figure 14(b) shows the location of the different transcript starts on the genomic DNA and the position of the S4 Lambda clone with respect to genomic DNA. Figure 14(c) shows the sequence near the 5' and 3' ends of the lambda S4 clone, identifying its composition corresponding to the 5' and at position 2260 of comid COGHIO and the 3' end of F45R10 at position 3287. Fig. 15 shows the alignment of UNC-53 protein with the carboxytermini of the α-actinin and β- spectrin family (QY is UNC-53) . Fig 16 shows the predicted actin binding sites of UNC-53. The comparison shows internal LKK repeats. Fig. 17 shows the alignment of the candidate SH3 binding sites in UNC-53 with known SH3 sites of other named proteins. Proteins at positions 4 and 7 are critical for binding into SH3 pockets. Fig. 18 shows the alignment of the predicted amino acid sequences from F45E10.1 (available in public database) with UNC-53. The different identified amino acid is shown at position 1186. The frameshift which results in the different amino acid sequence from position 1513 is a result of the different number of adenine bases in the nucleic acid sequence (see Fig. 1) . Fig. 19 is a series of photographs of C. elegans embryos (strain TB4EX25 (Table 1) [UNC-53-UNC-54 construct]). The photographs show increased outgrowth in the anterior-posterior axis of body wall cells in the C. elegans embryos which overexpress UNC-53 (im unofluorescence with UNC-53 mab 16-48-2) Individual photographs are as follows: A: early embryo comma stage B: 1.5 fold stage embryo C: 3 fold stage embryo, first plane of focus D: 3 fold stage embryo, second plane of focus E: 3 fold stage, mosaic animal, 3-cells in a quadrant giving expression. This demonstrates that immunofluorescence provides a measure of the expression in the transgenic lines of UNC-53. Fig. 20A is a photograph of C. elegans embryo containing DNA construct pTBllO (strain TBAIn76(table 1)). Shown is expression of UNC-53 following heat shock. Fig. 20B and C are photographs of C. elegans embryos containing DNA construct pTBlll (strain TBlExδ (table 1)). Shown is transgenic expression of UNC-53 in echano-sensory neurons. Fig. 21 shows photographs of the following: A: A wild-type UNC-53 LI larva of genotype 4-25 (strain TB4Ex25) as in photographs 19B, C and D. B: LI larva of 4-25 with morphological defects associated with muscle abnormalities. C: Lethal phenotype of 4-25. D: LI larva of 4-25 showing misshapen animal and muscle cells with increased extensions. Also shows constipation problems associated with abnormal muscle pattern. E: LI larva of the heat-shock line TBAIn76 (table 1) exhibiting morphological abnormalities following heat shock and recovery. F: LI larva of line TBAIn76 (table 1) showing morphological defects in the pharynx. All Figs. 19, 20 and 21 are Nor arski optics of live embryos. Fig. 22 is a map of plasmid pTBllO (tables 1 and 2) a heat shock promoter fusion, indicating restriction endonuclease sites. Fig. 23 is a map of plasmid pTB112 (tables 1 and 2) a muscle specific UNC-54 fusion, indicating restriction endonuclease sites. Fig. 24 is a map of plasmid pTB54 (the 8A clone variant) (tables 1 and 2) . In the construction of this plasmid the complete unc-53 cDNA (tb3M5) of the 8A variant, including 5' and 3' UTRs was cloned as a Notl-Apal fragment into the mammalian expression vector pcDNA3 (Invitrogen) . Figure 25 is a map of plasmid pTB72 (the construct encoding the 7A clone variant of UNC-53 cDNA of Figure 2. Figure 26 is nucleotide sequence of the plasmid map of Figure 25. Figure 27 is a map of plasmid pTB73. Figure 28 is a nucleotide sequence of plasmid pTB73 of Figure 27. Figure 29 is a map of plasmid pCB50. Figure 30 is a nucleotide sequence of plasmid pCB50 of Figure 29. Figure 31 is a map of plasmid pCB51. Figure 32 is a nucleotide sequence of the plasmid pCB51 of Figure 31. Figure 33 is a map of plasmid ppCB55. Figure 34 is a nucleotide sequence of plasmid pCB55 of Figure 33. Figure 35A illustrates a flowchart of the actin co-sedimentation assay. Soluble UNC53 protein was incubated with monomeric G-actin in a buffer containing ATP. Polymerization of G-actin to F-actin was induced by increasing the salt concentration to 100 mM, F-actin protein complexes were collected by centrifugation and analyzed by SDS-PAGE and fluorography. Figure 35(B) illustrates the concentration series of the actin co-sedimentation assay. The full length UNC-53 encoding cDNA (pTB72) was transcribed and translated in vitro and co-sedimented with F-actin at a starting G-actin concentrations ranging from 0 to 250 mg/ml. See methods for details. S=supernatant after airfuging. P=pellet after airfuging. Figure 35(C) illustrates both the full length (pTB72) and amino terminal deleted UNC53 (pTB73) protein co-sediment with F-actin. Starting G-actin concentration was 500 mg/ml. S=supernatant, P=pellet, R= starting in vitro reaction. Figure 36(A) is a flowchart of a SEM-5 binding experiment. The truncated UNC53 cDNA (pTB50) was transcribed and translated in vitro and incubated with SEM5-GST sepharose or GST sepharose. After four washes, the remaining proteins bound to the matrix were analyzed by SDS-PAGE and fluorography. Figure 36(B) illustrates an immunoprecipitation experiment of radioactively labelled UNC53 proteins from the TnT pTB50 reaction shows that monoclonal antibody 16-48-2 recognizes both the native (-SDS lanes) and denatured (+SDS) protein products in vitro. c=control reaction without anti-UNC53 monoclonal antibody 16-48-2. ab=reaction with monoclonal antibody 16-48-2. See methods for details. Figure 36(C) illustrates the results of SEM-5-GST binding experiments outlined in (a) . In vitro translated UNC53 protein were analyzed by SDS-PAGE and fluorography. See methods for details. sup=supernatant Figure 36(D) illustrates a western blot overlay experiment of UNC-53 (construct pTB61) expressed in bacterial cells. Cell lysates were denatured in Laemmli buffer and the proteins separated by 5-25% gradient SDS-PAGE. The arrowhead indicates the presence of full length UNC-53 in the induced bacterial lysate. Additional gels were blotted to nylon membrane, incubated with biotinylated GST or biotinylated GST-GRB2 protein and bound protein complexes subsequently detected with a streptavidin- alkaline phosphatase conjugated antibody. See methods for details. U=uninduced bacterial cell lysate, I=induced bacterial cell lysate. Figure 37 is a series of photographs of C . elegans which illustrates overexpression of UNC-53 in body muscle cells results in over-extension along the longitudinal axis. Transgenic C. elegans embryos carrying the construct pTB113 were analyzed for UNC-53 activity by immunohistochemistry with the 16-48-2 antibody. Starting from the photograph (a) of the top left panel of Figure 37. (A) and (B) illustrate ectopic growth cone spikes (indicated by the arrowheads) are observed early in myogenesis in the comma stage embryo. (C) and (D) illustrate over-extension of muscle cells in the head region of a three fold embryo during outgrowth. (E) illustrates over-extension is clearly observed along the anterior-posterior axis (indicated by the arrowheads) of a late 3 fold embryo. Figure 38 is a map of plasmid ptbll3. Figure 39 is a nucleotide sequence of the plasmid ptbll3 of Figure 38. Figure 40 illustrates neurite tree length and fraction positive cells enhancement in a transfected cell C9 compared to wild-type cells CO. Black bars indicate fraction positive cells whereas hatched bars indicate neurite tree length cells, as described in example 8. Figure 41 illustrates the results obtained following application of compound (I-(IH-pyrrol-2- ylmethyl)-2-piperidinone) to N4 transfected cells. The dark coloured bars indicate fraction positive CO clones whereas the hatched bars of the chart indicate fraction positive C9 clones. The following sequence listings are referred to in the specification. Sequence ID No 1: is a nucleic acid sequence - 29 - corresponding to the 7A nucleic acid sequence variant of Figure 2. Sequence ID No 2: is a nucleic acid sequence corresponding to the 8A nucleic acid sequence variant of figure 1. Sequence ID No 3 : is an amino acid sequence corresponding to the amino acid sequence of the 8A variant of figure 3. Sequence ID No 4: is an amino acid sequence corresponding to the amino acid sequence of the 7A variant of figure 2. Sequence ID No 5: is an amino acid corresponding to the amino acid sequence shown in figure 7. Sequence ID No 6: is a nucleic acid sequence of the oligo BG03 sequence of figure 12. Sequence ID No 7: nucleic acid sequence of the oligo BGOl sequence of figure 12. Sequence ID No 8: is a nucleic acid sequence of the oligo BG02 sequence of figure 12. Sequence ID No 9: is an amino acid sequence corresponding to the amino acid UNC-53(a) sequence shown in figure 17. Sequence ID No 10: is an amino acid sequence corresponding to amino acid sequence of sequence (b) of UNC-53 shown in figure 17. Sequence ID No 11: is an amino acid sequence corresponding to the sequence (c) of an SOS shown in figure 17. Sequence ID No 12: is an amino acid sequence corresponding to the sequence (d) of an SOS shown in figure 17. Sequence ID No 13: is an amino acid sequence corresponding to the sequence (d) of an SOS shown in figure 17. Sequence ID No 14: is an amino acid sequence corresponding to the sequence (f) of SOS 1359 shown in figure 17. Sequence ID No 15: is an amino acid sequence corresponding to the sequence (g) of SOS 1377 shown in figure 17. Sequence ID No 16: is an amino acid sequence corresponding to the sequence (h) of Dynamin shown in figure 17. Sequence ID No 17: is an amino acid sequence corresponding to the sequence (i) of dynamin shown in figure 17. Sequence ID No 18: is an amino acid sequence corresponding to the sequence (j) of PI3K p85 shown in figure 17. Sequence ID No 19: is an amino acid sequence corresponding to the sequence (k) of P13k p85 shown in figure 17. Sequence ID NO 20: is an amino acid sequence corresponding to the sequence (1) of AFAP-110 shown in figure 17. Sequence No 21: is an amino acid sequence corresponding to the sequence (m) of AFAP-110 shown in figure 17. Sequence No 22: is an amino acid sequence corresponding to the sequence (n) of 3BP-1 shown in figure 17. Sequence ID No 23: is an amino acid sequence corresponding to the sequence (o) of 3BP-1 shown in figure 17. Sequence ID No 24: is an amino acid sequence which corresponds to the amino acid sequence from positions 106 to 133 of UNC-53 shown in figure 16. Sequence ID No 25: is an amino acid sequence which corresponds to the amino acid sequence from positions 1093 to 1120 of UNC-53 shown in figure 16. Sequence ID No 26: is a nucleotide sequence corresponding to the nucleotide sequence of ptB72 shown in figure 26. Sequence ID No 27: is a nucleotide sequence corresponding to the nucleotide sequence of ptB73 shown in figure 28. Sequence ID No 28: is a nucleotide sequence corresponding to the nucleotide sequence of pCB50 shown in figure 30. Sequence ID No 29: is a nucleotide sequence corresponding to the nucleotide sequence of pCB51 shown in figure 32. Sequence ID No 30: is a nucleotide sequence corresponding to the sequence of pCB55 shown in figure 34. Sequence ID No 31: is a nucleotide sequence corresponding to the nucleotide sequence of ptbll3 shown in figure 39. Sequence ID No 32: is an amino acid sequence corresponding to the amino acid sequence as numbered from amino acid 1 to 110 of the sequence figure 3. Sequence ID No 33: is an amino acid sequence corresponding to the sequence as numbered from amino acid sequence 114 to 133 of the sequence of figure 3. Sequence ID No 34: is an amino acid sequence corresponding to the sequence as numbered from amino acid sequence 487 to 495 of the sequence of figure 3. Sequence ID No 35: is an amino acid sequence corresponding to the sequence as numbered from amino acid sequence 537 to 545 of the sequence of figure 3. Sequence ID No 36: is an amino acid sequence corresponding to the sequence as numbered from amino acid sequence 1032 to 1037 of the sequence of figure 3. Sequence ID No 37: is an amino acid sequence corresponding to the sequence as numbered from amino acid sequence 1097 to 1116 of the sequence of figure 3. Sequence ID No 38: is an amino acid sequenc ecorresponding to the sequence as numbered from amino acid sequence 1300 to 1307 of the sequence shown in figure 3. Sequence ID No 39: is an amino acid sequence corresponding to the amino acid sequence (a) of «-actinin (aact) shown in figure 15. Sequence ID No 40: is an amino acid sequence corresponding to the amino acid sequence (b) of unc-53 shown in figure 15. Sequence ID No 41: is an amino acid sequence corresponding to the amino acid sequence (c) of β-spectrin (spectrin) shown in figure 15. Sequence ID No 42: is an amino acid sequence corresponding to the amino acid sequence (d) of «actinin (aact) shown in figure 15. Sequence ID No 43: is an amino acid sequence corresponding to the amino acid sequence (e) of UNC-53 shown in figure 15. Sequence ID No 44: is a amino acid sequence corresponding to the amino acid sequence (f) of β-spectrin (spectrin) shown in figure 15. Sequence ID No 45: is an amino acid sequence corresponding to the amino acid sequence (g) of «-actinin shown in figure 15. Sequence ID No 46: is an amino acid sequence corresponding to the amino acid sequence (h) of UNC-53 shown in figure 15. Sequence ID No 47: is an amino acid sequence corresponding to the amino acid sequence (I) of β-spectrin shown in figure 15. Sequence ID No 48: is a nucleotide sequence corresponding to the nucleotide sequence of S4 lambda clone shown in figure 14(c). The inventors have established a set of processes particularly in C. elegans to select for inhibitors or enhancers of UNC-53. This screen is based on transgenic or mutant organisms or cells in which we have introduced a nucleic acid sequence encoding UNC- 53 under the control of a specific promoter. In these organisms UNC-53 is over-stimulated as judged by increased extension of growth cones of muscle cells which over-express UNC-53 in C. elegans. This leads to a range of phenotypes in both embryonic and poste bryonic development(from death to defective morphology and motility) . These phenotypes can be scored with simple means at high throughput. Similar results can be obtained with heat shock specific lines. The basis of our test for inhibitors of the UNC-53 signal transduction pathway is reversal of this phenotype to an improved state of health. We have constructed transgenic strains of C. elegans which over-express UNC-53 in body muscle. This results in increased extension of muscle cells and embryonic lethality (17 to 80% of transgenic organisms depending on the line used) . These strains are used to directly screen for drugs which interfere with unc-53 genes, UNC-53 protein activity or any regulatory factor thereof to thereby suppress the background lethality. Another process which may be used for selecting inhibitors or enhancers of UNC-53 uses a constitutively active unc-53. This is achieved by mutating the nucleotide binding domain such that GTP or ATP is always bound or by covalently attaching SEM- 5. In this strategy, transgenics (tissue cultured cell lines, or organisms such as nematodes) are generated which maintain unc-53 in a higher endogenous level of activity. Over-extension and subsequent lethality results in a greater proportion than that observed in the UNC-54/UNC-53 wild type lines. By screening for survivors after drug treatment, this assay specifically identifies inhibitors of downstream components in the signal transduction pathway. Another process utilises an UNC-53 promoter. In this approach, an UNC-53 promoter is fused to a nucleic acid sequence encoding a reporter molecule, for example green fluorescent protein (GFP) . Cells will glow when trans-acting factors bind to the promoter to activate transcription. By screening for cells which do not fluoresce, molecules which inhibit transcription of UNC-53 are identified. The processes for selecting inhibitors and/or enhancers according to the invention are preferably carried out on whole animals. This can be done using a C. elegans system. The advantages of these tests include: (1) The screening in a whole animal assay. C. elegans is a complex multicellular organism with a full nervous system, digestive system, etc. Its anatomy and development has been described in extreme detail. It is one of the best-characterised higher organisms at the genetic, molecular, developmental and cell biological level. Any observed changes to phenotype can be checked against this database. (2) To study effects on rate and directionality of cell migration and the change of cell shape it is important to leave the cells under study in a setting where they are surrounded by the in vivo interacting tissues, cells and substrates for cell migration etc. This can be done using whole C. elegans subjects. A situation has been created where the given pathway is over-stimulated leading to an easily scorable phenotype which can be reverted in any assay or process. (3) The endpoint of the screen is the substantially increased health of the organism. This permits the exclusion of non-specific and toxic compounds. (4) A complete and specific inhibition of UNC-53 in the transgenics will lead at the worst to the phenotype of an UNC-53 reduction or loss of function mutant which we have described, can recognise and have shown not to be essential for viability. (5) The test can be adapted to make full use of the advantages of the C. elegans model system such as the possibility to conduct the test chronically over several generations and the possibility to conduct the test in different genetic backgrounds, e.g. RTK constitutive or defective. (6) C. elegans exhibits a complex set of wild type, drug- and mutation-induced phenotypes such as changes in body shape, subtle changes in locomotion, mating behaviour, chemotaxis, pharyngeal pumping, egg laying behaviour, which can be used as part of a phenotype analysis or screen. The results of C. elegans research described herein has provided important breakthroughs in biomedical research fields such as programmed cell death, neuronal guidance, the Receptor Tyrosine Kinase/RAS signal transduction pathway, integrin/cell adhesion receptor signalling, etc., The biochemical association of UNC-53 in the RTK signal transduction pathway enables identification of genes or of biochemical pathways which are targets for pharmacologically or pharmaceutically active compounds and the development of high throughput and mode of action specific drug screens using wild type, mutant and transgenic animal strains including, in particular, C. elegans. Thus pharmacological manipulation of the UNC-53 pathway is now possible on the following rationale: We have scientific arguments to expect C. elegans UNC-53 to interact in vivo with the other components of RTK signal transduction pathways based on: (1) The observation that C. elegans SEM-5 and GRB-2 are mutually exchangeable in vivo, combined with our observed in vitro binding of both GRB-2 and SEM-5 to UNC-53. Thus, C. elegans UNC-53 will be able to interact with the activated GRB-2/RTK receptor in mammalian cells. (2) UNC-53 interacts with the rabbit actin- cytoskeleton Expression of C. elegans UNC-53 in mammalian cell lines represents a shortcut to develop pharmacological assays and screens to target this pathway. We have shown that over-expression of the C. elegans UNC-53 in C. elegans yoblasts leads to over-extension of these cells in the anterior/posterior axis of the embryo and ultimate disorganisation of the muscle cell and myofilament pattern. (Over)-expression of C. elegans UNC-53 in a human cell line leads to a detectable change in phenotype, in particular increased motility of cells, increased outgrowth of neurons and morphological changes in the elongation and cytoskeletal morphology of differentiating myotubes. The C. elegans unc-53 Open Reading Frame (ORF) (with and without optimised Kozak consensus sequence) of both 7A and 8A clone variants has been cloned between the CMV major intermediate early promoter/enhancer and bovine growth hormone polyA signal sequence of expression vector pcDNA3 (Invitrogen) . This vector is designed for high level stable and transient expression in most mammalian cells. The following additional considerations require mention: (1) Genetic analysis of reduction in UNC-53 function and ectopic expression experiments suggest that UNC-53 acts in a highly dosage-dependent manner. As is the case for RAS, increased expression may lead to lowering the threshold of RTK-signal required for a given response or may remove the requirement for an activating signal to obtain a phenotype response (Fig 10) . In addition UNC-53 is an unusually low abundance protein in wild type C. elegans. It is therefore likely to be necessary or useful to control the temporal and quantitative expression of UNC-53 in the proposed assay conditions in all organisms or cells to be assayed. The already available or a further optimised expression cassette is then cloned in expression vectors with IPTG- inducible or tetracycline-repressible promoters. It is realised that both the Lac and Tet expression systems are leaky. Additional other repressible/inducible expression systems (e.g. Mx promoter) or weak mammalian promoters might be preferred. (2) Over-expression of the endocytosis controlling protein dynamin leads to phenotypes which are not associated with dynamin function in the cell but which are thought to be due to sequestration of the GRB-2 pool in the cell (GRB-2 is an adaptor for a variety of signal transduction pathways) . Such sequestration is unlikely to lead to "positive effects" on the activity of the cell such as is observed in the presently described assay system (increased cell process extension or motility), see Fig 19. Based on the homology between UNC-53 and GTP-binding, we can also predict specific mutations in the nucleotide-binding pocket or the predicted effector region which should lead to loss of function. Sequence analysis of unc-53 alleles is instructive in determining which amino acids of UNC-53 are essential for function, e.g. as exemplified by the indication that an allele (nl52) which has a differential effect on anterior versus posterior guidance has a deletion in a region of differential splicing. The differential splices of the C. elegans unc-53 gene encode different variants of the protein which independently affect posterior or anterior migration and/or cell specificity. One predicted exon in C. elegans unc-53 is indicated in Fig 1. It is conceivable that of two variants of the same protein one is inhibited or enhanced by a particular compound whereas the other is not (or to a lesser degree) . Such a compound could then be used to control direction of migration or cell specificity by selective inhibition or enhancement. (3) To develop pharmacological screens for inhibitors of a biochemical pathway a "gain of function" phenotype has been invented which can be expected to revert to wild type in the presence of specific inhibitors. Overexpression of UNC-53 in C. elegans myoblasts already leads to lethal subviable muscle phenotypes which can be easily scored with high throughput or a scorable heat shock inducible phenotype (Fig 21) . They may form the basis for a pharmacological screen for inhibitors. A similar screen is obtained for over-expressing UNC-53 in mammalian cells. An alternative strategy is based on the homology to GTP binding proteins, RAS and dynamin and NTPases. We can introduce amino-acid changes in the nucleotide binding pocket which are predicted/expected to lead to a constitutively activated or inactivated UNC-53. Similar changes are based on homologies with SOS, dynamin or ATP/GTP binding proteins from homology tables. (4) Correct expression of UNC-53 in each cell line may be assessed by immunofluorescence and western blot analysis with the monoclonal antibody ( ab) designated as 16-48-2. The inventors have thus expressed and stably integrate the expression constructs in the neuronal, myoblast and 3T3 cell lines. These cell lines are primarily used to: - Assess the effect of UNC-53 expression on the morphology, motility, metastatic potential and growth cone extension of the cell lines. - Produce protein and mRNA - Screen for pharmacological compounds inhibiting observed UNC-53 mediated phenotypes - Analyse signal transduction pathways associated with UNC-53 activation (for example, phosphorylation,) - Immunofluorescence studies with mab 16-48-2 to assess changes in subcellular localisation following growth factor treatment. Thus, the present invention provides for the identification of compounds which inhibit or enhance the UNC-53 signal transduction pathway. Such compounds can be used in the control of cell directional migration, motility and differentiation. These compounds are useful in the treatment of oncogenesis, psoriasis, neuronal degeneration and cell migration (metastasis) . The present invention also provides the ability to identify nucleic acid sequences and proteins which are involved in the UNC-53 pathway in C. elegans. Such nucleic acid sequences and proteins may be UNC-53 equivalents, members of an UNC-53 pathway or may be _ __ - 4 1 - nucleic acid sequences or proteins which interact in the UNC-53 pathway, for example as demonstrated by the GRB-2/SEM-5 proteins. This knowledge of the UNC-53 pathway in C. elegans can be established as can factors which influence the functioning of the pathway, for example, factors/ proteins which feed into the pathway or are of a parallel pathway which at least, in vitro, compensates for steps in an UNC-53 pathway. The identification, of other components in the UNC-53 signal transduction pathway: (1) help to determine the interaction of UNC-53 with known signal transduction pathways (RAC-, RHO-, cdc42- RAS-pathway exchange factors, downstream or regulating kinases) (2) identify the new interacting proteins which may constitute additional potential pharmacological targets. (3) may assign functions to the more than 1000 amino acids of UNC-53 which have no homology to known proteins. Accordingly, proteins which cross-react with anti-C. elegans UNC-53 protein antibodies can be isolated. The basic experiment protocol for purifying antigen-antibody complexes is described in Example 11. This system can also be used to identify factors which interact with proteins which bind to anti-UNC-53 C. elegans antibodies. The following tissue sources may be used for immuno-precipitation: (1) Mammalian cells which exhibit a phenotype after transfection with unc-53 indicating that it interacts with vertebrate components of its signal transduction pathway. (2) UNC-53 protein may be too low abundance to make affinity purification from wild type C. elegans feasible. The inventors have affinity-purified UNC-53 from already constructed transgenic C. elegans lines which express UNC-53 under control of the hsp-16 promoter and/or the myosin promoter. These experiments in C. elegans are justified because with the vast amount of sequence information (genomic and cDNA) available, one has a good chance of identifying the corresponding genes in the databases with a minimum of peptide sequence. Several types of proteins may be expected to co- purify with UNC-53, including GRB-2 and other proteins with SH3 domains of the Grb2 class or phosphorylation sites, RTK-receptors, subunits of an UNC-53 homo- heterodimer complex, downstream regulating kinases or proteins from the microfila ent cytoskeleton. This co-immuno-precipitation approach can also be used to dissect the order of events in this signal transduction pathway. For example: UNC-53 immuno- purified after stimulation of mammalian cell-lines with growth factors and pharmacological agents can also be assayed with respect to its state of phosphorylation, or complex formation with interacting proteins. Proteins interacting with specific UNC-53 domains are identified using a yeast two-hybrid system, whereby two sets of hybrid proteins are used to assay for functional restoration of the GAL4 transcriptional activator: the first consisting of a GAL4 activation domain/UNC-53 structural domain of unknown function, the second derived from a cDNA library cloned into an expression vector to generate a library of hybrid proteins containing a GAL4 DNA binding domain. The yeast two-hybrid system is well know in the art. A set of unc-53-fusion constructs can be constructed, including a fusion to (1) the full length protein, (2) the carboxyterminal domain (from second actin binding domain to the ATP/GTP binding domain) , (3) The aminoterminus (predicted cortical localisation domain up to the SH3 binding sites) , (4) a variety of overlapping constructs within the central domain of 1000 amino acids to which no function can as yet be assigned. These are tested in yeast to exclude those which lead to activation of the reporter gene in the absence of the cDNA-activator fusion. cDNA libraries were transformed into these reporter strains and positive clones identified. (In this strategy, screening of multiple libraries requires very little effort (transformation followed by plating on selective and indicator medium) ) . A preferred cDNA library is from cell lines in which a phenotypic change is observed following UNC-53 expression such as mouse N4 neuroblastoma cells or MCF-7 breast carcinoma cells. The yeast two hybrid system can identify interacting proteins or "sections" of nucleic acid which may not be translated in vivo but which may inhibit UNC-53. Candidate positives are tested for the fusion- protein dependence of the reporter gene activation. The cDNA insert in remaining positive clones is sequenced. The obtained sequence is screened through the databases, which provides, especially in the case of C. elegans clones, significant extra sequence. Another system also exists for the identification of proteins which bind or modify UNC-53. An UNC-53 protein is bound by conventional techniques to a column. A sample to be tested is then passed over the column. This sample may be fractions from cells from C.elegans. mammals or any other organism. These sample fractions may have been incubated with 32 ATP. In this course the "reaction" of the labelled fraction with UNC-53 can be determined. If the UNC-53 on the column becomes 32 P phosphorylated then this indicates that the sample fraction contains an UNC-53 modifying protein. Alternatively a constituent of the sample may bind to the UNC-53 and remain bound therewith on the column. The retention of any fraction of the sample on the column and the identification of the fraction can easily be determined by techniques known in the art. Example 9 describes the identification of sensitive, dependant or resistant mutations as direct tools for the development of screens for compounds with similar or antagonistic activities. Both resistant and sensitising mutations may have a phenotype in the absence of the compound and no or a different phenotype in the presence of the compound. This permits the introduction of action-specificity in the screens. High throughput screens are a basic feature of C__ elegans genetic methodology. Non-complementation screens for new alleles in a locus require setting up of up to 8000 separate worm populations starting from one hand-picked individual each. This is done in 24 well plates or small Petri-plates. These are subsequently (after 1 or 2 generations) visually screened for a complex behavioural phenotype. For pharmacological screens where populations can be started from multiple individuals pipetted from a pool of synchronised eggs, high throughput screens can also be developed. If the endpoint of the assay can be scored in liquid, populations can be set up in icrotitreplates. If the end-point is linked to a reporter gene (e.g. β-galactosidase activity) ELISA type colour-metric assays can be used to score the end-point. C. elegans can also be introduced into soils, exposed to compounds and subsequently recovered and assayed. Such endpoints are used in the heat- shock assay developed by Stressgen (Stringham & Candido (1994), Environ. Toxicology and Chemistry, 11(8) , 1211-1220). Gain of function mutants of C. elegans or transgenic C. elegans in which a pathway of interest has been over- or constitutively activated, causing a dominant phenotype which can be used to develop specific screens for inhibitors. Transgenic lines expressing UNC-53 ectopically under the C. elegans heat-shock (hsp-16) promoter, and body wall muscle (unc-54) promoter have been constructed. These lines lead to dominant phenotypes in development and are used directly to screen a spectrum of compounds. Where necessary or deemed useful endogenous C. elegans genes can be replaced by or complemented with human signal transduction pathways. DEPOSITED CELL LINES AND PLASMIDS LMBP ACCESSION STRAIN NAME DATE OF DEPOSIT NUMBER pTB54 22 MAY 1995 3296 Plasmid pTB112 22 MAY 1995 3295 Plasmid pTB72 22 MAY 1996 3486 TB4EX25 22 MAY 1995 1384 CB Cell Line TBAIn76 22 MAY 1995 1385 CB Cell Line HYBRIDOMA 22 MAY 1995 1383 CB Cell Line MCF-7 TRANSFECTED BREAST CARCINOMA CELL LINE 24 MAY 1996 1550 CB TRANSFECTED N4 NEUROBLASTOMA CELL LINE 24 MAY 1996 1549 CB WILD TYPE MCF-7 BREAST CARCINOMA CELL LINE 24 MAY 1996 1551 CB The above plasmids and cell-lines were deposited at the Belgian Coordinated Collections of Micro organisms (BCCM) at Laboratorium voor Moleculaire Biologie - Plasmidencollective (LMBP) B-9000, Ghent, Belgium, in accordance with the provisions of the Budapest Treaty of 28 April 1977. The present invention will now be described with reference to the following Examples. Examples Example 1 - Molecular Characterisation of unc-53 gene in C. elegans Screen for muscle pattern mutants : C. elegans has two sets of muscles which are suitable to study this problem, the body wall muscles and the sex muscles. The sex muscles are a set of 16 muscle cells (4 muscle types) in the hermaphrodite and 41 cells in the male (10 muscle types) with distinct attachments points on the hypoder is and gonads. The sex muscles develop postembryonically and are not required for viability. The body wall muscles are arranged longitudinally (roughly 2 cells abreast) into four quadrants. At birth there are 81 cells. In postembryonic development, extra muscles interdigitate with these bringing the total number of body wall muscles in the hermaphrodite to 95. Head, neck and body muscles can be distinguished within these rows on the basis of their innervation and patterning within the rows. We have screened 4800 haploid genomes using Nomarski and polarized microscopy for mutants with specific attachment or pattern defects in a subset of the male sex muscles but with wild type body wall muscle pattern and myofilament organization, wild type movement and wild type male bursa anatomy (a sensitive indicator of wild type morphogenesis) . Amongst the 21 identified mutants we selected for further study those with specific phenotypes in both the male and hermaphrodite sex muscles. As these muscles lie in different regions of the animals this was thought to reduce the chance that the male tail phenotype is a pleiotropic consequence of changes in regional identity of the tail or defects in male tail hypodermal lineage or morphogenesis. Muscle phenotype of e2432. Mutant e2432 was isolated on the basis of its phenotype in the male spicule retractor muscles, a pair of bilaterally symmetrical muscles which attach anteriorly to the body wall and posteriorly to the base of the spicules. The spicule retractors of mutant e2432 are shorter than wild type. Their attachment to the spicules is wild type, but their attachment point to the body wall is shifted posteriorly. The spicule protractors sometimes extend processes onto the attachment point of the spicule retractors on the hypodermis, suggesting the defect is not in these attachment points, but rather in the extension of the muscles towards that point. The diagonal muscles are in most specimens wild type but they are occasionally not parallel to one another or are have a dorsal - 48 - attachment point that is more ventrally positioned than in wild tye. e2432 males have a nicely shaped fan with the normal pattern of rays, suggesting that the sex muscle defect is not pleiotropic due to defects in the hypodermis. e2432 hermaphrodites have a reduced ability to lay eggs which is variable from animal to animal. This is due to a muscle pattern defect in the vulval sex muscles. The uterine muscles, 8 muscle cells which circle the hermaphrodite uterus, are wild type in e2432. The vulval muscles are a set of 4 pairs of cells arranged symmetrically in a cross-pattern around the vulval slit. Each pair consists of one vml and one vm2 muscle cell. The vm2 muscles attach to the junction between uterus and vulva and extend anteriorly to attach to the hypodermis in between two muscle cells of the ventral body wall muscle quadrant. In e2432 these muscles are shorter than in wild type small. In e2432 they can only be visualized by laser confocal microscopy (after FITC-phalloidin staining of the myofilaments) . This showed that they attached to the uterus as in wild type, but that their attachment to the body wall is ectopic (in a random position lateral of the vulva, usually on the ventral edge of the muscle row) . In e2432 vm2 myofilaments are oriented more dorsoventrally than in wild type (where their orientation is essentially in the longitudinal axis of the animal) . This phenotype is not due to a defect in the attachment point on the epidermis to which these cells should attach in wild type, since we frequently observe that the vml sex muscles make an apparently wild type attachment to this unoccupied attachment point. In wild type hermaphrodites, the vml muscle cells attach close to the junction between epidermis and vulva and in the adult extend dorsally and anteriorly (under an angle of 45-50 degrees with respect of the vulval slit) to attach to the hypodermis at the dorsal edge of the ventral body wall muscle quadrants. In e2432 the attachment of the vml muscles to the vulva is wild type. With their other end they attach, like wild type vml cells, along the dorsal of the edge of the ventral body wall muscles. However the angle between the vulval slit and the myofilaments of the vml sex muscles is reduced (less than 45 degrees) so that their dorsal attachment point is closer to the vulva than in wild type. The forces acting on the vulva can be separated in an antero-posterior and a dorsal vector. In e2432, the antero-posterior vector of both the vml and vm2 muscle is significantly reduced, leading to a reduced ability to open the vulva upon contraction. Studies in which vulval muscles were ablated individually or in groups suggested that 2 vulval muscle cells of wild type orientation are sufficient for wild type function. Adult C. elegans hermaphrodites have 95 body wall muscle cells arranged longitudinally (roughly 2 cells abreast) into four quadrants. In wild type cells these cells are spindle shaped. e2432 adults have body wall muscles with a wild type muscle cell and myofilament pattern, except that cells with interdigitating tips occur more frequently than in wild type. Like the unc-53 phenotype in the male and hermaphrodite sex muscles, this body wall muscle defect, which can also be observed in other guidance and attachment mutants like unc-6 and mups, can also be attributed to a reduced ability to extend "growth cones" otherwise referred to as cell processes in the anterior-posterior axis of the animal. Position on the genetic map : e2432 was mapped to the left arm of chromosome II and was found not to complement unc-53(e404) . The unc- 53 locus was originally identified by Brenner (1974), Genetics, 22, 71-94 as one of the uncoordinated mutants but has received only sporadic attention in general phenotypic surveys of the UNC-collection (Hedgecock et al (1987), Development, iOjO, 365-382 and Siddiqui (1990), Neurosci. Res. (Suppl) 13, 171- 190, in a genome wide screen for egg laying defective mutants (Trent and Horvitz (1983), Genetics, 104, 619- 647) and using e2432 as a tool to study the effect of body shape on the pattern of neuronal processes (Hekimi and Kershaw (1993), J. Neuroscience, 13(10) 4254-4271) . We initiated a detailed genetic and phenotypic analysis of this locus using the existing available alleles which various colleagues isolated in different screens : The canonical unc-53 allele e404, a strong UNC was isolated by Sydney Brenner. Alleles nl52, nl66 and nll99 have been obtained in screens for egg laying defective mutants. Alleles NJ234 and NJ222 were isolated by Ed Hedgecock in a screen defective in excretory canal outgrowth. As these screens were aimed at isolating viable fertile alleles, we isolated additional alleles by pre-co plementation screens designed to yield loss of function alleles irrespective of their phenotype. e2432/mnDf90 hermaphrodites are egl, weak unc's with a slightly stronger phenotype than e2432. Matings were set up on 3 cm petri dishes between 2 to 3 unc-53 (e2432) sqt- l(scl3) /+ males and 2 e2431ts or dpy-6(el4) hermaphrodites mutagenized with EMS in the L4 stage (Brenner, 1974) , Genetics, 77_ 71-94. The FI egl, unc-53 like hermaphrodites, which may be unc-53(e2432) sqt-1(scl3)/unc-53(new) were cloned on petri dishes and their offspring examined for the segregation of new unc-53 alleles. In two screens, two unc-53 alleles, 5 and 8 were isolated in an estimated 13000 FI offspring, giving an approx. mutation rate 1/3250 mutagenized chromosomes. Sqt-l(scl3), an allele of sqt-1 that confers a roller phenotype was included because it is closely linked to unc-53 (0.2 m.u.) and marks the original allele e2432. e2431ts, an X-linked ts larval lethal with a up phenotype was included to eliminate FI hermaphrodites arising from selfing and FI males which can mate. In the second screen dpy- 6(el4) was included to prevent FI males from mating with FI hermaphrodites. All unc-53 alleles used in this study fail to complement to e2432. Complementation was tested by mating unc-53 (e2432) sqt-1 (scl3) /+ males to hermaphrodites of the respective alleles. The male sex muscle phenotype described above for e2432 was found to be the only 100% penetrant phenotype in the unc-53 locus (see below) and was the primary phenotype used in complementation tests. Each of these alleles was also complemented to mnDf90 by mating unc-4 mnDf90/mnCl males to unc-53 ho ozygotes and temporary unc-53/unc-4 mnDf90 lines were established to evaluate the phenotype. The male and hermaphrodite phenotypes of all alleles over deficiency is identical or slightly, but not substantially stronger than that of the homozygous lines (which is not unusual for a large deficiency) . S. Brenner mapped unc-53 to 2.9 +/- 0.7 map units from dpy-10 (chromosome II) . We refined this map position by mapping unc-53 with respect to different deficiencies in the region and doing three factor crosses between unc-4 and sqt-1, a 1.5 map unit interval. Unc-53 (e2432) /+ males were mated in unc-4 sqt-1 hermaphrodites. Non-rolling FI offspring were cloned on petriplates and their broods screened for the segregation of unc-53(e2432) . Unc-4 non sqt-1 and sqt-1 non unc-4 hermaphrodites were picked from those plates and cloned on petriplates. 6 out of 42 sqt-1 non unc-4 recombinants segregated unc-53 and 3 out of 18 unc-4 non sqt-1 recombinants did not segregate unc- 53. This yields a relative position of unc-4 / 51 / unc-53 / 9 / sqt-1. Or a calculated map position for unc-53 on chromosome II, 0.23 map units left of sqt-1. Unc-53(e2432) was mapped relative to three deficiencies in the region mnDf90 mnDf87 and mnDf77 by mating e2432/+ males to unc-4 Dfx/mnCl hermaphrodites and scoring for males and hermaphrodites with the unc- 53 phenotype in the FI. The experiment was also performed by mating unc-4 mnDfx/mnCl males to homozygous unc-53. mnDf87 and mnDf90 do not complement unc-53 while mnDf77 complements unc-53. Ooc-3, the only other gene on the genetic map in the region, was found to complement unc-53 in identical crosses between e2432 and unc-4 ooc-3/mnCl. Further mapping of unc-53 relative to RFLPs between wt strains in the region and the molecular cloning confirmed the map position of unc-53 (see below) . Molecular characterization : We started cloning the unc-53 locus because the study and interpretation of the unc-53 phenotype and the different mutants in the locus would be greatly facilitated by having information on and probes for the unc-53 mRNA and gene product. At the time we initiated cloning of unc-53, a contig extending between unc-4 and sqt-1 (approx. 1500 kb) had been identified by A. Coulεon and J. Sulston (C. elegans genome project LMB Cambridge) , with no clone markers in between. To correlate the genetic map with the physical map in this region we positioned cosmids of this contig relative to the deficiencies mnDf77, mnD87 and mnDf90 by comparing band intensities of Southern blots of mnDfx/mnCl strains probed with cosmids throughout the region. Cos id K02F7 is deleted in mnDf90 but not deleted in mnDf87 an mnDf77 thus identifying a leftmost location for unc-53. Cosmids W10G4, T08D11 and F33G3 are in the unc-53 region (not deleted in mnDf77 but deleted in mnDf87 and mnDf90) . Cosmid K04H9 is deleted in mnDf77 and identifies a rightmost location for the gene. The distance between K02F7 and K04H9 is approx. 10 cosmids. To narrow down the position of unc-53 further we looked for restriction fragment length polymorphisms between wild type strains in this interval and identified N2/RC301 RFLPs in cosmids W10G4, F40F8 and F22G3. We mapped these using three factor crosses with the strains unc-53 sqt-l/RC301 and unc-4 unc-53/RC301. We mapped F22G3 and F40F8 between unc-53 and sqt-1 at the following relative distances : unc-4 / 9 / W10G4 / 2 / unc-53 / 1 / F40F8 / 1 / F22G3 / sqt-1. These data localize unc-53 in an interval of approx. 80kb in which more than 15 differently over¬ lapping cosmids are available. Pools of cosmids were injected in unc-53(nl52) gonads together with the rol- 6 selectable marker. Transient roller lines were established and scored for rescue of the unc-53 phenotype. Cosmid T28D2 was found to rescue the backward movement egg laying phenotypes of allele nl52 . A genomic library of N2 in lambda 2001 was screened with T28D2 and flanking overlapping cosmids. These were assayed in pools and individually for transformation rescue. Lambda clone, S4 carrying a sixteen kb insert was shown to give some rescue activity. Using restriction fragments of S4 as a probe, cDNA clones M5 (3.8 kb) and M18 (1-2 kb) were isolated from a Lamda MGU1 cDNA library. Both M18 and M5 contain an identical 3'-end as judged by restriction fragment analysis. Partial sequence analysis showed that M18 is shorter version of M5. Insert M5 was sequenced on both strands and was found not to be a poly-A tail at its 3'-end but appears not to full length at its 5'-end. To find the 5' end of the unc-53 transcript we did nested PCR on L2 stage random primed cDNA, between antisense oligos tab2 and tab (43 bp away from the 5' end of cDNA M5) and an oligo to the SL1 trans-spliced leader sequence. This sequence is transspliced to the 5'-end of most C. elegans mRNAs. This yielded at least 6 classes of PCR-fragments which have been subcloned and sequenced. All contain the 43 bp between oligo tab2 and the 5' end of cDNA M5 (bpl281 to 1338). The longest PCR fragment (TB3) extends the sequence of cDNA M5 with 1280 bp. When added to the length of the cDNA M5, this unc-53 transcript which we constructed in vitro and named tb3-M5 would then be 5073 bp long (including some poly-A tail) and have a 1528 AA open reading frame. Recently a 5 kb cDNA, was identified in an embryonic cDNA library which has the TB3-5'-end (including part of the SL1) , and the same 3'-end as M5, suggesting that TB3-M5 occurs in vivo. Similar PCR reactions in which the SL1 oligo was replaced by an SL2 transplice oligo gave no reaction products. Preliminary Northern blot analysis identifies a major 5.0 kb transcript and at least 2 smaller transcripts that are expressed in L2, L4 and adult worms. It needs to be examined whether the unc-53 5' ends reported here are made in vivo and encode different proteins or whether they represent PCR noise. The smaller PCR-fragments TBlb, TB16, TB1, TB6b and TB22 are "nested deletions" of clone TB3 with SLl's at their 5' end. The sequence of each is identical in the regions of overlap. The shorter SL1 transspliced transcripts contain ATGs downstream of the SL1 addition sites at positions 466, 988 and 1324. Com¬ parison to the sequence of genomic clones confirmed that the SLls are spliced onto intron exon boundaries. However not all intron-exon boundaries receive SL1, suggesting that there is some specificity to this differential trans-splicing. Recently the C. elegans sequencing consortium has sequenced cosmids F45E10. We mapped cDNA tb3-M5 onto these cosmids and found that unc-53 is an unusually large locus. It has 23 exons spread over more than 31 kb of genomic DNA. The lambda clone S4 that rescues does not contain the first 430 bp of the unc-53 transcript. This suggests that the ORF between positions 63 and 430 is not essential for transformation rescue. This rescue may derive from expression of transcripts TB6b or TB22 or from "non-specific" initiation of transcription on the extrachromosomal arrays. Additional confirmation that M5 was derived from the unc-53 transcription unit is provided by the observation that allele nl52 has a 300 bp deletion, disrupting the sequence of cDNA M5 and leading to a large (possibly complete) reduction of UNC-53 protein in nl52 embryos stained in immunofluorescence with an anti-unc-53 antibody (16-48-2). In addition, allele e2432 was found to carry a 3-4 kb insertion in this transcription unit. Seguence homology Antibody staining : The Ndel-EcoRI fragment of cDNA M5, the 47 kd fragment of UNC-53 encoded by the Ndel-EcoRI (position 3187 to 4458 (tb-M5 fig 3) protein sequence fig 2) was subcloned in the T7 expression vector prkl72 (yielding vector TB66 and expressed in E. coli. Inclusion bodies containing recombinant protein were purified, by processes known in the art solubilized in 8 M Urea and the recombinant protein purified over a DEAE column equilibrated in 8M urea. Purified protein was mixed with complete Freund's adjuvant and injected in a rabbit and 4 Lou rats. This was followed six weeks later by bi-weekly boosts with antigen mixed with incomplete adjuvant. All sera are active in western blotting at titers of 1:30,000 on Western blots of the 47 kd unc-53 fragment expressed in E.coli. With this western blotting assay, a rat- mouse hybridoma cell line was prepared producing a monoclonal antibody to UNC-53. Mab 16-48-2 has the following properties : - protein G-binding - binding activity on western blots of (1) the 47 kd UNC-53 fragment expressed in E. coli. (pTB66) (2) the 57 kd carboxyterminal fragment of UNC-53 expressed in E. coli (construct pTB65.) (3) the full length TB3-M5 UNC-53 expressed in E. coli (construct pTB61) and mammalian cells (COS-cells; constructs pTB54 and 56) . - i unoprecipitation of native and SDS denatured full length TB3-M5 UNC-53 construct pTB50 expressed in vitro-transcription translation reactions in reticulocyte lysates. - immuno-histochemistry in wild-type C. elegans fixed with methanol, acetone or paraformaldehyde and transgenic C. elegans expressing UNC-53 tb3-m5 pTBllO, 111 or 112 in epidermis, neurones, gut and muscle. Mab 16-48-2 fail to detect antigen of the correct size on Western blots of total worm proteins or worm proteins fractioned by progressive extraction with detergents, urea and SDS. Excretory canal phenotype : The excretory canal of C. elegans is a large H- shaped cell. It's cell body is positioned ventrally at the level of the pharyngeal bulb and send out two processes dorsally. At the level of the lateral epidermis (seam) each of these bifurcates and extends anteriorly and posteriorly over the seam cells, until they extend over most of the whole body length. It has been reported that in unc-53 the posterior process of the excretory cell does not extend up to the V6/T seam-cell boundary (E. Hedgecock et al.. (1987), Development, 100 365-382). We have done an extensive characterization of this phenotype in all alleles listed, either by direct in vivo No arski microscopy or UL6 rol6d marked unc-53 strains which express LacZ in the epidermis and excretory cell (Hope(1991) Development 113 ( 2 ) 399- 408) . In wild type the excretory cell processes are straight. In unc-53 the canal is often meandering from left to right over the seam before it arrests prematurely, as if it has lost directional cues in its migration. It never leaves the lateral epidermis seam. Both the anterior and posteriorward processes are affected. In weak unc-53 alleles the posterior excretory canal processes arrest anywhere between the vulval region and the V6/T boundary. We noticed that in even the strongest alleles or in unc-53/Df heterozygotes the canal arrests unusually frequently at or close to the vulva and never substantially before the vulva . We therefore set out to test whether the gonad dependent attractive signal which attracts the sex myoblasts to the gonad also might attract the excretory canal in an unc-53 independent manner to the vulval region. If this is the case we would expect that in a strong unc-53 mutant nl52 in which the 2 somatic gonad cells (the source of the signal) have been ablated, the excretory canal migration would be fully arrested. As a control we ablated one germ cell and one somatic gonad cell (Zl and Z2 or Z2 and Z4) . Embryos were ablated in the comma to 2 fold stage and the position of the excretory canal scored double blind in hatched embryos. At the time of ablation, the canal may already have started growing out. At hatching, the endpoint of our experiment, the growth cone of the posterior canal process has reached just beyond the gonad. Although these are technically difficult laser ablations, the results show a sub- stantial difference in excretory canal outgrowth between embryo with an ablated somatic gonad and control ablated embryos. In the experimental series the canal usually arrested a significant distance from the gonad or any other potentially damaged cells, suggesting the loss of a long range signal as described for the SM myoblast migration (Thomas et al (1990) and Stern (1991)). In the control series the excretory canal usually extended as far as unablated nl52 and into region of the partially ablated gonad. This indicates that the premature arrest observed in the experimental series was not due to encountering a damaged region. A gonad dependent and independent pathway were found to act redundantly in the posteriorard migration of the sex yoblasts. The data suggest that in wild type the migration of excretory cell growth cones is also guided by a gonad dependent and a gonad independent cue. In both cases the gonad dependent cue acts towards the gonad, but from opposite directions. However the gonad independent signal act anteriorward on the SM myoblasts and posteriorward on the posterior excretory cell growth cones. Since single mutants in both the gonad dependent pathway (sem-5) and independent pathway (unc-53) have no excretory cell phenotype these pathways may be redundant in the trajectory up to the gonad. An analogous redundancy has been observed for the sex myoblast migration. In the trajectory between gonad and tail the gonad independent pathway acts in different directions on the SM cells versus the excretory cell. In the excretory cell it acts in both anteriorward and posteriorward migration. A simple explanation which is elaborated in detail below is that unc-53 (like sem-5) may act downstream of a variety of receptors interpreting different cues. The previously described interaction between the gonad and the sex myoblasts was rationalizable as an interaction between cells due to become part of the same organ. The interaction between the excretory cell and the gonad we report here suggests that the gonad may have a more general role as organizer cell migrations in the embryo. We wish to point out that the described dependent and independent pathways are formal genetic concepts. It is for example possible that in unc-53 embryos or unc-53 embryos in which the gonad dependent pathway has been genetically or laser ablated, as yet to be identified, pathway defining growth cones are misplaced leading indirectly to defective sex myoblast, neuronal (PLM, see below) or excretory canal migration. The observed highly restricted expression of unc-53 is an additional indication of this possibility. Sex muscle phenotype : All unc-53 alleles exhibit the sex muscle phenotype described for e2432. We quantified phenotype in eight alleles : Young adults grown at 20"C were mounted for polarized light or Nomarski microscopy on 2% agarose pads containing 0.2% phenoxypropanol as described in Sulston and Horvitz (1977) Dev. Biol. 5_6,110-156 . The vml sex muscles were examined under polarized light with a 4Ox objective and a Brace Kohler compensator and photographed. In addition, adults were fixed, incubated with fitc-coupled phalloidin and mounted for fluorescence microscopy as described in Goh and Bogaert (1991) Dev. Biol. __ , 110-156. The angle between the longitudinal axis of the animal and the central bundle of myofilaments of the anterior and posterior vml was measured from the negatives with a protractor. As the vulva is a transverse slit at a right angle to the cylindrical body axis, the angle between the vml and the vulval slit can be measured independently of which side of the animal faces the observer. Neuronal phenotype : Unc-53 animals move poorly backwards when prodded but has good forward movement (Brenner (1974) Genetics 77 71-94) . Various aspects of the neuronal phenotype of unc-53 has been reported in general phenotypic surveys of the UNC-collection (Brenner (1974) Genetics 77 71-94) . : The posterior branch of the PDE neuron can be abnormal ( Hedgecock et al. (1987) Development 100 365-382) and the mechanosensory PLMR & PLML neurons can have commissures into the ventral cord at a position much posterior than in the wild-type. There are also frequently multiple ventralward PLM commissures evenly spaced along the posterior half of the body (Siddiqui (1990) Neurosci. Res. (Suppl) H 171-190), Hedgecock et al. , (1987) Development 100 365-382) . Examples 2 to 5 - Biochemical Analysis of UNC-53 Example 2 - Immunoprecipitations of 35 S labelled unc-53 gene products. The rat anti-UNC-53 monoclonal antibody, 16-48-2 (obtained from the hybridoma LMBP Accession no. 1383CB) elicited against a 47 kD fragment of the 3' end of UNC-53 from C. elegans was used to i munoprecipitate UNC-53 proteins. In this experiment, the full length unc-53 construct pTB50 (Fig. 11) was transcribed and translated in vitro in rabbit reticulocyte lysates. The resulting radioactively labelled 35 S unc-53 gene products were incubated with the monoclonal antibody under both denaturing (using SDS)and non-denaturing conditions, then incubated with protein G sepharose. The bound products were analysed by SDS-PAGE and fluorography. Monoclonal antibody 16-48-2 recognised both native and SDS denatured radioactive UNC-53 products verifying that the protein translated in vitro was bona fide UNC-53. This result shows that immuno-precipitation is a useful tool in schemes to purify native protein and to identify UNC-53 protein complexes in biochemical experiments. Example 3 - Actin sedimentation assays (8A variant) . Besides the N-terminal region of the protein which is similar to actin binding proteins, the predicted protein sequence of UNC-53 identified two putative actin binding sites. The first borders on the 3' end of the region of α-actinin/β-spectrin homology and the second lies in the 3' end of the cDNA sequence. This suggests that UNC-53 could potentially bind two actin molecules and via actin cross-linking, stabilise a particular growth cone spike to promote directional extension. Alternatively, the two actin binding sites may serve to anchor UNC-53 (and its shorter gene products) to the microfilament cytoskeleton to then transduce a signal via the NTPase domain to the downstream pathway. To test the two site model, full length and truncated versions of UNC-53 (pTB50 and pTB52) were transcribed and translated in rabbit reticulocyte lysates for 90 minutes following standard protocols (Promega) . To remove insoluble components, the reactions were airfuged for 1 hour at 100,000 x g and the supernatant containing 35 S labelled UNC-53 products introduced in actin co-sedimentation assays according to the method of Vancompernolle et al. (1992), EMBO J. 11. 4739-4746. In this procedure, radioactively labelled UNC-53 was incubated with monomeric G-actin in G buffer (2 mM Tris pH 7.5, 0.2 mM CaCl 2 0.5 mM β- mercaptoethanol, 0.2 mM ATP) for one hour at room temperature. The salt concentration was then increased with F buffer (1 M KCl, 10 mM MgCl 2 ) to a final concentration of 100 mM to promote polymerisation of G-actin to F-actin. After an additional one hour incubation, polymerised F- actin/protein complexes were pelleted at 100,000 x g in an airfuge, washed with G buffer, resuspended in Laemmli buffer and separated by denaturing SDS-PAGE. The presence of actin in the pellets was confirmed by Coomasie staining while radioactively labelled UNC-53 products were detected by fluorography. Both the full length UNC-53 protein, pTB50, and the truncated construct, pTB52 translated in vitro in rabbit reticulocyte lysates cosedimented with F-actin at starting G-actin concentrations of 50-100 μg/ml. This suggests that UNC-53 binds to microfilament cytoskeleton. Moreover, deletion of the first putative actin binding site (pTB52) did not eliminate actin binding. Example 4 - UNC53 interacts with F-actin cytoskeleton (7A and 8A variant) Analysis of the predicted protein sequence of UNC-53 identified two putative actin binding sites of the LKK class. The first borders the 3' end of the region of α-actinin/β-spectrin homolgy in the amino terminus of the protein while the second lies in the 3' end of the protein sequence upstream of the putative nucleotide binding domain. A single UNC-53 monomer could thus potentially bind and crosslink two actin molecules. To test whether UNC-53 associates with the actin cytoskeleton, a 7A (pTB72) and 8A version (pTB73) of unc-53 (Figures 25 and 27 respectively) were transcribed and translated in rabbit reticulocyte lysates and the ''S labelled products introduced into F-actin co-sedimentation assays (Figure 35a). The full length UNC-53 protein (pTB72) translated in vi tro cosedimented with F-actin at starting G-actin concentrations of 100 mg/ml (Figure 35b) suggesting that UNC-53 interacts with F-actin. By 250 mg/ml, all of the UNC53 protein co-sedimented with the F-actin pellet. In contrast, no UNC53 was present in the pellet of the control reaction without actin. Thus, sedimentation was purely actin dependent. This result also indicated that the in vi tro UNC-53 protein remained soluble even after the salt concentration was raised. Deletion of the first putative actin binding site in pTB73 did not eliminate actin binding since the larger pTB73 products, including the largest fragment co-sedimented with F-actin under the identical set of conditions (Figure 35b) . However, since the rabbit reticulocyte lysates contain numerous proteins, it is possible that the interaction of UNC-53 with actin may not be direct but rather mediated through another associated protein. Several smaller radiolabelled protein fragments in the TnT reactions were observed in addition to the predicted protein products. Immunoprecipitation experiments confirmed that these products were UNC53 derived. Most likely they result from additional translational starts at internal methionines, since the identical set of smaller products was observed from reaction to reaction; or from premature termination and proteolytic degradation. Many of these smaller fragments also co-sedimented with F- actin. Since the second predicted actin binding site is within the 3' end of the molecule, truncated proteins that are the result of internal starts would be expected to have this site and to bind actin. EXPERIMENTAL PROCEDURES: Construction of UNC53 plasmids. The complete unc53 cDNA was cloned as a 5.1 kb Notl-Apal cassette in the mammalian expression vector pCDNA3 (Invitrogen) to generate plasmid pTB72, the 7A clone variant. To optimize translational initiation at the first methionine, a mammalian KOZAK consensus sequence was engineered upstream of the start methionine by PCR amplification of DNA coding for the first 139 amino acids of the amino terminus with the oligonucleotides BG03 (5 1 - ataagaatgcggccgccgccatgacgacgtcaaatgtagaattgata-3' ) and BG02 (5'-cgcggatcctcaaaccgcgggtggcataatggatg-3' ) . BG03 contains the mammalian KOZAK consensus sequence in addition to a NotI restriction site. pTB73 is a deletion of the first 408 base pairs of the unc53 cDNA contained in the vector Bluescript II-KS. This construction removes the first two methionines of the unc53 cDNA sequence such that the first possible start methionine in pTB73 is at amino acid position 165 in the cDNA sequence. In all these constructs, (pTB72, pTB73 and pTB50) the unc53 cDNA is inserted into the multiple cloning site such that the T7 promoter is immediately upstream of the 5' end of the cDNA sequence. The first 139 amino acids cf the UNC53 cDNA were amplified by PCR with oligonuclectides BGOl (5'ggaattccaaccatatgacgacgtcaaatgtagaattgaata-3 ' ) and BG02 (5* -cgcggatcctcaaaccgcgggtggcataatggatg-3' ) to generate a convenient Ndel cloning site immediately upstream of the start methionine. This amplification was cloned as an Ndel-BamHI fragment into the prokaryotic expression vector pR 172 (Godedert M. and Jakes R. (1990), EMBO J. Vol. 9, pp 4225-4230 and McLeod M et al , 1987 EMBO. J. Vcl 6, pp 729-736) to generate construct pTB57. pTB61 contains the PCR derived amino terminus of pTB57 in addition to the 3 1 end of pTB50. Thus pTB61 contains the identical unc53 8A variant cDNA as in pTB50, but as an Ndel-Ncol fragment in the vector pRK172 for prokaryotic expression. In vitro transcription/ translation reactions The UNC53 cDNA constructs pTB72, pTB73 or pTB50 were transcribed and translated for 90' at 30°C in a cell free T7 polymerase expression system in rabbit reticulocyte lysates following the company's protocols (ProMega) . Prior to further manipulations, the reactions were centrifuged for 1 hour at 100,000 x g to remove insoluble components. In all subsequent experiments, the supernatant containing the soluble fraction of - ,5 S labelled UNC-53 products was utilized. Actin co-sedimentation assays Soluble radioactively labelled ,C S-Met-UNC53 products were introduced in actin co-sedimentation assays according to the method of Vancompernolle et al. (1992). In this procedure, radioactively labelled UNC-53 was incubated with monomeric G-actin in G buffer (2 mM Tris-pH 7.5, 0.2 mM CaC12, 0.5 mM b- mercaptoethanol, 0.2 mM ATP ) for one hour at room temperature and then the salt concentration increased with F buffer (1 M KC1, 10 mM MgCl2) to a final concentration of 100 mM to promote pol merization of G-actin to F-actin. After an additional one hour incubation, polymerized F-actin/protein complexes were pelleted at 100,000 x g in an airfuge (Beckman), washed with G buffer, resuspended in Laemmli buffer and separated by denaturing SDS-PAGE. The presence of actin in the pellets was confirmed by Coomasie staining while radioactively labelled UNC-53 products were detected by fluorography. Briefly, after destaining, gels were soaked in 45 r. methanol, 7.5 % acetic acid (vol/vol) for 30 minutes, followed by 30 min. in dimethyl sulfoxide (DMSO) , and 1 hour in 10 % PPO dissolved in DMSO (wt/vol) . The scintillant was precipitated by rehydrating the gels with four five minute water washes. After drying, gels were exposed to Xray film (Hyperfilm-Amersham) . Immunoprecipitations To confirm that the radioactively labelled proteins translated in vi tro were of UNC53 origin, an anti-rat monoclonal antibody, 16-48-2, elicited against a 47 kD fragment of the 3' end of UNC-53 was used to immunoprecipitate UNC-53 proteins. In this experiment, the unc-53 construct pTB50 was transcribed and translated in vi tro in rabbit reticulocyte lysates. The resulting radioactively labelled - ,5 S UNC- 53 gene products were incubated with the monoclonal antibody under both denaturing (0.4 * 0 SDS, 2.0% Triton X-100) and non-denaturing conditions for 1 hour at room temperature, then incubated with protein G sepharose for 2 hours at room temperature, the beads washed 3 times with PBS and the bound products analyzed by SDS-PAGE and fluorography. Monoclonal antibody 16-48-2 recognized both native and denatured radioactive UNC-53 products. As a control, a reaction without monoclonal antibody 16-48-2 was treated identically. Example 5 - Interaction of UNC-53 with SEM-5/GRB-2 The observation that certain alleles of UNC-53 enhance the sex myoblast migration defect of sem-5 mutants is difficult to interpret. While the genetics suggests that UNC-53 and SEM-5 cooperate to regulate sex myoblast migration, it is unclear whether this is the result of a direct molecular interaction. To answer this question, two types of biochemical experiments were used to determine if UNC-53 physically interacts with SEM-5. In the first experiment, radioactively labelled 35 S UNC-53, synthesised in reticulocyte lysates, was incubated with SEM-5/GST (glutathione-S-transferase) fusion protein bound to glutathione resin or with GST protein bound to glutathione resin. After incubation, the beads were washed and the bound proteins analysed by SDS-PAGE and fluorography. This demonstrated that UNC-53 made in vitro specifically bound to the SEM- 5/GST fusion protein resin. The GST fusion proteins have been previously described. Purification of GST- fusion proteins was facilitated by using a commercially available kit (Pharmacia) . All purification methods followed the manufacturer's protocols. To further characterise the nature of the interaction with SEM-5, a second experiment utilised Western blot overlays. UNC-53 fusion proteins were expressed in E.coli and the denatured protein lysates separated by SDS-PAGE and blotted to Immobilon-P nylon membrane (Milipore) . Blots were incubated with biotin labelled SEM-5/GST, GRB-2/GST or GST protein, washed and bound multi-protein biotinylated complexes detected by probing with an avidin-alkaline phosphatase conjugate. The results from this experiment demonstrated that SEM-5 and its mammalian homologue GRB2 can interact with UNC-53 in vitro. Binding was observed in induced cell lysates only and probing with the UNC-53 monoclonal antibody 16-48-2 detected the identical sets of products. In addition, only the full length UNC-53 fusion, pTB61 (Fig. 7), which contained the SH3 binding sites gave a positive result (pTB52 was not tested) No signal was detectable for either of the SH3 binding site minus fusion proteins, pTB57 (Fig. 11) or pTB65 (Fig. 11). This provides supportive evidence that the polyproline repeats of the UNC-53 directly bind to the SH3 domains of SEM-5. Moreover, these results show that a SEM-5 or GRB-2/GST glutathione resin may be used in schemes to affinity purify native UNC-53 from tissue culture cells or nematodes or other organism extracts. Detailed Methodology Radioactively labelled -' • 'S UNC-53 synthesized in reticulocyte lysates was incubated with SEM-5/GST (glutathione-S-transferase) fusion protein bound to glutathione resin or with GST protein alone bound to glutathione resin for one hour at 20 C C. After incubation, the beads were washed four times with Phosphate Buffered Saline (PBS) /Triton X-100 (0.2%) and the bound proteins analyzed by SDS-PAGE and fluorography. The SEM5 and GRB2 GST fusions have been previously described (Lowenstein et al., 1992; Stern et al., 1993) . Purification of GST-fusion proteins was facilitated using a commercially available kit (Pharmacia) . All purification methods followed the company protocols. Western blot overlays Approximately 500-1000 mg each of purified GRB2- GST protein or GST protein were biotin labelled by the following procedure. After overnight dialysis in PBS at 4°C 1 M Hepes, pH7.4, was added to a final concentration of 100 mM and 50-100 mg of biotinylation reagent, dissolved in dimethyl sulfoxide, and the mixture incubated at 20°C for 90 minutes. The biotinylation reaction was stopped by the addition of 1 M Tris, pH7. to a final concentration of 100 mM and the labelled proteins stored on ice. The UNC-53 construct pTBβl was expressed in E. coli strain BL21 (DE3), and the denatured protein lysate separated by SDS-PAGE and electroblotted to Immobilon-P nylon membrane (Millipore) . Membranes were blocked with 1 % skim milk powder in TBS-T (20 mM Tris, pH7.6; 0.14 M NaCl; 0.1% Tween-20) for 1 hour at 37°C. Subsequently, membranes were incubated in equimolar amounts of either biotin labelled GRB-2/GST or biotin labelled GST protein for 1 hour at 20°C, washed 4 x with TBS-T and bound multi-protein biotinylated complexes detected by probing for 1 hour at 20°C with an avidin-alkaline phosphatase conjugate (dilution 1:5000). Biotinylated protein conjugate complexes were visualized with a chromogenic solution containing bromochloroindolyl phosphate (BCIP) /nitro blue tetrazolium (NBT) in 100 mM Tris (pH 9.5), 100 mM NaCl, 5 mM MgCl2•Development was terminated with 10 mM Tris (pHβ.O) . 1 mM EDTA. Example 6 - Transgenic Analysis To further our understanding of the function of unc-53 we developed an in vivo assay to test gene fusions generated in vitro. Nematode expression vectors containing the full length unc-53 cDNA, TB3M5, downstream of various tissue specific and inducible promoters were constructed. The mec-7 promoter of pTB112 (Fig. 7) confers tissue specific expression to the mechanosensory neurons, the unc-54 promoter of pTBlll (Fig. 7) confers tissue specific expression to body wall muscle and the hspl6-41 promoter of pTB109 (Fig. 7) confers and pTBllO (Fig. 7) confers heat inducible expression to somatic cells. pTB109 is a transcriptional fusion containing only the hspl6-41 gene promoter and has been shown to confer high levels of inducible expression in embryos. pTBllO contains a larger portion of the hspl6-41/2 intergenic region in addition to a synthetic intron. This plasmid is expected to be highly inducible in embryos and post¬ embryonic stages in most somatic cell types. Oocytes of both wild type (N2) and unc-53(nl52) hermaphrodites were microinjected according to the method of Fire (1986), EMBO J. , 5 , 2673-2680. Coinjection of the unc-53 fusion with a selection plasmid, pRF4, a dominant marker of rol-6, allowed identification of transgenic animals by their right rolling phenotype (Mello et al. (1991), EMBO J., 10, 3959-3970. In C. elegans, the injected DNA does not integrate into the genome but rather forms extrachromosomal arrays which are heritable at a frequency ranging from 20-95% (Stinchcomb et al. (1985), Mol. Cell. Biol., 5, 3483-3496; Fire et al. (1990), Gene, 92, 189-198; Mello et al, (1991), EMBO J. , 1S_, 3959-3970. Transgenic extrachromosomal lines were considered stable after the rolling phenotype had passed through four generations. Some transgenic HS- unc-53 strains were mutagenised with 3550 rads of y rays emanating from a 60 Co source which produces breaks in the chromosomes allowing for insertion of the extrachromosomal array. Stable integrants were identified by screening for homozygous rolling F3 broods. The names and genotypes of all transgenic strains are listed in Table 1 with details of the unc- 53 fusions (constructs/vectors) listed in Table 2: Table 1 - Extend in other constructs STRAIN PARENTAL unc53 lacZ NAME STRAIN FUSION SELECTION MARKER TB3In54 nl52 pTB109 pRF4 UL6 TBAInδ N2 pTBllO pRF4 pPCZl TBAInδl N2 pTBllO pRF4 pPCZl TBAIn69 N2 pTBllO pRF4 pPCZl TBAIn76 N2 pTBllO pRF4 pPCZl Accession No 1385CB (See Fig 17A) TBAIn90 N2 pTBllO pRF4 pPCZl TBAIn210 N2 pTBllO pRF4 pPCZl TBAIn222 N2 pTBllO pRF4 pPCZl TBAIn306 N2 pTBllO pRF4 pPCZl TBAIn327 N2 pTBllO pRF4 pPCZl TBBIn3 N2 pTBllO pRF4 pPCZl TBBIn267 N2 pTBllO pRF4 pPCZl TBIExlO nl52 pTB112 pRF4 none TB1EX23 nl52 pTB112 pRF4 none TB1EX8 N2 pTB112 pRF4 none TB1EX16 N2 pTB112 pRF4 none TB2EX1 N2 pTB112 pRF4 none TB2EX37 N2 pTB112 pRF4 none TB3EX10 N2 pTB112 pRF4 none TB3EX12 N2 pTB112 pRF4 none TB3EX20 N2 pTB112 pRF4 none TB3EX37 N2 pTB112 pRF4 none TB4EX14 N2 pTB112 pRF4 none TB EX18 N2 pTB112 pRF4 none TB4EX22 N2 pTB112 pRF4 none TB4EX25 N2 pTB112 pRF4 none Accession No LMBP 1384CB (See Fig 16) TB1EX3 nl52 pTBlll pRF4 none 73 - 2 11 TB1EX6 nl52 pTBlll pRF4 none (See Fig 17B, C) TB1EX11 nl52 pTBlll pRF4 none Notes for Table 1: Ex-extrachromosomal In-integrated pTB109 , pTBHO-Heat shock unc-53 fusions pTBlll-mec-7 fusion pTB112-unc-54 fusion pRF4-rol-6 ( sul006) (Mel lo et a l . ( 1991 ) , EMBO J . , 5 , 3959-3970) UL6-excretory canal promoter lacZ fusion pPCZl-Hspl6-48/l lacZ fusion (Stringham et al. (1992) Molec.Biol.Cell 3., 221-233) Table 2 Full length cDNA tb3M5 (still has SLl and 5' UTR) pTB50 (Notl-Apal fragment in Bluescript II-KS, for in vitro transcription) pTB51 (Notl-Apal fragment in Bluescript II-SK, for in vitro transcription) pTB54 (Notl-Apal fragment in pCDNA3, for mammalian expression) (Deposited as accession no. LMBP3296) pTB109 (Notl-Apal fragment in hspl6-pucBM21, for in vivo expression) pTB67 (Notl-Apa fragment in pGEM5 +) PCR1 of amino terminus of cDNA (*PCR using oligos BGOl and BG02) pTB57 (Ndel-Ba HI fragment in pRK172, for E. coli expression) pTB58 (Ndel-Ncol fragment in pGEM5) pTB63 (Sacl-Ncol fragment in pRSETA, for E. coli expression) pTB64 (BamHI fragment in pBluescriptll-KS) Full length cDNA utilizing PCRl amino terminus pTB61 (Ndel-Ncol fragment in pRK172, for E. coli expression) pTBllO (Xbal-Kpnl fragment in pPD49.83, for in vivo expression) pTBlll (Xbal-Kpnl fragment in pPD52.102, for jβ vivo expression) pTB112 (Xbal-Kpnl fragment in pPD30.38, for in vivo expression) (Deposited as accession no. LMBP3295) PCR2 of amino terminus of cDNA (*PCR using oligos BG03 and BGOl) pTB59 (Notl-BamHI fragment in pBluescript II-KS) pTB60 (Notl-Xhol fragment in pCDNA3, for mammalian expression) Full length cDNA utilizing PCR2 amino terminus pTB55 (Notl-Eael fragment in pBluescriptll-KS) pTB56 (Notl-Apal fragment in pCDNA3, for mammalian expression) Other constructs pTB52 (SacII deletion of amino terminus of pTB50) pTB53 (SacII deletion of amino terminus of pTB51) pTB62 (Smal fragment of pTB52 in pGEX2T, for prokaryotic expression) pTB65 (Ndel-Ncol fragment of 3' terminus in pRK172, for prokaryotic expression) pTB66 (Ndel-EcoRI fragment of 3' terminus in pRK172, for prokaryotic expression, MAB 16- 48-2) Initially, the phenotype of each transgenic line was characterised by inspection with a dissecting microscope and/or Nomarski optics. Transgenic strains were directly analysed for expression of unc-53 by immunohistochemistry. Briefly, embryos were adhered to polylysine coated slides and permeabilised by a combination of freeze fracturing and immersion in cold methanol and acetone (3-4 minutes each) . Embryos were rehydrated through an acetone/distilled water series and then incubated for 30 minutes at room temperature in TBS-Tween (0.1%). The anti-UNC-53 monoclonal 16- 48-2 anti-sera was applied undiluted and the slides incubated at 4°C overnight. The embryos were washed three times with TBS-T and then incubated in a secondary rhodamine like (Cy3-M)conjugated antibody for 1 hour at 37°C. After 3-4 washed in TBS-T the slides were mounted for fluorescence microscopy in 2% propylgallate, 80% glycerol-pH 8.0. Characterisation of transgenic strains carrying pTB112 UNC-53 was over-expressed in the muscle of wild type animals (pTB112 in N2) . Each extrachromosomal PTB112/N2 line consisted of wild type and rolling animals as expected, but in addition, several mutant phenotypes were observed at low frequency. These animals varied considerably in phenotype and included embryos which arrested at the two fold stage, larvae which hatched but died soon afterward, animals with extra protrusions on the epidermis and animals with a truncated posterior end. This phenotype is consistent with that of the mup or mua classes of muscle mutants in which the positioning and/or integrity of muscle attachments to the hypodermis has been disrupted. Most of these animals were either inviable or sterile. The progeny of the viable mutants contained the same frequency of rollers, wild type and mutants as did the progeny of rolling individuals. Since the extrachromosomal array may be lost at each cell division, every animal is a mosaic. The healthy rollers may have lost the transgene from most muscle cells and may represent weak phenotypes whereas the 2 fold arrests represent the situation where the array has been lost from few muscle cells. Nomarski and polarised light microscopy of the severe larval lethals showed that the muscle cells were disorganised and over-extended. Detailed analysis of the underlying defect in embryonic development that leads to this terminal phenotype were performed with immunofluorescence microscopy (Fig 21) . Since the unc-54 gene encodes the myosin heavy chain, we expected that this promoter would be active in body muscle descendants from the comma stage onwards. In the unc-54 - unc-53 strains, signal was indeed localised to the body muscle cells in comma and later stages as predicted. The immunofluorescence was localised to the cytoplasm of the cell bodies and was particularly intense at the tips of the extending processes. Increased process length was observed very early in muscle development (comma to 1.5 fold stage) and increased up to the three fold stage. No other abnormalities in shape or muscle myofilament pattern were observed in the anterior-posterior axis of the animal. Two and three fold embryos which were εtained with the monoclonal antibody NE8(4c6.3) (Goh and Bogaert, (1991) , Dev. Biol. 5_6, 110-156) appeared to have a relatively wild type myofilament structure. As these animals are mosaic, it may be possible that severe cases die in late morphogenesis and those which survive through embryogenesis to adulthood can tolerate a few distorted muscle cells. pTBlll transgenic lines Immunostains indicates that the transgene is expressed efficiently in the mechanosensory neurons of a transgenic extrachromosomal line carrying the pTBlll transgene in an unc-53 (nl52) genetic background (Fig 20) . pTB109 and pTBllO lines Twelve integrated lines derived from three separate utageneses of extrachromosomal lines have been isolated. TB3In54 carries the pTB109 fusion in addition to pRF4. Nine TBA strains were isolated after mutagenesis of an extrachromosomal strain, HSA. There are two strains (TBB) derived from mutagenesis of the extrachromosomal strain HS B. Both TBA and TBB strains contain the transgenes pTBllO, pPCZl and pRF4. Inclusion of the HS-lacZ plasmid, pPCZl (Stringham et al, (1992), Molec.Bio.Cell 3 , 221-233) allows one to monitor the strength of the heat shock induction by assaying for β-galactosidase activity. Immunostains of embryos freeze fractured after a two hour heat shock showed that the signal was most prominent in the pharynx, gut and neurons. Surprisingly, the signal had a speckled appearance. This may be a feature of heat shock. Heat shock proteins may sequester UNC-53 to "chaperone" it during stress. Alternatively, UNC-53 may be targeted for degradation. In one experiment, embryos were heat shocked for two hours, allowed to recover overnight and then freeze fractured the next morning. While levels were reduced, there was a little residual UNC- 53 signal in the gut cells. Thus, about 16 hours later most the protein has gone. Level of heat shock and recovery times are therefore important factors in the mutant rescue experiments and the preferred assay system described in example 10. In addition, experiments suggest that heat shock induction in liquid culture versus agar plates or dry incubators versus water baths need careful calibration. After a strong three hour heat shock, a high percentage of animals were not able to recover from the stress. Embryos which were not subjected to a double shock (2-two hour heat shocks at 33°C separated by a two-hour recovery) hatch out as malformed worms reminiscent of the muscle overexpression lines (Fig 21) . The heat shock promoter used is especially active in the pharynx. Consistent with this, a strong pharyngeal morphogenetic phenotype was observed (Fig 21) . Pharyngeal phenotypes are easy to score and quantify (feeding rate, dye uptake, LacZ lines staining the pharynx) by anyone skilled in the C. elegans field and may form a preferred embodiment of the assay. Example 7 Over-expression of UNC-53 results in directional over-extension : Assay with 7A variant. In wild type C. elegans, body muscle cells are normally spindle shaped while in UNC53 mutants, a number of these cells have a reduced process which results in a fork shaped tip. This phenotype is consistent with the general reduction of extension observed in many growth cone types along the longitudinal axis of the animal in unc-53 mutants. Recalling the extremely limited pattern of UNC53 expression in embryogenesis detected by immunostaining with monoclonal antibody 16-48-2;no UNC53 activity was discernable in wild type body muscle cells during outgrowth suggesting that the levels of UNC53 activity required for this extension may be extremely low. We overexpressed unc-53 in the muscle of wild type animals by expressing the full length cDNA under the control of the unc-54 myosin heavy chain promoter in the fusion pTB113. Plasmid pTB113 is a translational fusion containing the 7A variant unc-53 cDNA sequence as an Xbal-Kpnl fragment starting from the first methionine and including the unc-53 cDNA poly adenylation tail under control of the myosin heavy chain unc-54 promoter of the nematode expression vector pPD30.38 available on Internet web site ftp archive: ciwl, ciwemb.edu. Plasmid pTB114 contains the identical cDNA fragment under control of the hspl6-41 -2 promoter (Jones et al.,1995, Dev. Biol. VOL. 171, PAGES 60-72) which confers heat inducible expression to somatic cells, in the expression vector pPD 49.83 (Fire, pers. comm. ) The amino terminus of the UNC53 cDNA is identical to the PCR amplification with BGOl and BG02 of pTB5 . Thus, both pTB113 and pTB114 are in frame translational fusions devoid of the SLl leader sequence and upstream untranslated region of the cDNA. Each transgenic mosaic line (3 were examined) consisted of wild type and rolling animals as expected, but in addition, several mutant phenotypes were observed at a low frequency. These animals varied considerably in phenotype and included, embryos which arrested at the two fold stage, larvae which hatched but died soon afterwards, animals with extra protrusions on the epidermis and animals with a truncated posterior end. Most of these latter animals were either inviable or sterile. The progeny of the viable mutants contained the same frequency of rollers, wild type and mutants as did the progeny of rolling individuals. Since the extrachromosomal array may be lost at each cell division, every animal is a mosaic. The healthy rollers may have lost the transgene from most muscle cells and may represent weak phenotypes whereas the 2 fold arrests represent the situation where the array has been retained in most muscle cells. The truncated posterior end may be the result of lethality in the D lineage due to mosaicism. Nomarski and polarized light microscopy of the severe larval lethals showed that the muscle cells were disorganized and over-extended in the longitudinal axis. In some cases the muscle cells appeared detached from the hypodermis. As these animals are mosaic, it may be possible that severe cases die early in morphogenesis whereas those which survive through embryogenesis to adulthood can tolerate a few distorted muscle cells. In transgenic pTB113 strains, UNC53 expression, as detected by immunostaining with monoclonal antibody 16-48-2, was localized to the body muscle cells in comma and later stages as predicted for the UNC-53 promoter (myosin heavy chain) . The pattern of immunofluoresence with the anti UNC-53 antibody was localized to the cytoplasm of the cell bodies and was particularly intense at the tips of the extending processes and in the cytoskeleton, when compared to phalloidin staining which specifically stains the actin cytoskeleton. The identical pattern of sub- cellular localization, in the cytoplasm and cytoskeleton, was also observed in the intestinal cells of pTB114 transgenic embryos expressing UNC-53 ectopically after heat shock. In addition, the growth cone processes appeared to be overextended specifically in the anterior- posterior axis of the animal. To verify this, the length of body muscle cells over-expressing the UNC53 cDNA in the pTB113 strains were measured and compared to the length of wild-type muscle growth cones expressing an unc-54 promoter-GFP (green fluorescent protein) fusion, pPD49.83 (available on Internet Web Ste Ftp archive: ciwl . ciwemb.edu. The GFP reporter allowed visualization of the entire cell body and boundaries of the muscle cells in wild-type animals. We estimated that the processes of the pTB113 expressing cells were roughly 14 times the length of pPD49.83 expressing wild type cells. The lethality in the transgenic progeny of the three pTB113 strains examined ranged from 32% to 78%. Thus a significant proportion of the transformed mosaic progeny did not survive morphogenesis. In contrast, no lethality was observed in the pPD93.48 (unc-54-GFP) control strains. The lethality observed in the pTB113 lines is likely the consequence of overextension of muscle cells during embryogenesis because (a) both pTB113 and pPD93.48 utilize the identical promoter and should be expressed in the same cells at the same point in development, and (b) rol-6 selection was used to identify transformants for both constructs . Example 8 Transient and stable transfection of UNC-53 in N4 neuroblastoma cells. pTB72 and a plasmid expressing LacZ under the CMV promoter were transfected transiently with the Ca- phosphate method in N4 neuroblastoma cells. N4 cells and their stably transfected counterparts were grown in Minimum Essential Medium (MEM)-REGA 3 (GIBCO BRL) supplemented with 10% Foetal Calf Serum, 1% L-Glutamine, 2% Sodium Bicarbonate, 200 units/ml penicilline and 200 μg/ml Streptomycine, in a humidified atmosphere of 90% air and 10% C0 2 at 37SC. Transfections were performed by the Lipofectamine method (GIBCO BRL) . 18 to 24 hrs before transfection cells were seeded in complete growth medium at a density of 7xl0 5 per well in a six well tissue culture plate, and incubated at 372 c in a C0 2 incubator. For each transfection the following solutions were prepared. : SolA = 4 μg of DNA diluted in 200 ul of Optimem (GIBCO BRL) SolB = 12 ul of Lipofectamine reagent diluted in 200 ul of Optimem (GIBCO BRL) Solutions A and B were combined, gently mixed and incubated at room temperature for 30 minutes. For each transfection 0.6 ml of Optimem was added to the lipid-DNA complex to reach the final volume of 1 ml. This mixture was then added onto the cells (which had been previously rinsed once with 2 ml of Optimem) . The cells were incubated in the transfection mixture for 5 hrs at 37C in a C02 incubator. At the beginning of the sixth hour from transfection, 1 ml of complete growth medium supplemented with 20% of Foetal calf serum was added to the transfected cells. The cells were incubated for 18 hrs at 37C in a C02 incubator. 24 hrs following the beginning of transfection the supernatans was replaced with fresh growth medium. 72hrs post transfection cell cultures from each well were harvested, diluted 1:24 and distributed over 24 well plates with the growth medium containing 500, 750 ug/ml or lmg/ml of geneticin (G418, GIBCO BRL). After ~12 days from the start of selection, single clones were picked and allowed to grow in the absence of selection. Of 27 initial clones, 7 were lost while expanding the clones because of their slow growth rate and the apparent general toxicity of caused by the transfected construct. Clone 9 was selected for further analysis. Functional assay for neurite extension in N4 neuroblastoma Step ( 1 ) : Quantitative determination of neuronal morphology, i.e. length of neurites and fraction of positive cells is performed fully automatically. As an example we studied the degree of morphological differentiation in the wild-type N4 cells to a stably transfected C9 clone. Step (2) : Quantitative neuronal morphology Morphological changes of neurones were quantitated as described in GEERTS et al (1992 Restorative Neurology and Neuroscience 4: 21-32 and Katsuhito et al Neurodegeration, 2: 173-181) . Briefly, at appropriate times, glutaraldehyde was applied to cell cultures. No washing steps were performed. This ensured that the morphology of the cells at that time point was frozen. The cells were observed in transmitted light mode on an Axiovert microscope, equipped with a Marzhauser scanning stage driven by an Indy workstation (Silicon graphics) . Images were captured using a MC5 video camera (HCS) . About 3000 cells were detected in 64 neatly aligned images, forming a 8x8 square matrix of images. The exact alignment of the images ensured that neurites could be followed from one image field to the next. The analysis software automatically detected cell bodies and neurites and saved cell body size and length of each individual neurite on a file. Different parameters were subsequently calculated. The neurite length per cell was calculated on freely lying cells (not within a cluster) . The fraction positive cells is the fraction of cells having at least one neurite with a length exceeding twice the cell body diameter. Figure 40 clearly shows that clone C9 increases both neurite length (free length) and fraction of positive cells, compared to wild-type N4 cells clone. Example 9 Transient and stable transfection of UNC-53 in MCF-7 breast carcinoma cells. pTB72 and a plasmid expressing Lac Z under the CMV promoter where transfected transiently with the Ca-phosphate method in MCF-7 breast carcinoma cells. MCF7 cells and their stably transfected counterparts were grown in Dulbecco's Modified Eagle's Medium (DMEM, GIBCO BRL) supplemented with 10% foetal Calf Serum, 1% L-Glutamine, 1% of a 5mg/ml stock of Gentamicine and 1% of a lOOmM stock of Sodium Pyruvate in an humidified atmosphere of 90% air and 10% C02 at 37 C. Construct pTB72 was transfected by the Calcium- phosphate method (ref) : 18-24hrs before transfection. cells were seeded at a density of 3x10 s in a six well tissue culture plate with complete growth medium. Two hours before transfection the culture medium was removed and replaced with 1.8 ml of fresh medium. The cells were put back in the incubator until the moment of transfection. DNA-Ca 3 (P04) 2 precipitates were prepared one hour before transfection : For each transfection (1 well): 4 ug of DNA (=3-4 ul) was combined with 76 ul of TE (Tris HCl-EDTA pH 8) O.IM to a final volume of 80 ul. To these DNA's diluted in TE, 20 ul of CaCl 2 Hepes solution was added to a final volume of 100 ul of DNA/CaCl 2 mixture. The 100 ul of DNA/CaCl 2 mixture was added very slowly, drop-by-drop to lOOul of 2x BS/Hepes while shaking, to a final volume of 200 ul. The resulting 200 ul DNA/Calcium Phosphate mixture was added to the cells and the mixture incubated for 8 hrs at 37 C in a C0 2 incubator. At the beginning of the ninth hour from the start of transfection, the supernatans with the DNA/Calcium phosphate mixture was replaced with 3 ml of complete culture medium. 72hrs post transfection, cells from each well were harvested, splitl:24 in complete growth medium supplemented with lmg/ml of Geneticin (G418, GIBCO-BRL) and plated out in 24 well plates. 15 days from the start of selection, single clones where picked and allowed to grow without selection. Three clones MCF7-pTB72-clone9, MCF7-pTB72- 14 and MCF7-pTB72-15 were retained all of which have a similar phenotype. 1) Phenotyping UNC-53 transfected MCF-7 breast carcinoma cells: The general morphology and motile behaviour of the three transfected MCF-7 clones are different from non-transfected cells. The assay consists of a tyramide amplification of a classical immunofluorescent reaction. The cells were grown in defined medium with 10% charcoal treated serum and supplemented by 10 μg/ml insulin (final concentration) and 5 ng/ml basic fibroblast growth factor (final concentration) . The substrate consisted of 50 μg/ml poly-L-lysine in chamber slides; cultures were maintained in a humidified atmosphere of 95/5% air/C0 2 . - 86 - Inductin of expression of vimentin and of increased levels of fosfotyrosine was found in the transfected subclones. Vimentin formed dense clusters around the cell nucleus with some filamentous structures in the pseudo-podes. Fosfotyrosine, on the other hand, was predominantly found at the border of the cell ruffles, at the same subcellular area where UNC53 expression was found. This provides evidence of a controlling molecule functioning in a signal transduction pathway and that vimentin is an indicator of metastasis in cancerous cell lines. 2) Functional assay to establish the signal transduction role of UNC-53. Cells locomote in tissues and on substrates. The type and amount of cell locomotion depends on different factors: (1) the physiological conditions perceived through receptors, which can be - for example - stimulation with or deprivation of serum, growth factor(s), cytokine(s), chemokine(s) or (pro-) inflammatory mediators; (2) the type and functionality of cell adhesion molecules expressed by cells and extracellular matrix molecules present in tissue or in culture model, (3) the actin, tubulin and/or intermediate filament cytoskeleton and (4) proper functioning of integrator proteins such as UNC-53, homologues or other molecules that translate physiological stimuli (or lack of stimuli) into increased or decreased cell motility, directional or random motility or different types of motility. Cell locomotion can be measured in different types of assays, such as disperse cells or in monolayer cultures, as cellular outgrowth from tissues in culture or in organotype cultures. Motility of live cells can be quantified microscopically as in example 8 or by time-lapse video or cinematography or by phagokinetic assays (Albrecht-Buehler, 1977, Cell, 11:395) amongst other methods. Cell motility assays are interesting tools to study the functioning and pharmacology of UNC-53 and the unc-53 pathway. All previous observations were performed on MCF-7 cells grown in defined medium supplemented by 10 μg/ml insulin (final concentration) and 5ng/ml basic fibroblast growth factor (final concentration) . This approach offers the possibility of investigating the role of FGF in the UNC53 role of signal transmission. Indeed, by comparing wild-type versus UNC53 transfected cells cultured in medium with or without FGF/insulin and/or by microinjection of UNC53 protein, it can be investigated if UNC53 is responsible directly for regulating a signal transduction pathway linking extracellular growth factors to the assembly of, amongst others, focal adhesions. Example 10: Enhanced phagokinesis in Ce-unc-53 transfected MCF-7 cells. In this example evidence is presented that transfection of a plasmid containing the Ce-unc-53 sequence under a suitable promoter enhances cell motility in the phagokinesis assay. When culture plastics are coated with colloidal gold particles, a variety of cells types were shown to migrate over the plate and displace or phagocytose the gold lawn on their way while locomoting. The track left bare is a qualitative and quantitative measure of cell motility and/or locomotion. The basic methods have been described in detail elsewhere (Albrecht- Buehler, 1977, Cell, 11:395; Zetter, 1980, Nature, 285:41; O'Keefe et al., 1983, J. Invest. Dermatol., 85:130). Methods 12 well plates were coated for 15 minutes with 5 μg/ml gelatin in water and gold coated as described by Albrecht-Bueller (1977) . Ce-unc-53 transfected MCF-7 cells and the parent MCF-7 were cultured in parallel, trypsinised dispersed in culture medium and seeded in 12-well plates at a density of 2550 cells per well. The cells were allowed to adhere to the plate and to locomote for 16 hours. After incubation the cells were chemically fixed to the plate using paraformaldehyde, washed with distilled water and finally air-dried. Subsequently, images of the gold lawns were captured using automated videomicroscopy, composite images of the wells were generated and single-cell phagokinetic tracks were measured using a home-made routine in SCIL™ software. Results The parent MCF-7 line displayed two cell populations with " different motile behaviour in phagokinesis assays. In table 3 the fraction of parent and Ce-unc-53 transfected MCF-7 cells that produced linear tracks in the phagokinesis assay are shown. In the parent MCF-7 cells, 88% of the cells produce a round track (long and short axis less than 2-fold different) and 12% cells produce 'linear' tracks (long and short axis more than 2-fold different). Ce- unc-53 transfection of MCF-7 cells produced an increase of the fraction of cells displaying 'linear' tracks to 28% at the cost of the cells producing round tracks. These observation suggest that Ce-unc-53 transfection into MCF-7 is capable of increasing in situ locomotion of MCF-7 e.g. by increased spreading, ruffling or other forms of non-directional motility in the 'round* population as well as by driving a fraction of transfected MCF-7 cells from non-directional motility (round tracks) into directional migration (linear tracks) . In tissue culture, cells are provided with non- directional signals. It is likely that providing directionality to these signals will enhance observed effects. Significant enhancement was observed for the fraction of linear tracks. In addition, a significant increase of 35% in the area of tracks was observed in the Ce-unc-53 transfected MCF-7 cells versus the parent MCF-7 cells (Table 3) . This increase occurred in the round track population; the area of linear tracks was found not to be changed by transfection. These obsevations in phagokinesis suggest that Ce-unc-53 transfection into MCF-7 cells is capable of increasing insitu locomotion in Ce-unc-53 MCF-7, e.g. by increasing spreading, ruffling, or other forms of non-directional motility in the "round" population. In addition the Ce-unc-53 transgene in MCF-7 cells drives a fraction of the MCF-7 cells from non- directional motility (round tracks) into directional migration (linear tracks) . Table 3 . Analysis of phagokinesis assays with parent and Ce-unc-53 transfected MCF-7 cells . parent MCF-7 Ce-unc-53 MCF-7 increase Fraction linear % +- SD(n) %+-SD(n) tracks ( * ) 12+-3 (8) 28+-6 (8) 2.33 Track area ( ** ) pixels+-SD(n) picels+SD (n) all tracks 1261 +-128(8) 1698+-179(8) 1.35 round tacks 1229+-162(8) 1464+-204(8) 1.19 linear tacks 2367+-424(8) 2300+-319(8) 0.97 ( * ) the fraction of li lear tracks in 8 wells was pooled. MCF-7 cells expressing low levels of UNC-53 exhibit increased motility. Individual transfected cells are much more flattened in appearance than wild type and have a broad lamellipodium extending from the edge of the cell. Ruffling edges are more frequent than in wild type. Transfected cells in clusters have a broad lamellipodium edge around the cluster while cluster of the non-transfected. Within the cluster the nuclei are more widely spaced from one-another than in wild type cells (also due to a lamellipodium edge) . Example 11 Method for Protein micro-sequencing of co- affinity purifying proteins UNC-53 protein was immuno-affinity purified from extracts of cells expressing C. elegans UNC-53 using monoclonal antibody 16-48-2. One to five mg of Mab 16-48-2 was prepared, purified on protein-G sepharose and subsequently covalently linked to sepharose beads. A column of such beads was loaded with both crude cytosolic and Triton-XlOO extracts (containing solubilised RTKs) and eluted with 4M MgCl 2 or other chaotropic agents. A co-immuno-purifying band was identified on SDS-denaturing PAGE gels, eluted from these gels and micro-sequenced. This protein sequence or mass information of peptides generated by proteolysis was used to identify the co- immunoprecipitation directly from the sequence databases. Alternatively the sequence was reverse translated and oligonucleotides based on the sequence prepared. This is used to clone the corresponding gene as well as other techniques well known in the art. Example 12 C. elegans as a model assay system. We have constructed transgenic strains which overexpress UNC-53 in body muscle. This results in increased extension of muscle cells and embryonic lethality at low frequency. These strains were used to screen for drugs which interfere with UNC-53 activity and thereby suppress the background lethality. Another related assay was used to screen specifically to identify inhibitors of downstream components in the signal transduction pathway. This assay utilised constitutively active mutant cDNA (or corresponding nucleic acid sequence) . Such a mutant may be formed by mutating the nucleotide binding domain such that GTP or ATP is always bound or by covalently attaching SEM-5. In this strategy, transgenics/mutants (nematodes or tissue cultured cell lines) were generated which maintain the pathway in a permanently switched on state. Over-extension and subsequent lethality results in a greater frequency than that observed in the unc-54 - unc-53 wild-type lines. By screening for survivors after drug treatment, this assay specifically identifies inhibitors of downstream components in the signal transduction pathway. A range of other embodiments of the assay are obvious to a person skilled in the art of C. elegans genetics, including the use of alternative selectable markers, genetic backgrounds, histochemical detection and visual detection systems to identify phenotypic changes following contacting a single worm or a population of worms with a compound. Another assay previously described herein utilizes the unc-53 promoter. The unc-53 promoter is fused to a nucleic acid sequence encoding a reporter molecule. By screening for cells which do not express the wild type pattern, molecules which increase or reduce transcription of unc-53 may be identified. Example 13 - Heterologous expression of C. elegans UNC-53 in insect cells. C. elegans UNC53 cDNAs have been expressed in a Baculovirus system to obtain sufficient amounts of protein for biochemical and structural studies. Two UNC53 cDNA clones (UNC53(7A) and UNC53(8A) have been documented differing in the number of adenosine (A) residues (7 or 8) in a polyA stretch of the of the 3' coding region; the two clones therefore have different reading frames in the carboxyterminal coding region. The 5' (N-terminal) part of the UNC53 coding region was excised from pTB564 with SacII after linearizing the plasmid with Ndel . The Ndei site was blunted with Klenow. The remaining C-terminal part of the coding region was excised from pTB68(7A) and pTB50(8A) with SacII plus Kpnl . The Ndel /SacII fragment from pTB64 and the SacII/Kpnl fragment from either pTB68 or pTB50 were ligated simultaneously into pBacPAK9 (Clontech) which had been linearized with Ecl l36II (blunt end) and Kpnl . In this way, a minimum amount of 5' untranslated region is left in the final construct. The desired recombinant viruses were obtained by co-transfection of Sf21 cells (Spodoptera frugiperda) with one of the aforementioned pBacPAK9 constructs and BacPAKδ Bsu361-digested DNA (Clontech) . Several candidate recombinant viruses plaques were picked and screened by PCR for the presence of the target gene and the absence of wild-type virus. Sf9 cells were infected at a high multiplicity with UNC53(7A) or UNC53(8A) recombinant Baculoviruses for protein expression. Proteins from whole cell lysates were separated by denaturing (SDS) polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes. The expression of UNC53 in those cell lysates was confirmed by immunoreaction with a monoclonal antibody (16-49-2) to UNC53 and subsequent che iluminescent detection (ECL™ Amersham) . A Coomassie-stained band of the expected size was observed in lysates of Sf9 cells infected with UNC-53(7A) or UNC53(8A) recombinant baculoviruses, but not with control constructs. Within the accuracy of the methods, this Coomassie- stained band coincided with the largest immunoreactive band. Their estimated mass was approximately 180 kDa, which is compatible with the theoretically calculated mass (167 kDa) . We therefore conclude that this band most likely corresponds to intact UNC53. For both UNC53(7A) and UNC53(8A) baculoviral expression constructs, mostly intact recombinant UNC53-protein was detected by im unoblotting in lysates from infected cells harvested 24 hours post infection. Larger amounts of recombinant protein could be detected in lysates from cells prepared during later stages of infection (48 and 72 hours post infection) but in those preparations a considerable amount of smaller fragments (presumptive degradation products) is observed. Example 14 The UNC-53 protein expressed in Sf9 cells using a Baculovirus expression system is a valid tool to study its biochemical functions and a valid tool to identify interacting proteins. 3x10+6 SF9 cells infected with recombinant virus UNC53 7A(L2.3)/pBacPAK9 were resuspended in 100 microliter Phosphate Buffered Saline supplemented with 0.14 micromolar of pepstatin, 10 mM of benzamidine and 0.015 micromolar aprotinin. The cells were briefly sonicated and the obtained material was centrifuged at 30,000 g for 30 minutes at 4 degrees centrigade. The clear supernatant (soluble fraction) was frozen in 50% glycerol. An aliquot of this fraction was incubated in the cold room for 48 hrs. The protein samples were analyzed by SDS-PAGE, blotted to nitrocellulose and probed with mab 16-48-2. This showed that UNC-53 protein made in SF9 cells is soluble and stable under the conditions tested. 20 microlitres of the UNC-53 SF9 lysate were incubated with 5 microlitre GST-Sepharose beads loaded with equal amouts (approx. 10 microgram) of GST-GRB-2 or GST alone. The beads were rinsed 3 times in 500 microlitres of solution PBS-0.2'.. Tween 20 and eluted with 50 microliter SDS sample buffer. The eluted material was analyzed by SDS-PAGE and Western blot analysis with mab 16-48-2. UNC-53 was retained on the GST-GRB2 column and not on the GST demonstrating that UNC-53 interacts in vi tro with GRB-2. Example 15 Identification of proteins interacting with UNC- 53 : Vectors pCB50 and pCB51 were constructed as bait vectors for the yeast two hybrid system expressing resp. the full length and the carboxyterminal part of UNC-53. pCB50 was constructed by cloning the full length UNC-53 cDNA (7A variant; Ndel-Ncol fragment from pTB74) into pASl-CYH2 vector from Clontech. (Figure 30) . pCB51 (Figure 32) was constructed by cloning the 1880 bp Ndel-Ncol fragment from pTB74 into vector pASl-CYH2 from Clontech. This protein encodes among others, the GTP/ATP binding domains, a leucine zipper domain, and an additional coiled-coil domain. pCB50 and pCB51 were transformed in yeast strain Hf7c (YRG2) . Expression was confirmed by western blotting using antibodies to the GAL4 protein fused to UNC-53 in these constructs. Bands of expected size (190 kd for pCB50 and 90 kd for pcB51) were observed both in yeast strains with pCB50 and pCB51 indicating that both fusion proteins are expressed in the yeast. The expression of the pCB50 and pCB51 fusion proteins in yeast strain Hf7C does not lead to expression of the LacZ or HIS reporter genes. These experiments demonstrate that the constructed fusions are useful baits in yeast two hybrid screens. Vector pCB55 was made by cloning the 984 bp BamHI-Bglll of pTB74 construct into the yeast two hybrid activation vector (pGAD-424 vector from Clontech) (Figure 34) . In order to check the possible interactions of UNC-53 either with itself (homodimerization) or other proteins. This vector expresses a Gal-4 activation domain fused to amongst others the predicted coiled coil or leucine zipper domain of UNC-53. The following combinations of plasmids were co- transformed in yeast strain HF7C : (1) pCB51 and pCB55 (2) pCB55 with control plasmid- pTDl and (3) positive control plasmids pTDl and PVA3 (two proteins known to interact (Bartel,P.L et al., Biotechniques Vol. 14 nr.6 (1993)) . Yeast cotransfor ed with combination (1) and (3) grew well on -LEU;-TRYP plates and -LEU;- TRYP;-HIS plates indicating that an interacting protein is present in both co-transformations. Only yeast co-transformed with (3) was positive in a lacZ assay indicating that the observed interaction in (1) (between pCB50 and pCB 55) is weak.For co- transformation (2), colonies grew on -LEU;-TRYP plates and as expected not on -LEU;-TRYP;-HIS plates. The positive control were thus positive whereas the negative controls were negative. We conclude that there is a weak but significant interaction between pCB51 and pCB55, which is strong enough to activate the HIS but not the lacZ reporter gene in this Hf7c strain. Example 16 Protocol to screen for components which inhibit or enhance UNC-53 using C. elegans cell line pTBIn76 -97- Embryos from large liquid C. elegans cultures of line pTBIn76 (table 1) are collected by sucrose flotation of a bleached population (Goh and Bogaert (1991), Dev. Biol. 56, 110-156). Embryos are dispensed in 96 well icrotiter plates with M9 medium and various concentrations of the compound to be tested. The embryos are allowed to hatch and are synchronised in the LI stage by starvation. After a suitable exposure to the compound (by standard calibration) a standard quantity of E. coli (food) is dispersed in the 96 well plates, which starts C. elegans post-embryonic development. The microtiter plates are then placed in an incubator to induce heat shock and subsequently placed at 25°C to permit continued development. After 0 to 1 generations of C. elegans development wells are inspected to assess the degree of population growth inhibition. This inspection can consist of an optical density measurement to assess the amount of food consumed by the developing nematodes. Very little food is consumed when no test compound is present: most food is consumed if an UNC-53 inhibitor has blocked the lethal or subviable phenotype induced by the transgene. The inspection can also be a visual inspection of the number of healthy or subviable worms or a histochemical measurement of C. elegans viability or of the remainder of E. coli (food) . Example 17 - Protocol to screen for compounds which inhibit or enhance cell regulation or motility. Transfected cells used in this example were the same as those obtained from example 8. Compounds to be tested were added to each of the cells and their effects on the cells monitored. Functional assays to determine neurite extension were also the same as used in example 8 as described by Geests et al . One compound (of the Formula I below) was used for further testing. Example 18 - Compounds targetted at the unc-53 pathway. Snythesis of (l-(lH-pyrrol-2-ylmethyl) -2-piperidone. Step 1 To a stirred solution of 150g of lH-pyrrol-2- carboxaldehyde in 1500g parts of trichloromethane were added 690, of 5A molecular Sieves. A kit solution of 264, of methyl 5-aminopentanoate hydrochloride in 1500g of tricholoro ethane was added. After stirring for 5 minutes, 465g of thiethylamine were added over 10 minutes. Upon complete addition, the reaction mixture was stirred for 20 hours at ambient temperature. The mixture was filtered over diatomaceous earth and the filtrate was concentrated by evaporation of the solvent. The concentrate was triturated in 1 , 1'-oxybisethane. The precipitate was filtered off and the filtrate was concentrated, yielding 300g (91.1%) of 5-[ [ (lH-pyrrol-2- Step 2 A mixture of I50g of 5-[ [ (lH-pyrrol-2- yl)methylen]amino]pentanoate hydrogenated at 3.l0 5 Pa and at ambient temperature with 3.3 parts of platinum oxide. After the calculated amount of hydrogen was consumed, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in dichloromethane and the organic phase was washed three times with a sodium hydroxide 3 N solution. The product was distilled at 13.30 Pa (bp 100-130SC) . The residue was crystallized from cyclohexane and hexane. The product was filtered off and dried, yielding 193 parts (100%) of l-(lH-pyrrol-2-ylmethyl)-2-piperidone. ; mp. 105.80C. The compound (1-(lH-pyrrol-2-ylmethyl)-2- piperidinone) when applied for 24 hours to cultures of both wild-type and transfected N4 (mouse neuroblastoma) cells displays a differential behaviour. There is no effect (or at most a small stimulatory) effect on the wild-type N4 cells, up to concentrations of 1 μM, the compound clearly becomes toxic for both types of cells. The results indicate that this compound conteracts the effects of overexpression of UNC-53 and may have beneficial effects therefore in for example metastasis. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: BOGAERT; THIERRY (B) STREET: Voorstraat 36 bus 11 (C) CITY: Kortrijk (E) COUNTRY: Belgium (F) POSTAL CODE (ZIP) : B-8500 (A) NAME: STRINGHAM; EVE (B) STREET: 9326-133 A Street (C) CITY: Surrey (D) STATE: British Columbia (E) COUNTRY: Canada (F) POSTAL CODE (ZIP) : V3V 5R5 (A) NAME: VANDEKERCKHOVE; JOEL (B) STREET: Rode Benkendreef 27 (C) CITY: Loppem (D) STATE: - (E) COUNTRY: Belgium (F) POSTAL CODE (ZIP) : none (ii) TITLE OF INVENTION: Processes for the identification of compounds which control cell behaviour, the compounds identified and pharmaceutical compositions containing them and their use in the control of cell behaviour (iii) NUMBER OF SEQUENCES: 48 (iv) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (EPO) (v) CURRENT APPLICATION DATA: APPLICATION NUMBER: EP PCT/EP96/02311 (vi) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: GB 9510944.3 (B) FILING DATE: 31-MAY-1995 (2) INFORMATION FOR SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5073 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (vi) ORIGINAL SOURCE: (A) ORGANISM: Caenorhabditis elegans (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: GGTTTAATTA CCCAAGTTTG AGACATCAAT TCCATCGAAC GAAATGTTGG TGCTCCGAAT 60 AAAATGACGA CGTCAAATGT AGAATTGATA CCAATCTACA CGGATTGGGC CAATCGGCAC 120 CTTTCGAAGG GCAGCTTATC AAAGTCGATT AGGGATATTT CCAATGATTT TCGCGACTAT 180 CGACTGGTTT CTCAGCTTAT TAATGTGATC GTTCCGATCA ACGAATTCTC GCCTGCATTC 240 ACGAAACGTT TGGCAAAAAT CACATCGAAC CTGGATGGCC TCGAAACGTG TCTCGACTAC 300 CTGAAAAATC TGGGTCTCGA CTGCTCGAAA CTCACCAAAA CCGATATCGA CAGCGGAAAC 360 TTGGGTGCAG TTCTCCAGCT GCTCTTCCTG CTCTCCACCT ACAAGCAGAA GCTTCGGCAA 420 CTGAAAAAAG ATCAGAAGAA ATTGGAGCAA CTACCCACAT CCATTATGCC ACCCGCGGTT 480 TCTAAATTAC CCTCGCCACG TGTCGCCACG TCAGCAACCG CTTCAGCAAC TAACCCAAAT 540 TCCAACTTTC CACAAATGTC AACATCCAGG CTTCAGACTC CACAGTCAAG AATATCGAAA 600 ATTGATTCAT CAAAGATTGG TATCAAGCCA AAGACGTCTG GACTTAAACC ACCCTCATCA 660 TCAACCACTT CATCAAATAA TACAAATTCA TTCCGTCCGT CGAGCCGTTC GAGTGGCAAT 720 AATAATGTTG GCTCGACGAT ATCCACATCT GCGAAGAGCT TAGAATCATC ATCAACGTAC 780 AGCTCTATTT CGAATCTAAA CCGACCTACC TCCCAACTCC AAAAACCTTC TAGACCACAA 840 ACCCAGCTAG TTCGTGTTGC TACAACTACA AAAATCGGAA GCTCAAAGCT AGCCGCTCCG 900 AAAGCCGTGA GCACCCCAAA ACTTGCTTCT GTGAAGACTA TTGGAGCAAA ACAAGAGCCC 960 GATAACAGCG GTGGTGGTGG TGGTGGAATG CTGAAATTAA AGTTATTCAG TAGCAAAAAC 1020 CCATCTTCCT CATCGAATAG CCCACAACCT ACGAGAAAGG CGGCGGCGGT GCCTCAACAA 1080 CAAACTTTGT CGAAAATCGC TGCCCCAGTG AAAAGTGGCC TGAAGCCGCC GACCAGTAAG 1140 CTGGGAAGTG CCACGTCTAT GTCGAAGCTT TGTACGCCAA AAGTTTCCTA CCGTAAAACG 1200 GACGCCCCAA TCATATCTCA ACAAGACTCG AAACGATGCT CAAAGAGCAG TGAAGAAGAG 1260 TCCGGATACG CTGGATTCAA CAGCACGTCG CCAACGTCAT CATCGACGGA AGGTTCCCTA 1320 AGCATGCATT CCACATCTTC CAAGAGTTCA ACGTCAGACG AAAAGTCTCC GTCATCAGAC 1380 GATCTTACTC TTAACGCCTC CATCGTGACA GCTATCAGAC AGCCGATAGC CGCAACACCG 1440 GTTTCTCCAA ATATTATCAA CAAGCCTGTT GAGGAAAAAC CAACACTGGC AGTGAAAGGA 1500 GTGAAAAGCA CAGCGAAAAA AGATCCACCT CCAGCTGTTC CGCCACGTGA CACCCAGCCA 1560 ACAATCGGAG TTGTTAGTCC AATTATGGCA CATAAGAAGT TGACAAATGA CCCCGTGATA 1620 TCTGAAAAAC CAGAACCTGA AAAGCTCCAA TCAATGAGCA TCGACACGAC GGACGTTCCA 1680 CCGCTTCCAC CTCTAAAATC AGTTGTTCCA CTTAAAATGA CTTCAATCCG ACAACCACCA 1740 ACGTACGATG TTCTTCTAAA ACAAGGAAAA ATCACATCGC CTGTCAAGTC GTTTGGATAT 1800 GAGCAGTCGT CCGCGTCTGA AGACTCCATT GTGGCTCATG CGTCGGCTCA GGTGACTCCG 1860 CCGACAAAAA CTTCTGGTAA TCATTCGCTG GAGAGAAGGA TGGGAAAGAA TAAGACATCA 1920 GAATCCAGCG GCTACACCTC TGACGCCGGT GTTGCGATGT GCGCCAAAAT GAGGGAGAAG 1980 CTGAAAGAAT ACGATGACAT GACTCGTCGA GCACAGAACG GCTATCCTGA CAACTTCGAA 2040 GACAGTTCCT CCTTGTCGTC TGGAATATCC GATAACAACG AGCTCGACGA CATATCCACG 2100 GACGATTTGT CCGGAGTAGA CATGGCAACA GTCGCCTCCA AACATAGCGA CTATTCCCAC 2160 TTTGTTCGCC ATCCCACGTC TTCTTCCTCA AAGCCCCGAG TCCCCAGTCG GTCCTCCACA 2220 TCAGTCGATT CTCGATCTCG AGCAGAACAG GAGAATGTGT ACAAACTTCT GTCCCAGTGC 2280 CGAACGAGCC AACGTGGCGC CGCTGCCACC TCAACCTTCG GACAACATTC GCTAAGATCC 2340 CCGGGATACT CATCCTATTC TCCACACTTA TCAGTGTCAG CTGATAAGGA CACAATGTCT 2400 ATGCACTCAC AGACTAGTCG ACGACCTTCT TCACAAAAAC CAAGCTATTC AGGCCAATTT 2460 CATTCACTTG ATCGTAAATG CCACCTTCAA GAGTTCACAT CCACCGAGCA CAGAATGGCG 2520 GCTCTCTTGA GCCCGAGACG GGTGCCGAAC TCGATGTCGA AATATGATTC TTCAGGATCC 2580 TACTCGGCGC GTTCCCGAGG TGGAAGCTCT ACTGGTATCT ATGGAGAGAC GTTCCAACTG 2640 CACAGACTAT CCGATGAAAA ATCCCCCGCA CATTCTGCCA AAAGTGAGAT GGGATCCCAA 2700 CTATCACTGG CTAGCACGAC AGCATATGGA TCTCTCAATG AGAAGTACGA ACATGCTATT 2760 CGGGACATGG CACGTGACTT GGAGTGTTAC AAGAACACTG TCGACTCACT AACCAAGAAA 2820 CAGGAGAACT ATGGAGCATT GTTTGATCTT TTTGAGCAAA AGCTTAGAAA ACTCACTCAA 2880 CACATTGATC GATCCAACTT GAAGCCTGAA GAGGCAATAC GATTCAGGCA GGACATTGCT 2940 CATTTGAGGG ATATTAGCAA TCATCTTGCA TCCAACTCAG CTCATGCTAA CGAAGGCGCT 3000 GGTGAGCTTC TTCGTCAACC ATCTCTGGAA TCAGTTGCAT CCCATCGATC ATCGATGTCA 3060 TCGTCGTCGA AAAGCAGCAA GCAGGAGAAG ATCAGCTTGA GCTCGTTTGG CAAGAACAAG 3120 AAGAGCTGGA TCCGCTCCTC ACTCTCCAAG TTCACCAAGA AGAAGAACAA GAACTACGAC 3180 GAAGCACATA TGCCATCAAT TTCCGGATCT CAAGGAACTC TTGACAACAT TGATGTGATT 3240 GAGTTGAAGC AAGAGCTCAA AGAACGCGAT AGTGCACTTT ACGAAGTCCG CCTTGACAAT 3300 CTGGATCGTG CCCGCGAAGT TGATGTTCTG AGGGAGACAG TGAACAAGTT GAAAACCGAG 3360 AACAAGCAAT TAAAGAAAGA AGTGGACAAA CTCACCAACG GTCCAGCCAC TCGTGCTTCT 3420 TCCCGCGCCT CAATTCCAGT TATCTACGAC GATGAGCATG TCTATGATGC AGCGTGTAGC 3480 AGTACATCAG CTAGTCAATC TTCGAAACGA TCCTCTGGCT GCAACTCAAT CAAGGTTACT 3540 GTAAACGTGG ACATCGCTGG AGAAATCAGT TCGATCGTTA ACCCGGACAA AGAGATAATC 3600 GTAGGATATC TTGCCATGTC AACCAGTCAG TCATGCTGGA AAGACATTGA TGTTTCTATT 3660 CTAGGACTAT TTGAAGTCTA CCTATCCAGA ATTGATGTGG AGCATCAACT TGGAATCGAT 3720 GCTCGTGATT CTATCCTTGG CTATCAAATT GGTGAACTTC GACGCGTCAT TGGAGACTCC 3780 ACAACCATGA TAACCAGCCA TCCAACTGAC ATTCTTACTT CCTCAACTAC AATCCGAATG 3840 TTCATGCACG GTGCCGCACA GAGTCGCGTA GACAGTCTGG TCCTTGATAT GCTTCTTCCA 3900 AAGCAAATGA TTCTCCAACT CGTCAAGTCA ATTTTGACAG AGAGACGTCT GGTGTTAGCT 3960 GGAGCAACTG GAATTGGAAA GAGCAAACTG GCGAAGACCC TGGCTGCTTA TGTATCTATT 4020 CGAACAAATC AATCCGAAGA TAGTATTGTT AATATCAGCA TTCCTGAAAA CAATAAAGAA 4080 GAATTGCTTC AAGTGGAACG ACGCCTGGAA AAGATCTTGA GAAGCAAAGA ATCATGCATC 4140 GTAATTCTAG ATAATATCCC AAAGAATCGA ATTGCATTTG TTGTATCCGT TTTTGCAAAT 4200 GTCCCACTTC AAAACAACGA AGGTCCATTT GTAGTATGCA CAGTCAACCG ATATCAAATC 4260 CCTGAGCTTC AAATTCACCA CAATTTCAAA ATGTCAGTAA TGTCGAATCG TCTCGAAGGA 4320 TTCATCCTAC GTTACCTCCG ACGACGGGCG GTAGAGGATG AGTATCGTCT AACTGTACAG 4380 ATGCCATCAG AGCTCTTCAA AATCATTGAC TTCTTCCCAA TAGCTCTTCA GGCCGTCAAT 4440 AATTTTATTG AGAAAACGAA TTCTGTTGAT GTGACAGTTG GTCCAAGAGC ATGCTTGAAC 4500 TGTCCTCTAA CTGTCGATGG ATCCCGTGAA TGGTTCATTC GATTGTGGAA TGAGAACTTC 4560 ATTCCATATT TGGAACGTGT TGCTAGAGAT GGCAAAAAAA ACCTTCGGTC GCTGCACTTC 4620 CTTCGAGGAT CCCACCGACA TCGTCTCTAA AAAATGGCCG TGGTTCGATG GTGAAAACCC 4680 GGAGAATGTG CTCAAACGTC TTCAACTCCA AGACCTCGTC CCGTCACCTG CCAACTCATC 4740 CCGACAACAC TTCAATCCCC TCGAGTCGTT GATCCAATTG CATGCTACCA AGCATCAGAC 4800 CATCGACAAC ATTTGAACAG AAGACTCTAA TCTTCTCTCG CCTCTCCCCC GCTTTCCTTA 4860 TCTTCGTACC GGTACCTGAT GATTCCCCAT TTTCCCCCTT TTCCCCCCAA TTTCCCAGAA 4920 CCTCCTGTTC CCTTTGTTCC TAGTCCTCCC GGGTGCCGAC GCCGAAGCGA TTTAAAAACC 4980 TTTTTCTTTC CGAAACATTT CCCATTGCTC ATTAATAGTC AAATTGAATA AACAGTGTAT 5040 GTACTTAAAA AAAAAAAAAA AAAAAAAAAA AAA 5073 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5072 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: GGTTTAATTA CCCAAGTTTG AGACATCAAT TCCATCGAAC GAAATGTTGG TGCTCCGAAT 60 AAAATGACGA CGTCAAATGT AGAATTGATA CCAATCTACA CGGATTGGGC CAATCGGCAC 120 CTTTCGAAGG GCAGCTTATC AAAGTCGATT AGGGATATTT CCAATGATTT TCGCGACTAT 180 CGACTGGTTT CTCAGCTTAT TAATGTGATC GTTCCGATCA ACGAATTCTC GCCTGCATTC 240 ACGAAACGTT TGGCAAAAAT CACATCGAAC CTGGATGGCC TCGAAACGTG TCTCGACTAC 300 CTGAAAAATC TGGGTCTCGA CTGCTCGAAA CTCACCAAAA CCGATATCGA CAGCGGAAAC 360 TTGGGTGCAG TTCTCCAGCT GCTCTTCCTG CTCTCCACCT ACAAGCAGAA GCTTCGGCAA 420 CTGAAAAAAG ATCAGAAGAA ATTGGAGCAA CTACCCACAT CCATTATGCC ACCCGCGGTT 480 TCTAAATTAC CCTCGCCACG TGTCGCCACG TCAGCAACCG CTTCAGCAAC TAACCCAAAT 540 TCCAACTTTC CACAAATGTC AACATCCAGG CTTCAGACTC CACAGTCAAG AATATCGAAA 600 ATTGATTCAT CAAAGATTGG TATCAAGCCA AAGACGTCTG GACTTAAACC ACCCTCATCA 660 TCAACCACTT CATCAAATAA TACAAATTCA TTCCGTCCGT CGAGCCGTTC GAGTGGCAAT 720 AATAATGTTG GCTCGACGAT ATCCACATCT GCGAAGAGCT TAGAATCATC ATCAACGTAC 780 AGCTCTATTT CGAATCTAAA CCGACCTACC TCCCAACTCC AAAAACCTTC TAGACCACAA 840 ACCCAGCTAG TTCGTGTTGC TACAACTACA AAAATCGGAA GCTCAAAGCT AGCCGCTCCG 900 AAAGCCGTGA GCACCCCAAA ACTTGCTTCT GTGAAGACTA TTGGAGCAAA ACAAGAGCCC 960 GATAACAGCG GTGGTGGTGG TGGTGGAATG CTGAAATTAA AGTTATTCAG TAGCAAAAAC 1020 CCATCTTCCT CATCGAATAG CCCACAACCT ACGAGAAAGG CGGCGGCGGT GCCTCAACAA 1080 CAAACTTTGT CGAAAATCGC TGCCCCAGTG AAAAGTGGCC TGAAGCCGCC GACCAGTAAG 1140 CTGGGAAGTG CCACGTCTAT GTCGAAGCTT TGTACGCCAA AAGTTTCCTA CCGTAAAACG 1200 GACGCCCCAA TCATATCTCA ACAAGACTCG AAACGATGCT CAAAGAGCAG TGAAGAAGAG 1260 TCCGGATACG CTGGATTCAA CAGCACGTCG CCAACGTCAT CATCGACGGA AGGTTCCCTA 1320 AGCATGCATT CCACATCTTC CAAGAGTTCA ACGTCAGACG AAAAGTCTCC GTCATCAGAC 1380 GATCTTACTC TTAACGCCTC CATCGTGACA GCTATCAGAC AGCCGATAGC CGCAACACCG 1440 GTTTCTCCAA ATATTATCAA CAAGCCTGTT GAGGAAAAAC CAACACTGGC AGTGAAAGGA 1500 GTGAAAAGCA CAGCGAAAAA AGATCCACCT CCAGCTGTTC CGCCACGTGA CACCCAGCCA 1560 ACAATCGGAG TTGTTAGTCC AATTATGGCA CATAAGAAGT TGACAAATGA CCCCGTGATA 1620 TCTGAAAAAC CAGAACCTGA AAAGCTCCAA TCAATGAGCA TCGACACGAC GGACGTTCCA 1680 CCGCTTCCAC CTCTAAAATC AGTTGTTCCA CTTAAAATGA CTTCAATCCG ACAACCACCA 1740 ACGTACGATG TTCTTCTAAA ACAAGGAAAA ATCACATCGC CTGTCAAGTC GTTTGGATAT 1800 GAGCAGTCGT CCGCGTCTGA AGACTCCATT GTGGCTCATG CGTCGGCTCA GGTGACTCCG 1860 CCGACAAAAA CTTCTGGTAA TCATTCGCTG GAGAGAAGGA TGGGAAAGAA TAAGACATCA 1920 GAATCCAGCG GCTACACCTC TGACGCCGGT GTTGCGATGT GCGCCAAAAT GAGGGAGAAG 1980 CTGAAAGAAT ACGATGACAT GACTCGTCGA GCACAGAACG GCTATCCTGA CAACTTCGAA 2040 GACAGTTCCT CCTTGTCGTC TGGAATATCC GATAACAACG AGCTCGACGA CATATCCACG 2100 GACGATTTGT CCGGAGTAGA CATGGCAACA GTCGCCTCCA AACATAGCGA CTATTCCCAC 2160 TTTGTTCGCC ATCCCACGTC TTCTTCCTCA AAGCCCCGAG TCCCCAGTCG GTCCTCCACA 2220 TCAGTCGATT CTCGATCTCG AGCAGAACAG GAGAATGTGT ACAAACTTCT GTCCCAGTGC 2280 CGAACGAGCC AACGTGGCGC CGCTGCCACC TCAACCTTCG GACAACATTC GCTAAGATCC 2340 CCGGGATACT CATCCTATTC TCCACACTTA TCAGTGTCAG CTGATAAGGA CACAATGTCT 2400 ATGCACTCAC AGACTAGTCG ACGACCTTCT TCACAAAAAC CAAGCTATTC AGGCCAATTT 2460 CATTCACTTG ATCGTAAATG CCACCTTCAA GAGTTCACAT CCACCGAGCA CAGAATGGCG 2520 GCTCTCTTGA GCCCGAGACG GGTGCCGAAC TCGATGTCGA AATATGATTC TTCAGGATCC 2580 TACTCGGCGC GTTCCCGAGG TGGAAGCTCT ACTGGTATCT ATGGAGAGAC GTTCCAACTG 2640 CACAGACTAT CCGATGAAAA ATCCCCCGCA CATTCTGCCA AAAGTGAGAT GGGATCCCAA 2700 CTATCACTGG CTAGCACGAC AGCATATGGA TCTCTCAATG AGAAGTACGA ACATGCTATT 2760 CGGGACATGG CACGTGACTT GGAGTGTTAC AAGAACACTG TCGACTCACT AACCAAGAAA 2820 CAGGAGAACT ATGGAGCATT GTTTGATCTT TTTGAGCAAA AGCTTAGAAA ACTCACTCAA 2880 CACATTGATC GATCCAACTT GAAGCCTGAA GAGGCAATAC GATTCAGGCA GGACATTGCT 2940 CATTTGAGGG ATATTAGCAA TCATCTTGCA TCCAACTCAG CTCATGCTAA CGAAGGCGCT 3000 GGTGAGCTTC TTCGTCAACC ATCTCTGGAA TCAGTTGCAT CCCATCGATC ATCGATGTCA 3060 TCGTCGTCGA AAAGCAGCAA GCAGGAGAAG ATCAGCTTGA GCTCGTTTGG CAAGAACAAG 3120 AAGAGCTGGA TCCGCTCCTC ACTCTCCAAG TTCACCAAGA AGAAGAACAA GAACTACGAC 3180 GAAGCACATA TGCCATCAAT TTCCGGATCT CAAGGAACTC TTGACAACAT TGATGTGATT 3240 GAGTTGAAGC AAGAGCTCAA AGAACGCGAT AGTGCACTTT ACGAAGTCCG CCTTGACAAT 3300 CTGGATCGTG CCCGCGAAGT TGATGTTCTG AGGGAGACAG TGAACAAGTT GAAAACCGAG 3360 AACAAGCAAT TAAAGAAAGA AGTGGACAAA CTCACCAACG GTCCAGCCAC TCGTGCTTCT 3420 TCCCGCGCCT CAATTCCAGT TATCTACGAC GATGAGCATG TCTATGATGC AGCGTGTAGC 3480 AGTACATCAG CTAGTCAATC TTCGAAACGA TCCTCTGGCT GCAACTCAAT CAAGGTTACT 3540 GTAAACGTGG ACATCGCTGG AGAAATCAGT TCGATCGTTA ACCCGGACAA AGAGATAATC 3600 GTAGGATATC TTGCCATGTC AACCAGTCAG TCATGCTGGA AAGACATTGA TGTTTCTATT 3660 CTAGGACTAT TTGAAGTCTA CCTATCCAGA ATTGATGTGG AGCATCAACT TGGAATCGAT 3720 GCTCGTGATT CTATCCTTGG CTATCAAATT GGTGAACTTC GACGCGTCAT TGGAGACTCC 3780 ACAACCATGA TAACCAGCCA TCCAACTGAC ATTCTTACTT CCTCAACTAC AATCCGAATG 3840 TTCATGCACG GTGCCGCACA GAGTCGCGTA GACAGTCTGG TCCTTGATAT GCTTCTTCCA 3900 AAGCAAATGA TTCTCCAACT CGTCAAGTCA ATTTTGACAG AGAGACGTCT GGTGTTAGCT 3960 GGAGCAACTG GAATTGGAAA GAGCAAACTG GCGAAGACCC TGGCTGCTTA TGTATCTATT 4020 CGAACAAATC AATCCGAAGA TAGTATTGTT AATATCAGCA TTCCTGAAAA CAATAAAGAA 4080 GAATTGCTTC AAGTGGAACG ACGCCTGGAA AAGATCTTGA GAAGCAAAGA ATCATGCATC 4140 GTAATTCTAG ATAATATCCC AAAGAATCGA ATTGCATTTG TTGTATCCGT TTTTGCAAAT 4200 GTCCCACTTC AAAACAACGA AGGTCCATTT GTAGTATGCA CAGTCAACCG ATATCAAATC 4260 CCTGAGCTTC AAATTCACCA CAATTTCAAA ATGTCAGTAA TGTCGAATCG TCTCGAAGGA 4320 TTCATCCTAC GTTACCTCCG ACGACGGGCG GTAGAGGATG AGTATCGTCT AACTGTACAG 4380 ATGCCATCAG AGCTCTTCAA AATCATTGAC TTCTTCCCAA TAGCTCTTCA GGCCGTCAAT 4440 AATTTTATTG AGAAAACGAA TTCTGTTGAT GTGACAGTTG GTCCAAGAGC ATGCTTGAAC 4500 TGTCCTCTAA CTGTCGATGG ATCCCGTGAA TGGTTCATTC GATTGTGGAA TGAGAACTTC 4560 ATTCCATATT TGGAACGTGT TGCTAGAGAT GGCAAAAAAA CCTTCGGTCG CTGCACTTCC 4620 TTCGAGGATC CCACCGACAT CGTCTCTAAA AAATGGCCGT GGTTCGATGG TGAAAACCCG 4680 GAGAATGTGC TCAAACGTCT TCAACTCCAA GACCTCGTCC CGTCACCTGC CAACTCATCC 4740 CGACAACACT TCAATCCCCT CGAGTCGTTG ATCCAATTGC ATGCTACCAA GCATCAGACC 4800 ATCGACAACA TTTGAACAGA AGACTCTAAT CTTCTCTCGC CTCTCCCCCG CTTTCCTTAT 4860 CTTCGTACCG GTACCTGATG ATTCCCCATT TTCCCCCTTT TCCCCCCAAT TTCCCAGAAC 4920 CTCCTGTTCC CTTTGTTCCT AGTCCTCCCG GGTGCCGACG CCGAAGCGAT TTAAAAACCT 4980 TTTTCTTTCC GAAACATTTC CCATTGCTCA TTAATAGTCA AATTGAATAA ACAGTGTATG 5040 TACTTAAAAA AAAAAAAAAA AAAAAAAAAA AA 5072 (2) INFORMATION FOR SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1528 amino acids (B) TYPE: amino acid ( C ) STRANDEDNESS : (D ) TOPOLOGY : unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Met Thr Thr Ser Asn Val Glu Leu lie Pro lie Tyr Thr Asp Trp Ala 1 5 10 15 Asn Arg His Leu Ser Lys Gly Ser Leu Ser Lys Ser lie Arg Asp He 20 25 30 Ser Asn Asp Phe Arg Asp Tyr Arg Leu Val Ser Gin Leu He Asn Val 35 40 45 He Val Pro He Asn Glu Phe Ser Pro Ala Phe Thr Lys Arg Leu Ala 50 55 60 Lys He Thr Ser Asn Leu Asp Gly Leu Glu Thr Cys Leu Asp Tyr Leu 65 70 75 80 Lys Asn Leu Gly Leu Asp Cys Ser Lys Leu Thr Lys Thr Asp He Asp 85 90 95 Ser Gly Asn Leu Gly Ala Val Leu Gin Leu Leu Phe Leu Leu Ser Thr 100 105 110 Tyr Lys Gin Lys Leu Arg Gin Leu Lys Lys Asp Gin Lys Lys Leu Glu 115 120 125 Gin Leu Pro Thr Ser He Met Pro Pro Ala Val Ser Lys Leu Pro Ser 130 135 140 Pro Arg Val Ala Thr Ser Ala Thr Ala Ser Ala Thr Asn Pro Asn Ser 145 150 155 160 Asn Phe Pro Gin Met Ser Thr Ser Arg Leu Gin Thr Pro Gin Ser Arg 165 170 175 He Ser Lys He Asp Ser Ser Lys He Gly He Lys Pro Lys Thr Ser 180 185 190 Gly Leu Lys Pro Pro Ser Ser Ser Thr Thr Ser Ser Asn Asn Thr Asn 195 200 205 Ser Phe Arg Pro Ser Ser Arg Ser Ser Gly Asn Asn Asn Val Gly Ser 210 215 220 Thr He Ser Thr Ser Ala Lys Ser Leu Glu Ser Ser Ser Thr Tyr Ser 225 230 235 240 Ser He Ser Asn Leu Asn Arg Pro Thr Ser Gin Leu Gin Lys Pro Ser 245 250 255 Arg Pro Gin Thr Gin Leu Val Arg Val Ala Thr Thr Thr Lys He Gly 260 265 270 Ser Ser Lys Leu Ala Ala Pro Lys Ala Val Ser Thr Pro Lys Leu Ala 275 280 285 Ser Val Lys Thr He Gly Ala Lys Gin Glu Pro Asp Asn Ser Gly Gly 290 295 300 Gly Gly Gly Gly Met Leu Lys Leu Lys Leu Phe Ser Ser Lys Asn Pro 305 310 315 320 Ser Ser Ser Ser Asn Ser Pro Gin Pro Thr Arg Lys Ala Ala Ala Val 325 330 335 Pro Gin Gin Gin Thr Leu Ser Lys He Ala Ala Pro Val Lys Ser Gly 340 345 350 Leu Lys Pro Pro Thr Ser Lys Leu Gly Ser Ala Thr Ser Met Ser Lys 355 360 365 Leu Cys Thr Pro Lys Val Ser Tyr Arg Lys Thr Asp Ala Pro He He 370 375 380 Ser Gin Gin Asp Ser Lys Arg Cys Ser Lys Ser Ser Glu Glu Glu Ser 385 390 395 400 Gly Tyr Ala Gly Phe Asn Ser Thr Ser Pro Thr Ser Ser Ser Thr Glu 405 410 415 Gly Ser Leu Ser Met His Ser Thr Ser Ser Lys Ser Ser Thr Ser Asp 420 425 430 Glu Lys Ser Pro Ser Ser Asp Asp Leu Thr Leu Asn Ala Ser He Val 435 440 445 Thr Ala He Arg Gin Pro He Ala Ala Thr Pro Val Ser Pro Asn He 450 455 460 He Asn Lys Pro Val Glu Glu Lys Pro Thr Leu Ala Val Lys Gly Val 465 470 475 480 Lys Ser Thr Ala Lys Lys Asp Pro Pro Pro Ala Val Pro Pro Arg Asp 485 490 495 Thr Gin Pro Thr He Gly Val Val Ser Pro He Met Ala His Lys Lys 500 505 510 Leu Thr Asn Asp Pro Val He Ser Glu Lys Pro Glu Pro Glu Lys Leu 515 520 525 Gin Ser Met Ser He Asp Thr Thr Asp Val Pro Pro Leu Pro Pro Leu 530 535 540 Lys Ser Val Val Pro Leu Lys Met Thr Ser He Arg Gin Pro Pro Thr 545 550 555 560 Tyr Asp Val Leu Leu Lys Gin Gly Lys He Thr Ser Pro Val Lys Ser 565 570 575 Phe Gly Tyr Glu Gin Ser Ser Ala Ser Glu Asp Ser He Val Ala His 580 585 590 Ala Ser Ala Gin Val Thr Pro Pro Thr Lys Thr Ser Gly Asn His Ser 595 600 605 Leu Glu Arg Arg Met Gly Lys Asn Lys Thr Ser Glu Ser Ser Gly Tyr 610 615 620 Thr Ser Asp Ala Gly Val Ala Met Cys Ala Lys Met Arg Glu Lys Leu 625 630 635 640 Lys Glu Tyr Asp Asp Met Thr Arg Arg Ala Gin Asn Gly Tyr Pro Asp 645 650 655 Asn Phe Glu Asp Ser Ser Ser Leu Ser Ser Gly He Ser Asp Asn Asn 660 665 670 Glu Leu Asp Asp He Ser Thr Asp Asp Leu Ser Gly Val Asp Met Ala 675 680 685 Thr Val Ala Ser Lys His Ser Asp Tyr Ser His Phe Val Arg His Pro 690 695 700 Thr Ser Ser Ser Ser Lys Pro Arg Val Pro Ser Arg Ser Ser Thr Ser 705 710 715 720 Val Asp Ser Arg Ser Arg Ala Glu Gin Glu Asn Val Tyr Lys Leu Leu 725 730 735 Ser Gin Cys Arg Thr Ser Gin Arg Gly Ala Ala Ala Thr Ser Thr Phe 740 745 750 Gly Gin His Ser Leu Arg Ser Pro Gly Tyr Ser Ser Tyr Ser Pro His 755 760 765 Leu Ser Val Ser Ala Asp Lys Asp Thr Met Ser Met His Ser Gin Thr 770 775 780 Ser Arg Arg Pro Ser Ser Gin Lys Pro Ser Tyr Ser Gly Gin Phe His 785 790 795 800 Ser Leu Asp Arg Lys Cys His Leu Gin Glu Phe Thr Ser Thr Glu His 805 810 815 Arg Met Ala Ala Leu Leu Ser Pro Arg Arg Val Pro Asn Ser Met Ser 820 825 830 Lys Tyr Asp Ser Ser Gly Ser Tyr Ser Ala Arg Ser Arg Gly Gly Ser 835 840 845 Ser Thr Gly He Tyr Gly Glu Thr Phe Gin Leu His Arg Leu Ser Asp 850 855 860 Glu Lys Ser Pro Ala His Ser Ala Lys Ser Glu Met Gly Ser Gin Leu 865 870 875 880 Ser Leu Ala Ser Thr Thr Ala Tyr Gly Ser Leu Asn Glu Lys Tyr Glu 885 890 895 His Ala He Arg Asp Met Ala Arg Asp Leu Glu Cys Tyr Lys Asn Thr 900 905 910 Val Asp Ser Leu Thr Lys Lys Gin Glu Asn Tyr Gly Ala Leu Phe Asp 915 920 925 Leu Phe Glu Gin Lys Leu Arg Lys Leu Thr Gin His He Asp Arg Ser 930 935 940 Asn Leu Lys Pro Glu Glu Ala He Arg Phe Arg Gin Asp He Ala His 945 950 955 960 Leu Arg Asp He Ser Asn His Leu Ala Ser Asn Ser Ala His Ala Asn 965 970 975 Glu Gly Ala Gly Glu Leu Leu Arg Gin Pro Ser Leu Glu Ser Val Ala 980 985 990 Ser His Arg Ser Ser Met Ser Ser Ser Ser Lys Ser Ser Lys Gin Glu 995 1000 1005 Lys He Ser Leu Ser Ser Phe Gly Lys Asn Lys Lys Ser Trp He Arg 1010 1015 1020 Ser Ser Leu Ser Lys Phe Thr Lys Lys Lys Asn Lys Asn Tyr Asp Glu 1025 1030 1035 1040 Ala His Met Pro Ser He Ser Gly Ser Gin Gly Thr Leu Asp Asn He 1045 1050 1055 Asp Val He Glu Leu Lys Gin Glu Leu Lys Glu Arg Asp Ser Ala Leu 1060 1065 1070 Tyr Glu Val Arg Leu Asp Asn Leu Asp Arg Ala Arg Glu Val Asp Val 1075 1080 1085 Leu Arg Glu Thr Val Asn Lys Leu Lys Thr Glu Asn Lys Gin Leu Lys 1090 1095 1100 Lys Glu Val Asp Lys Leu Thr Asn Gly Pro Ala Thr Arg Ala Ser Ser 1105 1110 1115 1120 Arg Ala Ser He Pro Val He Tyr Asp Asp Glu His Val Tyr Asp Ala 1125 1130 1135 Ala Cys Ser Ser Thr Ser Ala Ser Gin Ser Ser Lys Arg Ser Ser Gly 1140 1145 1150 Cys Asn Ser He Lys Val Thr Val Asn Val Asp He Ala Gly Glu He 1155 1160 1165 Ser Ser He Val Asn Pro Asp Lys Glu He He Val Gly Tyr Leu Ala 1170 1175 1180 Met Ser Thr Ser Gin Ser Cys Trp Lys Asp He Asp Val Ser He Leu 1185 1190 1195 1200 Gly Leu Phe Glu Val Tyr Leu Ser Arg He Asp Val Glu His Gin Leu 1205 1210 1215 Gly He Asp Ala Arg Asp Ser He Leu Gly Tyr Gin He Gly Glu Leu 1220 1225 1230 Arg Arg Val He Gly Asp Ser Thr Thr Met He Thr Ser His Pro Thr 1235 1240 1245 Asp He Leu Thr Ser Ser Thr Thr He Arg Met Phe Met His Gly Ala 1250 1255 1260 Ala Gin Ser Arg Val Asp Ser Leu Val Leu Asp Met Leu Leu Pro Lys 1265 1270 1275 1280 Gin Met He Leu Gin Leu Val Lys Ser He Leu Thr Glu Arg Arg Leu 1285 1290 1295 Val Leu Ala Gly Ala Thr Gly He Gly Lys Ser Lys Leu Ala Lys Thr 1300 1305 1310 Leu Ala Ala Tyr Val Ser He Arg Thr Asn Gin Ser Glu Asp Ser He 1315 1320 1325 Val Asn He Ser He Pro Glu Asn Asn Lys Glu Glu Leu Leu Gin Val 1330 1335 1340 Glu Arg Arg Leu Glu Lys He Leu Arg Ser Lys Glu Ser Cys He Val 1345 1350 1355 1360 He Leu Asp Asn He Pro Lys Asn Arg He Ala Phe Val Val Ser Val 1365 1370 1375 Phe Ala Asn Val Pro Leu Gin Asn Asn Glu Gly Pro Phe Val Val Cys 1380 1385 1390 Thr Val Asn Arg Tyr Gin He Pro Glu Leu Gin He His His Asn Phe 1395 1400 1405 Lys Met Ser Val Met Ser Asn Arg Leu Glu Gly Phe He Leu Arg Tyr 1410 1415 1420 Leu Arg Arg Arg Ala Val Glu Asp Glu Tyr Arg Leu Thr Val Gin Met 1425 1430 1435 1440 Pro Ser Glu Leu Phe Lys He He Asp Phe Phe Pro He Ala Leu Gin 1445 1450 1455 Ala Val Asn Asn Phe He Glu Lys Thr Asn Ser Val Asp Val Thr Val 1460 1465 1470 Gly Pro Arg Ala Cys Leu Asn Cys Pro Leu Thr Val Asp Gly Ser Arg 1475 1480 1485 Glu Trp Phe He Arg Leu Trp Asn Glu Asn Phe He Pro Tyr Leu Glu 1490 1495 1500 Arg Val Ala Arg Asp Gly Lys Lys Asn Leu Arg Ser Leu His Phe Leu 1505 1510 1515 1520 Arg Gly Ser His Arg His Arg Leu 1525 (2) INFORMATION FOR SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1583 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Met Thr Thr Ser Asn Val Glu Leu He Pro He Tyr Thr Asp Trp Ala 1 5 10 15 Asn Arg His Leu Ser Lys Gly Ser Leu Ser Lys Ser He Arg Asp He 20 25 30 Ser Asn Asp Phe Arg Asp Tyr Arg Leu Val Ser Gin Leu He Asn Val 35 40 45 He Val Pro He Asn Glu Phe Ser Pro Ala Phe Thr Lys Arg Leu Ala 50 55 60 Lys He Thr Ser Asn Leu Asp Gly Leu Glu Thr Cys Leu Asp Tyr Leu 65 70 75 80 Lys Asn Leu Gly Leu Asp Cys Ser Lys Leu Thr Lys Thr Asp He Asp 85 90 95 Ser Gly Asn Leu Gly Ala Val Leu Gin Leu Leu Phe Leu Leu Ser Thr 100 105 110 Tyr Lys Gin Lys Leu Arg Gin Leu Lys Lys Asp Gin Lys Lys Leu Glu 115 120 125 Gin Leu Pro Thr Ser He Met Pro Pro Ala Val Ser Lys Leu Pro Ser 130 135 140 Pro Arg Val Ala Thr Ser Ala Thr Ala Ser Ala Thr Asn Pro Asn Ser 145 150 155 160 Asn Phe Pro Gin Met Ser Thr Ser Arg Leu Gin Thr Pro Gin Ser Arg 165 170 175 He Ser Lys He Asp Ser Ser Lys He Gly He Lys Pro Lys Thr Ser 180 185 190 Gly Leu Lys Pro Pro Ser Ser Ser Thr Thr Ser Ser Asn Asn Thr Asn 195 200 205 Ser Phe Arg Pro Ser Ser Arg Ser Ser Gly Asn Asn Asn Val Gly Ser 210 215 220 Thr He Ser Thr Ser Ala Lys Ser Leu Glu Ser Ser Ser Thr Tyr Ser 225 230 235 240 Ser He Ser Asn Leu Asn Arg Pro Thr Ser Gin Leu Gin Lys Pro Ser 245 250 255 Arg Pro Gin Thr Gin Leu Val Arg Val Ala Thr Thr Thr Lys He Gly 260 265 270 Ser Ser Lys Leu Ala Ala Pro Lys Ala Val Ser Thr Pro Lys Leu Ala 275 280 285 Ser Val Lys Thr He Gly Ala Lys Gin Glu Pro Asp Asn Ser Gly Gly 290 295 300 Gly Gly Gly Gly Met Leu Lys Leu Lys Leu Phe Ser Ser Lys Asn Pro 305 310 315 320 Ser Ser Ser Ser Asn Ser Pro Gin Pro Thr Arg Lys Ala Ala Ala Val 325 330 335 Pro Gin Gin Gin Thr Leu Ser Lys He Ala Ala Pro Val Lys Ser Gly 340 345 350 Leu Lys Pro Pro Thr Ser Lys Leu Gly Ser Ala Thr Ser Met Ser Lys 355 360 365 Leu Cys Thr Pro Lys Val Ser Tyr Arg Lys Thr Asp Ala Pro He He 370 375 380 Ser Gin Gin Asp Ser Lys Arg Cys Ser Lys Ser Ser Glu Glu Glu Ser 385 390 395 400 Gly Tyr Ala Gly Phe Asn Ser Thr Ser Pro Thr Ser Ser Ser Thr Glu 405 410 415 Gly Ser Leu Ser Met His Ser Thr Ser Ser Lys Ser Ser Thr Ser Asp 420 425 430 Glu Lys Ser Pro Ser Ser Asp Asp Leu Thr Leu Asn Ala Ser He Val 435 440 445 Thr Ala He Arg Gin Pro He Ala Ala Thr Pro Val Ser Pro Asn He 450 455 460 He Asn Lys Pro Val Glu Glu Lys Pro Thr Leu Ala Val Lys Gly Val 465 470 475 480 Lys Ser Thr Ala Lys Lys Asp Pro Pro Pro Ala Val Pro Pro Arg Asp 485 490 495 Thr Gin Pro Thr He Gly Val Val Ser Pro He Met Ala His Lys Lys 500 505 510 Leu Thr Asn Asp Pro Val He Ser Glu Lys Pro Glu Pro Glu Lys Leu 515 520 525 Gin Ser Met Ser He Asp Thr Thr Asp Val Pro Pro Leu Pro Pro Leu 530 535 540 Lys Ser Val Val Pro Leu Lys Met Thr Ser He Arg Gin Pro Pro Thr 545 550 555 560 Tyr Asp Val Leu Leu Lys Gin Gly Lys He Thr Ser Pro Val Lys Ser 565 570 575 Phe Gly Tyr Glu Gin Ser Ser Ala Ser Glu Asp Ser He Val Ala His 580 585 590 Ala Ser Ala Gin Val Thr Pro Pro Thr Lys Thr Ser Gly Asn His Ser 595 600 605 Leu Glu Arg Arg Met Gly Lys Asn Lys Thr Ser Glu Ser Ser Gly Tyr 610 615 620 Thr Ser Asp Ala Gly Val Ala Met Cys Ala Lys Met Arg Glu Lys Leu 625 630 635 640 Lys Glu Tyr Asp Asp Met Thr Arg Arg Ala Gin Asn Gly Tyr Pro Asp 645 650 655 Asn Phe Glu Asp Ser Ser Ser Leu Ser Ser Gly He Ser Asp Asn Asn 660 665 670 Glu Leu Asp Asp He Ser Thr Asp Asp Leu Ser Gly Val Asp Met Ala 675 680 685 Thr Val Ala Ser Lys His Ser Asp Tyr Ser His Phe Val Arg His Pro 690 695 700 Thr Ser Ser Ser Ser Lys Pro Arg Val Pro Ser Arg Ser Ser Thr Ser 705 710 715 720 Val Asp Ser Arg Ser Arg Ala Glu Gin Glu Asn Val Tyr Lys Leu Leu 725 730 735 Ser Gin Cys Arg Thr Ser Gin Arg Gly Ala Ala Ala Thr Ser Thr Phe 740 745 750 Gly Gin His Ser Leu Arg Ser Pro Gly Tyr Ser Ser Tyr Ser Pro His 755 760 765 Leu Ser Val Ser Ala Asp Lys Asp Thr Met Ser Met His Ser Gin Thr 770 775 780 Ser Arg Arg Pro Ser Ser Gin Lys Pro Ser Tyr Ser Gly Gin Phe His 785 790 795 800 Ser Leu Asp Arg Lys Cys His Leu Gin Glu Phe Thr Ser Thr Glu His 805 810 815 Arg Met Ala Ala Leu Leu Ser Pro Arg Arg Val Pro Asn Ser Met Ser 820 825 830 Lys Tyr Asp Ser Ser Gly Ser Tyr Ser Ala Arg Ser Arg Gly Gly Ser 835 840 845 Ser Thr Gly He Tyr Gly Glu Thr Phe Gin Leu His Arg Leu Ser Asp 850 855 860 Glu Lys Ser Pro Ala His Ser Ala Lys Ser Glu Met Gly Ser Gin Leu 865 870 875 880 Ser Leu Ala Ser Thr Thr Ala Tyr Gly Ser Leu Asn Glu Lys Tyr Glu 885 890 895 His Ala He Arg Asp Met Ala Arg Asp Leu Glu Cys Tyr Lys Asn Thr 900 905 910 Val Asp Ser Leu Thr Lys Lys Gin Glu Asn Tyr Gly Ala Leu Phe Asp 915 920 925 Leu Phe Glu Gin Lys Leu Arg Lys Leu Thr Gin His He Asp Arg Ser 930 935 940 Asn Leu Lys Pro Glu Glu Ala He Arg Phe Arg Gin Asp He Ala His 945 950 955 960 Leu Arg Asp He Ser Asn His Leu Ala Ser Asn Ser Ala His Ala Asn 965 970 975 Glu Gly Ala Gly Glu Leu Leu Arg Gin Pro Ser Leu Glu Ser Val Ala 980 985 990 Ser His Arg Ser Ser Met Ser Ser Ser Ser Lys Ser Ser Lys Gin Glu 995 1000 1005 Lys He Ser Leu Ser Ser Phe Gly Lys Asn Lys Lys Ser Trp He Arg 1010 1015 1020 Ser Ser Leu Ser Lys Phe Thr Lys Lys Lys Asn Lys Asn Tyr Asp Glu 1025 1030 1035 1040 Ala His Met Pro Ser He Ser Gly Ser Gin Gly Thr Leu Asp Asn He 1045 1050 1055 Asp Val He Glu Leu Lys Gin Glu Leu Lys Glu Arg Asp Ser Ala Leu 1060 1065 1070 Tyr Glu Val Arg Leu Asp Asn Leu Asp Arg Ala Arg Glu Val Asp Val 1075 1080 1085 Leu Arg Glu Thr Val Asn Lys Leu Lys Thr Glu Asn Lys Gin Leu Lys 1090 1095 1100 Lys Glu Val Asp Lys Leu Thr Asn Gly Pro Ala Thr Arg Ala Ser Ser 1105 1110 1115 1120 Arg Ala Ser He Pro Val He Tyr Asp Asp Glu His Val Tyr Asp Ala 1125 1130 1135 Ala Cys Ser Ser Thr Ser Ala Ser Gin Ser Ser Lys Arg Ser Ser Gly 1140 1145 1150 Cys Asn Ser He Lys Val Thr Val Asn Val Asp He Ala Gly Glu He 1155 1160 1165 Ser Ser He Val Asn Pro Asp Lys Glu He He Val Gly Tyr Leu Ala 1170 1175 1180 Met Ser Thr Ser Gin Ser Cys Trp Lys Asp He Asp Val Ser He Leu 1185 1190 1195 1200 Gly Leu Phe Glu Val Tyr Leu Ser Arg He Asp Val Glu His Gin Leu 1205 1210 1215 Gly He Asp Ala Arg Asp Ser He Leu Gly Tyr Gin He Gly Glu Leu 1220 1225 1230 Arg Arg Val He Gly Asp Ser Thr Thr Met He Thr Ser His Pro Thr 1235 1240 1245 Asp He Leu Thr Ser Ser Thr Thr He Arg Met Phe Met His Gly Ala 1250 1255 1260 Ala Gin Ser Arg Val Asp Ser Leu Val Leu Asp Met Leu Leu Pro Lys 1265 1270 1275 1280 Gin Met He Leu Gin Leu Val Lys Ser He Leu Thr Glu Arg Arg Leu 1285 1290 1295 Val Leu Ala Gly Ala Thr Gly He Gly Lys Ser Lys Leu Ala Lys Thr 1300 1305 1310 Leu Ala Ala Tyr Val Ser He Arg Thr Asn Gin Ser Glu Asp Ser He 1315 1320 1325 Val Asn He Ser He Pro Glu Asn Asn Lys Glu Glu Leu Leu Gin Val 1330 1335 1340 Glu Arg Arg Leu Glu Lys He Leu Arg Ser Lys Glu Ser Cys He Val 1345 1350 1355 1360 He Leu Asp Asn He Pro Lys Asn Arg He Ala Phe Val Val Ser Val 1365 1370 1375 Phe Ala Asn Val Pro Leu Gin Asn Asn Glu Gly Pro Phe Val Val Cys 1380 1385 1390 Thr Val Asn Arg Tyr Gin He Pro Glu Leu Gin He His His Asn Phe 1395 1400 1405 Lys Met Ser Val Met Ser Asn Arg Leu Glu Gly Phe He Leu Arg Tyr 1410 1415 1420 Leu Arg Arg Arg Ala Val Glu Asp Glu Tyr Arg Leu Thr Val Gin Met 1425 1430 1435 1440 Pro Ser Glu Leu Phe Lys He He Asp Phe Phe Pro He Ala Leu Gin 1445 1450 1455 Ala Val Asn Asn Phe He Glu Lys Thr Asn Ser Val Asp Val Thr Val 1460 1465 1470 Gly Pro Arg Ala Cys Leu Asn Cys Pro Leu Thr Val Asp Gly Ser Arg 1475 1480 1485 Glu Trp Phe He Arg Leu Trp Asn Glu Asn Phe He Pro Tyr Leu Glu 1490 1495 1500 Arg Val Ala Arg Asp Gly Lys Lys Thr Phe Gly Arg Cys Thr Ser Phe 1505 1510 1515 1520 Glu Asp Pro Thr Asp He Val Ser Lys Lys Trp Pro Trp Phe Asp Gly 1525 1530 1535 Glu Asn Pro Glu Asn Val Leu Lys Arg Leu Gin Leu Gin Asp Leu Val 1540 1545 1550 Pro Ser Pro Ala Asn Ser Ser Arg Gin His Phe Asn Pro Leu Glu Ser 1555 1560 1565 Leu He Gin Leu His Ala Thr Lys His Gin Thr He Asp Asn He 1570 1575 1580 (2) INFORMATION FOR SEQ ID NO: 5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 47 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: ATAAGAATGC GGCCGCCGCC ATGACGACGT CAAATGTAGA ATTGATA 47 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 41 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: GGAATTCCAA CCATATGACG ACGTCAAATG TAGAATTGAT A 41 (2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 7: CGCGGATCCT CAAACCGCGG GTGGCATAAT GGATG 35 (2) INFORMATION FOR SEQ ID NO: 8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Lys Lys Asp Pro Pro Pro Ala Val Pro Pro Arg Asp Thr 1 5 10 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: Thr Thr Asp Val Pro Pro Leu Pro Pro Leu Lys Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: Glu Val Pro Val Pro Pro Pro Val Pro Pro Arg Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO: 11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: His Leu Asp Ser Pro Pro Ala He Pro Pro Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO: 12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12: His Ser He Ala Gly Pro Pro Val Pro Pro Arg 1 5 10 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: Tyr Arg Ala Val Pro Pro Pro Leu Pro Pro Arg Arg Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: Gly Glu Leu Ser Pro Pro Pro He Pro Pro Arg Leu Asn 1 5 10 (2) INFORMATION FOR SEQ ID NO: 15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15: Ala Pro Ala Val Pro Pro Ala Arg Pro Gly Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Pro Ala Val Pro Pro Ala Arg Pro 1 5 (2) INFORMATION FOR SEQ ID NO: 17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: Pro Pro Arg Pro Leu Pro Val Ala Pro Gly Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO: 18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: Pro Ala Pro Ala Pro Pro Lys Pro Pro Lys 1 5 10 (2) INFORMATION FOR SEQ ID NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: Pro Pro Asp Asn Gly Pro Pro Pro Leu Pro Thr Ser Ser 1 5 10 (2) INFORMATION FOR SEQ ID NO: 20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20: Pro Pro Gin Met Pro Leu Pro Glu He Pro Gin Gin Trp 1 5 10 (2) INFORMATION FOR SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 21: Ala Pro Thr Met Pro Pro Pro Leu Pro Pro Val Pro Pro 1 5 10 (2) INFORMATION FOR SEQ ID NO: 22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 22: Phe Pro Ala Tyr Pro Pro Pro Pro Val Pro Val Pro 1 5 10 (2) INFORMATION FOR SEQ ID NO: 23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: Leu Leu Phe Leu Leu Ser Thr Tyr Lys Gin Lys Leu Arg Gin Leu Lys 1 5 10 15 Lys Asp Gin Lys Lys Leu Glu Gin Leu Pro Thr Ser 20 25 (2) INFORMATION FOR SEQ ID NO: 24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: Glu Thr Val Asn Val Asn Lys Leu Lys Thr Glu Asn Lys Gin Leu Lys 1 5 10 15 Lys Glu Val Asp Lys Leu Thr Asn Gly Pro Ala Thr 20 25 (2) INFORMATION FOR SEQ ID NO: 25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10443 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: circular (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "plasmid" (iii) HYPOTHETICAL: NO (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25: GGCCGCCGCC ATGACGACGT CAAATGTAGA ATTGATACCA ATCTACACGG ATTGGGCCAA 60 TCGGCACCTT TCGAAGGGCA GCTTATCAAA GTCGATTAGG GATATTTCCA ATGATTTTCG 120 CGACTATCGA CTGGTTTCTC AGCTTATTAA TGTGATCGTT CCGATCAACG AATTCTCGCC 180 TGCATTCACG AAACGTTTGG CAAAAATCAC ATCGAACCTG GATGGCCTCG AAACGTGTCT 240 CGACTACCTG AAAAATCTGG GTCTCGACTG CTCGAAACTC ACCAAAACCG ATATCGACAG 300 CGGAAACTTG GGTGCAGTTC TCCAGCTGCT CTTCCTGCTC TCCACCTACA AGCAGAAGCT 360 TCGGCAACTG AAAAAAGATC AGAAGAAATT GGAGCAACTA CCCACATCCA TTATGCCACC 420 CGCGGTTTCT AAATTACCCT CGCCACGTGT CGCCACGTCA GCAACCGCTT CAGCAACTAA 480 CCCAAATTCC AACTTTCCAC AAATGTCAAC ATCCAGGCTT CAGACTCCAC AGTCAAGAAT 540 ATCGAAAATT GATTCATCAA AGATTGGTAT CAAGCCAAAG ACGTCTGGAC TTAAACCACC 600 CTCATCATCA ACCACTTCAT CAAATAATAC AAATTCATTC CGTCCGTCGA GCCGTTCGAG 660 TGGCAATAAT AATGTTGGCT CGACGATATC CACATCTGCG AAGAGCTTAG AATCATCATC 720 AACGTACAGC TCTATTTCGA ATCTAAACCG ACCTACCTCC CAACTCCAAA AACCTTCTAG 780 ACCACAAACC CAGCTAGTTC GTGTTGCTAC AACTACAAAA ATCGGAAGCT CAAAGCTAGC 840 CGCTCCGAAA GCCGTGAGCA CCCCAAAACT TGCTTCTGTG AAGACTATTG GAGCAAAACA 900 AGAGCCCGAT AACAGCGGTG GTGGTGGTGG TGGAATGCTG AAATTAAAGT TATTCAGTAG 960 CAAAAACCCA TCTTCCTCAT CGAATAGCCC ACAACCTACG AGAAAGGCGG CGGCGGTGCC 1020 TCAACAACAA ACTTTGTCGA AAATCGCTGC CCCAGTGAAA AGTGGCCTGA AGCCGCCGAC 1080 CAGTAAGCTG GGAAGTGCCA CGTCTATGTC GAAGCTTTGT ACGCCAAAAG TTTCCTACCG 1140 TAAAACGGAC GCCCCAATCA TATCTCAACA AGACTCGAAA CGATGCTCAA AGAGCAGTGA 1200 AGAAGAGTCC GGATACGCTG GATTCAACAG CACGTCGCCA ACGTCATCAT CGACGGAAGG 1260 TTCCCTAAGC ATGCATTCCA CATCTTCCAA GAGTTCAACG TCAGACGAAA AGTCTCCGTC 1320 ATCAGACGAT CTTACTCTTA ACGCCTCCAT CGTGACAGCT ATCAGACAGC CGATAGCCGC 1380 AACACCGGTT TCTCCAAATA TTATCAACAA GCCTGTTGAG GAAAAACCAA CACTGGCAGT 1440 GAAAGGAGTG AAAAGCACAG CGAAAAAAGA TCCACCTCCA GCTGTTCCGC CACGTGACAC 1500 CCAGCCAACA ATCGGAGTTG TTAGTCCAAT TATGGCACAT AAGAAGTTGA CAAATGACCC 1560 CGTGATATCT GAAAAACCAG AACCTGAAAA GCTCCAATCA ATGAGCATCG ACACGACGGA 1620 CGTTCCACCG CTTCCACCTC TAAAATCAGT TGTTCCACTT AAAATGACTT CAATCCGACA 1680 ACCACCAACG TACGATGTTC TTCTAAAACA AGGAAAAATC ACATCGCCTG TCAAGTCGTT 1740 TGGATATGAG CAGTCGTCCG CGTCTGAAGA CTCCATTGTG GCTCATGCGT CGGCTCAGGT 1800 GACTCCGCCG ACAAAAACTT CTGGTAATCA TTCGCTGGAG AGAAGGATGG GAAAGAATAA 1860 GACATCAGAA TCCAGCGGCT ACACCTCTGA CGCCGGTGTT GCGATGTGCG CCAAAATGAG 1920 GGAGAAGCTG AAAGAATACG ATGACATGAC TCGTCGAGCA CAGAACGGCT ATCCTGACAA 1980 CTTCGAAGAC AGTTCCTCCT TGTCGTCTGG AATATCCGAT AACAACGAGC TCGACGACAT 2040 ATCCACGGAC GATTTGTCCG GAGTAGACAT GGCAACAGTC GCCTCCAAAC ATAGCGACTA 2100 TTCCCACTTT GTTCGCCATC CCACGTCTTC TTCCTCAAAG CCCCGAGTCC CCAGTCGGTC 2160 CTCCACATCA GTCGATTCTC GATCTCGAGC AGAACAGGAG AATGTGTACA AACTTCTGTC 2220 CCAGTGCCGA ACGAGCCAAC GTGGCGCCGC TGCCACCTCA ACCTTCGGAC AACATTCGCT 2280 AAGATCCCCG GGATACTCAT CCTATTCTCC ACACTTATCA GTGTCAGCTG ATAAGGACAC 2340 AATGTCTATG CACTCACAGA CTAGTCGACG ACCTTCTTCA CAAAAACCAA GCTATTCAGG 2400 CCAATTTCAT TCACTTGATC GTAAATGCCA CCTTCAAGAG TTCACATCCA CCGAGCACAG 2460 AATGGCGGCT CTCTTGAGCC CGAGACGGGT GCCGAACTCG ATGTCGAAAT ATGATTCTTC 2520 AGGATCCTAC TCGGCGCGTT CCCGAGGTGG AAGCTCTACT GGTATCTATG GAGAGACGTT 2580 CCAACTGCAC AGACTATCCG ATGAAAAATC CCCCGCACAT TCTGCCAAAA GTGAGATGGG 2640 ATCCCAACTA TCACTGGCTA GCACGACAGC ATATGGATCT CTCAATGAGA AGTACGAACA 2700 TGCTATTCGG GACATGGCAC GTGACTTGGA GTGTTACAAG AACACTGTCG ACTCACTAAC 2760 CAAGAAACAG GAGAACTATG GAGCATTGTT TGATCTTTTT GAGCAAAAGC TTAGAAAACT 2820 CACTCAACAC ATTGATCGAT CCAACTTGAA GCCTGAAGAG GCAATACGAT TCAGGCAGGA 2880 CATTGCTCAT TTGAGGGATA TTAGCAATCA TCTTGCATCC AACTCAGCTC ATGCTAACGA 2940 AGGCGCTGGT GAGCTTCTTC GTCAACCATC TCTGGAATCA GTTGCATCCC ATCGATCATC 3000 GATGTCATCG TCGTCGAAAA GCAGCAAGCA GGAGAAGATC AGCTTGAGCT CGTTTGGCAA 3060 GAACAAGAAG AGCTGGATCC GCTCCTCACT CTCCAAGTTC ACCAAGAAGA AGAACAAGAA 3120 CTACGACGAA GCACATATGC CATCAATTTC CGGATCTCAA GGAACTCTTG ACAACATTGA 3180 TGTGATTGAG TTGAAGCAAG AGCTCAAAGA ACGCGATAGT GCACTTTACG AAGTCCGCCT 3240 TGACAATCTG GATCGTGCCC GCGAAGTTGA TGTTCTGAGG GAGACAGTGA ACAAGTTGAA 3300 AACCGAGAAC AAGCAATTAA AGAAAGAAGT GGACAAACTC ACCAACGGTC CAGCCACTCG 3360 TGCTTCTTCC CGCGCCTCAA TTCCAGTTAT CTACGACGAT GAGCATGTCT ATGATGCAGC 3420 GTGTAGCAGT ACATCAGCTA GTCAATCTTC GAAACGATCC TCTGGCTGCA ACTCAATCAA 3480 GGTTACTGTA AACGTGGACA TCGCTGGAGA AATCAGTTCG ATCGTTAACC CGGACAAAGA 3540 GATAATCGTA GGATATCTTG CCATGTCAAC CAGTCAGTCA TGCTGGAAAG ACATTGATGT 3600 TTCTATTCTA GGACTATTTG AAGTCTACCT ATCCAGAATT GATGTGGAGC ATCAACTTGG 3660 AATCGATGCT CGTGATTCTA TCCTTGGCTA TCAAATTGGT GAACTTCGAC GCGTCATTGG 3720 AGACTCCACA ACCATGATAA CCAGCCATCC AACTGACATT CTTACTTCCT CAACTACAAT 3780 CCGAATGTTC ATGCACGGTG CCGCACAGAG TCGCGTAGAC AGTCTGGTCC TTGATATGCT 3840 TCTTCCAAAG CAAATGATTC TCCAACTCGT CAAGTCAATT TTGACAGAGA GACGTCTGGT 3900 GTTAGCTGGA GCAACTGGAA TTGGAAAGAG CAAACTGGCG AAGACCCTGG CTGCTTATGT 3960 ATCTATTCGA ACAAATCAAT CCGAAGATAG TATTGTTAAT ATCAGCATTC CTGAAAACAA 4020 TAAAGAAGAA TTGCTTCAAG TGGAACGACG CCTGGAAAAG ATCTTGAGAA GCAAAGAATC 4080 ATGCATCGTA ATTCTAGATA ATATCCCAAA GAATCGAATT GCATTTGTTG TATCCGTTTT 4140 TGCAAATGTC CCACTTCAAA ACAACGAAGG TCCATTTGTA GTATGCACAG TCAACCGATA 4200 TCAAATCCCT GAGCTTCAAA TTCACCACAA TTTCAAAATG TCAGTAATGT CGAATCGTCT 4260 CGAAGGATTC ATCCTACGTT ACCTCCGACG ACGGGCGGTA GAGGATGAGT ATCGTCTAAC 4320 TGTACAGATG CCATCAGAGC TCTTCAAAAT CATTGACTTC TTCCCAATAG CTCTTCAGGC 4380 CGTCAATAAT TTTATTGAGA AAACGAATTC TGTTGATGTG ACAGTTGGTC CAAGAGCATG 4440 CTTGAACTGT CCTCTAACTG TCGATGGATC CCGTGAATGG TTCATTCGAT TGTGGAATGA 4500 GAACTTCATT CCATATTTGG AACGTGTTGC TAGAGATGGC AAAAAAACCT TCGGTCGCTG 4560 CACTTCCTTC GAGGATCCCA CCGACATCGT CTCTAAAAAA TGGCCGTGGT TCGATGGTGA 4620 AAACCCGGAG AATGTGCTCA AACGTCTTCA ACTCCAAGAC CTCGTCCCGT CACCTGCCAA 4680 CTCATCCCGA CAACACTTCA ATCCCCTCGA GTCGTTGATC CAATTGCATG CTACCAAGCA 4740 TCAGACCATC GACAACATTT GAACAGAAGA CTCTAATCTT CTCTCGCCTC TCCCCCGCTT 4800 TCCTTATCTT CGTACCGGTA CCTGATGATT CCCCATTTTC CCCCTTTTCC CCCCAATTTC 4860 CCAGAACCTC CTGTTCCCTT TGTTCCTAGT CCTCCCGGGT GCCGACGCCG AAGCGATTTA 4920 AAAACCTTTT TCTTTCCGAA ACATTTCCCA TTGCTCATTA ATAGTCAAAT TGAATAAACA 4980 GTGTATGTAC TTAAAAAAAA AAAAAAAAAA ACTCGAGGGG GGGCCCTATT CTATAGTGTC 5040 ACCTAAATGC TAGAGCTCGC TGATCAGCCT CGACTGTGCC TTCTAGTTGC CAGCCATCTG 5100 TTGTTTGCCC CTCCCCCGTG CCTTCCTTGA CCCTGGAAGG TGCCACTCCC ACTGTCCTTT 5160 CCTAATAAAA TGAGGAAATT GCATCGCATT GTCTGAGTAG GTGTCATTCT ATTCTGGGGG 5220 GTGGGGTGGG GCAGGACAGC AAGGGGGAGG ATTGGGAAGA CAATAGCAGG CATGCTGGGG 5280 ATGCGGTGGG CTCTATGGCT TCTGAGGCGG AAAGAACCAG CTGGGGCTCT AGGGGGTATC 5340 CCCACGCGCC CTGTAGCGGC GCATTAAGCG CGGCGGGTGT GGTGGTTACG CGCAGCGTGA 5400 CCGCTACACT TGCCAGCGCC CTAGCGCCCG CTCCTTTCGC TTTCTTCCCT TCCTTTCTCG 5460 CCACGTTCGC CGGCTTTCCC CGTCAAGCTC TAAATCGGGG CATCCCTTTA GGGTTCCGAT 5520 TTAGTGCTTT ACGGCACCTC GACCCCAAAA AACTTGATTA GGGTGATGGT TCACGTAGTG 5580 GGCCATCGCC CTGATAGACG GTTTTTCGCC CTTTGACGTT GGAGTCCACG TTCTTTAATA 5640 GTGGACTCTT GTTCCAAACT GGAACAACAC TCAACCCTAT CTCGGTCTAT TCTTTTGATT 5700 TATAAGGGAT TTTGGGGATT TCGGCCTATT GGTTAAAAAA TGAGCTGATT TAACAAAAAT 5760 TTAACGCGAA TTAATTCTGT GGAATGTGTG TCAGTTAGGG TGTGGAAAGT CCCCAGGCTC 5820 CCCAGGCAGG CAGAAGTATG CAAAGCATGC ATCTCAATTA GTCAGCAACC AGGTGTGGAA 5880 AGTCCCCAGG CTCCCCAGCA GGCAGAAGTA TGCAAAGCAT GCATCTCAAT TAGTCAGCAA 5940 CCATAGTCCC GCCCCTAACT CCGCCCATCC CGCCCCTAAC TCCGCCCAGT TCCGCCCATT 6000 CTCCGCCCCA TGGCTGACTA ATTTTTTTTA TTTATGCAGA GGCCGAGGCC GCCTCTGCCT 6060 CTGAGCTATT CCAGAAGTAG TGAGGAGGCT TTTTTGGAGG CCTAGGCTTT TGCAAAAAGC 6120 TCCCGGGAGC TTGTATATCC ATTTTCGGAT CTGATCAAGA GACAGGATGA GGATCGTTTC 6180 GCATGATTGA ACAAGATGGA TTGCACGCAG GTTCTCCGGC CGCTTGGGTG GAGAGGCTAT 6240 TCGGCTATGA CTGGGCACAA CAGACAATCG GCTGCTCTGA TGCCGCCGTG TTCCGGCTGT 6300 CAGCGCAGGG GCGCCCGGTT CTTTTTGTCA AGACCGACCT GTCCGGTGCC CTGAATGAAC 6360 TGCAGGACGA GGCAGCGCGG CTATCGTGGC TGGCCACGAC GGGCGTTCCT TGCGCAGCTG 6420 TGCTCGACGT TGTCACTGAA GCGGGAAGGG ACTGGCTGCT ATTGGGCGAA GTGCCGGGGC 6480 AGGATCTCCT GTCATCTCAC CTTGCTCCTG CCGAGAAAGT ATCCATCATG GCTGATGCAA 6540 TGCGGCGGCT GCATACGCTT GATCCGGCTA CCTGCCCATT CGACCACCAA GCGAAACATC 6600 GCATCGAGCG AGCACGTACT CGGATGGAAG CCGGTCTTGT CGATCAGGAT GATCTGGACG 6660 AAGAGCATCA GGGGCTCGCG CCAGCCGAAC TGTTCGCCAG GCTCAAGGCG CGCATGCCCG 6720 ACGGCGAGGA TCTCGTCGTG ACCCATGGCG ATGCCTGCTT GCCGAATATC ATGGTGGAAA 6780 ATGGCCGCTT TTCTGGATTC ATCGACTGTG GCCGGCTGGG TGTGGCGGAC CGCTATCAGG 6840 ACATAGCGTT GGCTACCCGT GATATTGCTG AAGAGCTTGG CGGCGAATGG GCTGACCGCT 6900 TCCTCGTGCT TTACGGTATC GCCGCTCCCG ATTCGCAGCG CATCGCCTTC TATCGCCTTC 6960 TTGACGAGTT CTTCTGAGCG GGACTCTGGG GTTCGAAATG ACCGACCAAG CGACGCCCAA 7020 CCTGCCATCA CGAGATTTCG ATTCCACCGC CGCCTTCTAT GAAAGGTTGG GCTTCGGAAT 7080 CGTTTTCCGG GACGCCGGCT GGATGATCCT CCAGCGCGGG GATCTCATGC TGGAGTTCTT 7140 CGCCCACCCC AACTTGTTTA TTGCAGCTTA TAATGGTTAC AAATAAAGCA ATAGCATCAC 7200 AAATTTCACA AATAAAGCAT TTTTTTCACT GCATTCTAGT TGTGGTTTGT CCAAACTCAT 7260 CAATGTATCT TATCATGTCT GTATACCGTC GACCTCTAGC TAGAGCTTGG CGTAATCATG 7320 GTCATAGCTG TTTCCTGTGT GAAATTGTTA TCCGCTCACA ATTCCACACA ACATACGAGC 7380 CGGAAGCATA AAGTGTAAAG CCTGGGGTGC CTAATGAGTG AGCTAACTCA CATTAATTGC 7440 GTTGCGCTCA CTGCCCGCTT TCCAGTCGGG AAACCTGTCG TGCCAGCTGC ATTAATGAAT 7500 CGGCCAACGC GCGGGGAGAG GCGGTTTGCG TATTGGGCGC TCTTCCGCTT CCTCGCTCAC 7560 TGACTCGCTG CGCTCGGTCG TTCGGCTGCG GCGAGCGGTA TCAGCTCACT CAAAGGCGGT 7620 AATACGGTTA TCCACAGAAT CAGGGGATAA CGCAGGAAAG AACATGTGAG CAAAAGGCCA 7680 GCAAAAGGCC AGGAACCGTA AAAAGGCCGC GTTGCTGGCG TTTTTCCATA GGCTCCGCCC 7740 CCCTGACGAG CATCACAAAA ATCGACGCTC AAGTCAGAGG TGGCGAAACC CGACAGGACT 7800 ATAAAGATAC CAGGCGTTTC CCCCTGGAAG CTCCCTCGTG CGCTCTCCTG TTCCGACCCT 7860 GCCGCTTACC GGATACCTGT CCGCCTTTCT CCCTTCGGGA AGCGTGGCGC TTTCTCAATG 7920 CTCACGCTGT AGGTATCTCA GTTCGGTGTA GGTCGTTCGC TCCAAGCTGG GCTGTGTGCA 7980 CGAACCCCCC GTTCAGCCCG ACCGCTGCGC CTTATCCGGT AACTATCGTC TTGAGTCCAA 8040 CCCGGTAAGA CACGACTTAT CGCCACTGGC AGCAGCCACT GGTAACAGGA TTAGCAGAGC 8100 GAGGTATGTA GGCGGTGCTA CAGAGTTCTT GAAGTGGTGG CCTAACTACG GCTACACTAG 8160 AAGGACAGTA TTTGGTATCT GCGCTCTGCT GAAGCCAGTT ACCTTCGGAA AAAGAGTTGG 8220 TAGCTCTTGA TCCGGCAAAC AAACCACCGC TGGTAGCGGT GGTTTTTTTG TTTGCAAGCA 8280 GCAGATTACG CGCAGAAAAA AAGGATCTCA AGAAGATCCT TTGATCTTTT CTACGGGGTC 8340 TGACGCTCAG TGGAACGAAA ACTCACGTTA AGGGATTTTG GTCATGAGAT TATCAAAAAG 8400 GATCTTCACC TAGATCCTTT TAAATTAAAA ATGAAGTTTT AAATCAATCT AAAGTATATA 8460 TGAGTAAACT TGGTCTGACA GTTACCAATG CTTAATCAGT GAGGCACCTA TCTCAGCGAT 8520 CTGTCTATTT CGTTCATCCA TAGTTGCCTG ACTCCCCGTC GTGTAGATAA CTACGATACG 8580 GGAGGGCTTA CCATCTGGCC CCAGTGCTGC AATGATACCG CGAGACCCAC GCTCACCGGC 8640 TCCAGATTTA TCAGCAATAA ACCAGCCAGC CGGAAGGGCC GAGCGCAGAA GTGGTCCTGC 8700 AACTTTATCC GCCTCCATCC AGTCTATTAA TTGTTGCCGG GAAGCTAGAG TAAGTAGTTC 8760 GCCAGTTAAT AGTTTGCGCA ACGTTGTTGC CATTGCTACA GGCATCGTGG TGTCACGCTC 8820 GTCGTTTGGT ATGGCTTCAT TCAGCTCCGG TTCCCAACGA TCAAGGCGAG TTACATGATC 8880 CCCCATGTTG TGCAAAAAAG CGGTTAGCTC CTTCGGTCCT CCGATCGTTG TCAGAAGTAA 8940 GTTGGCCGCA GTGTTATCAC TCATGGTTAT GGCAGCACTG CATAATTCTC TTACTGTCAT 9000 GCCATCCGTA AGATGCTTTT CTGTGACTGG TGAGTACTCA ACCAAGTCAT TCTGAGAATA 9060 GTGTATGCGG CGACCGAGTT GCTCTTGCCC GGCGTCAATA CGGGATAATA CCGCGCCACA 9120 TAGCAGAACT TTAAAAGTGC TCATCATTGG AAAACGTTCT TCGGGGCGAA AACTCTCAAG 9180 GATCTTACCG CTGTTGAGAT CCAGTTCGAT GTAACCCACT CGTGCACCCA ACTGATCTTC 9240 AGCATCTTTT ACTTTCACCA GCGTTTCTGG GTGAGCAAAA ACAGGAAGGC AAAATGCCGC 9300 AAAAAAGGGA ATAAGGGCGA CACGGAAATG TTGAATACTC ATACTCTTCC TTTTTCAATA 9360 TTATTGAAGC ATTTATCAGG GTTATTGTCT CATGAGCGGA TACATATTTG AATGTATTTA 9420 GAAAAATAAA CAAATAGGGG TTCCGCGCAC ATTTCCCCGA AAAGTGCCAC CTGACGTCGA 9480 CGGATCGGGA GATCTCCCGA TCCCCTATGG TCGACTCTCA GTACAATCTG CTCTGATGCC 9540 GCATAGTTAA GCCAGTATCT GCTCCCTGCT TGTGTGTTGG AGGTCGCTGA GTAGTGCGCG 9600 AGCAAAATTT AAGCTACAAC AAGGCAAGGC TTGACCGACA ATTGCATGAA GAATCTGCTT 9660 AGGGTTAGGC GTTTTGCGCT GCTTCGCGAT GTACGGGCCA GATATACGCG TTGACATTGA 9720 TTATTGACTA GTTATTAATA GTAATCAATT ACGGGGTCAT TAGTTCATAG CCCATATATG 9780 GAGTTCCGCG TTACATAACT TACGGTAAAT GGCCCGCCTG GCTGACCGCC CAACGACCCC 9840 CGCCCATTGA CGTCAATAAT GACGTATGTT CCCATAGTAA CGCCAATAGG GACTTTCCAT 9900 TGACGTCAAT GGGTGGACTA TTTACGGTAA ACTGCCCACT TGGCAGTACA TCAAGTGTAT 9960 CATATGCCAA GTACGCCCCC TATTGACGTC AATGACGGTA AATGGCCCGC CTGGCATTAT 10020 GCCCAGTACA TGACCTTATG GGACTTTCCT ACTTGGCAGT ACATCTACGT ATTAGTCATC 10080 GCTATTACCA TGGTGATGCG GTTTTGGCAG TACATCAATG GGCGTGGATA GCGGTTTGAC 10140 TCACGGGGAT TTCCAAGTCT CCACCCCATT GACGTCAATG GGAGTTTGTT TTGGCACCAA 10200 AATCAACGGG ACTTTCCAAA ATGTCGTAAC AACTCCGCCC CATTGACGCA AATGGGCGGT 10260 AGGCGTGTAC GGTGGGAGGT CTATATAAGC AGAGCTCTCT GGCTAACTAG AGAACCCACT 10320 GCTTACTGGC TTATCGAAAT TAATACGACT CACTATAGGG AGACCCAAGC TTGGTACCGA 10380 GCTCGGATCC ACTAGTAACG GCCGCCAGTG TGCTGGAATT CTGCAGATAT CCATCACACT 10440 GGC 10443 (2) INFORMATION FOR SEQ ID NO: 26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7474 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: circular (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "plasmid" (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26: CTAAATTGTA AGCGTTAATA TTTTGTTAAA ATTCGCGTTA AATTTTTGTT AAATCAGCTC 60 ATTTTTTAAC CAATAGGCCG AAATCGGCAA AATCCCTTAT AAATCAAAAG AATAGACCGA 120 GATAGGGTTG AGTGTTGTTC CAGTTTGGAA CAAGAGTCCA CTATTAAAGA ACGTGGACTC 180 CAACGTCAAA GGGCGAAAAA CCGTCTATCA GGGCGATGGC CCACTACGTG AACCATCACC 240 CTAATCAAGT TTTTTGGGGT CGAGGTGCCG TAAAGCACTA AATCGGAACC CTAAAGGGAG 300 CCCCCGATTT AGAGCTTGAC GGGGAAAGCC GGCGAACGTG GCGAGAAAGG AAGGGAAGAA 360 AGCGAAAGGA GCGGGCGCTA GGGCGCTGGC AAGTGTAGCG GTCACGCTGC GCGTAACCAC 420 CACACCCGCC GCGCTTAATG CGCCGCTACA GGGCGCGTCC CATTCGCCAT TCAGGCTGCG 480 CAACTGTTGG GAAGGGCGAT CGGTGCGGGC CTCTTCGCTA TTACGCCAGC TGGCGAAAGG 540 GGGATGTGCT GCAAGGCGAT TAAGTTGGGT AACGCCAGGG TTTTCCCAGT CACGACGTTG 600 TAAAACGACG GCCAGTGAGC GCGCGTAATA CGACTCACTA TAGGGCGAAT TGGAGCTCCA 660 CCGCGGTTTC TAAATTACCC TCGCCACGTG TCGCCACGTC AGCAACCGCT TCAGCAACTA 720 ACCCAAATTC CAACTTTCCA CAAATGTCAA CATCCAGGCT TCAGACTCCA CAGTCAAGAA 780 TATCGAAAAT TGATTCATCA AAGATTGGTA TCAAGCCAAA GACGTCTGGA CTTAAACCAC 840 CCTCATCATC AACCACTTCA TCAAATAATA CAAATTCATT CCGTCCGTCG AGCCGTTCGA 900 GTGGCAATAA TAATGTTGGC TCGACGATAT CCACATCTGC GAAGAGCTTA GAATCATCAT 960 CAACGTACAG CTCTATTTCG AATCTAAACC GACCTACCTC CCAACTCCAA AAACCTTCTA 1020 GACCACAAAC CCAGCTAGTT CGTGTTGCTA CAACTACAAA AATCGGAAGC TCAAAGCTAG 1080 CCGCTCCGAA AGCCGTGAGC ACCCCAAAAC TTGCTTCTGT GAAGACTATT GGAGCAAAAC 1140 AAGAGCCCGA TAACAGCGGT GGTGGTGGTG GTGGAATGCT GAAATTAAAG TTATTCAGTA 1200 GCAAAAACCC ATCTTCCTCA TCGAATAGCC CACAACCTAC GAGAAAGGCG GCGGCGGTGC 1260 CTCAACAACA AACTTTGTCG AAAATCGCTG CCCCAGTGAA AAGTGGCCTG AAGCCGCCGA 1320 CCAGTAAGCT GGGAAGTGCC ACGTCTATGT CGAAGCTTTG TACGCCAAAA GTTTCCTACC 1380 GTAAAACGGA CGCCCCAATC ATATCTCAAC AAGACTCGAA ACGATGCTCA AAGAGCAGTG 1440 AAGAAGAGTC CGGATACGCT GGATTCAACA GCACGTCGCC AACGTCATCA TCGACGGAAG 1500 GTTCCCTAAG CATGCATTCC ACATCTTCCA AGAGTTCAAC GTCAGACGAA AAGTCTCCGT 1560 CATCAGACGA TCTTACTCTT AACGCCTCCA TCGTGACAGC TATCAGACAG CCGATAGCCG 1620 CAACACCGGT TTCTCCAAAT ATTATCAACA AGCCTGTTGA GGAAAAACCA ACACTGGCAG 1680 TGAAAGGAGT GAAAAGCACA GCGAAAAAAG ATCCACCTCC AGCTGTTCCG CCACGTGACA 1740 CCCAGCCAAC AATCGGAGTT GTTAGTCCAA TTATGGCACA TAAGAAGTTG ACAAATGACC 1800 CCGTGATATC TGAAAAACCA GAACCTGAAA AGCTCCAATC AATGAGCATC GACACGACGG 1860 ACGTTCCACC GCTTCCACCT CTAAAATCAG TTGTTCCACT TAAAATGACT TCAATCCGAC 1920 AACCACCAAC GTACGATGTT CTTCTAAAAC AAGGAAAAAT CACATCGCCT GTCAAGTCGT 1980 TTGGATATGA GCAGTCGTCC GCGTCTGAAG ACTCCATTGT GGCTCATGCG TCGGCTCAGG 2040 TGACTCCGCC GACAAAAACT TCTGGTAATC ATTCGCTGGA GAGAAGGATG GGAAAGAATA 2100 AGACATCAGA ATCCAGCGGC TACACCTCTG ACGCCGGTGT TGCGATGTGC GCCAAAATGA 2160 GGGAGAAGCT GAAAGAATAC GATGACATGA CTCGTCGAGC ACAGAACGGC TATCCTGACA 2220 ACTTCGAAGA CAGTTCCTCC TTGTCGTCTG GAATATCCGA TAACAACGAG CTCGACGACA 2280 TATCCACGGA CGATTTGTCC GGAGTAGACA TGGCAACAGT CGCCTCCAAA CATAGCGACT 2340 ATTCCCACTT TGTTCGCCAT CCCACGTCTT CTTCCTCAAA GCCCCGAGTC CCCAGTCGGT 2400 CCTCCACATC AGTCGATTCT CGATCTCGAG CAGAACAGGA GAATGTGTAC AAACTTCTGT 2460 CCCAGTGCCG AACGAGCCAA CGTGGCGCCG CTGCCACCTC AACCTTCGGA CAACATTCGC 2520 TAAGATCCCC GGGATACTCA TCCTATTCTC CACACTTATC AGTGTCAGCT GATAAGGACA 2580 CAATGTCTAT GCACTCACAG ACTAGTCGAC GACCTTCTTC ACAAAAACCA AGCTATTCAG 2640 GCCAATTTCA TTCACTTGAT CGTAAATGCC ACCTTCAAGA GTTCACATCC ACCGAGCACA 2700 GAATGGCGGC TCTCTTGAGC CCGAGACGGG TGCCGAACTC GATGTCGAAA TATGATTCTT 2760 CAGGATCCTA CTCGGCGCGT TCCCGAGGTG GAAGCTCTAC TGGTATCTAT GGAGAGACGT 2820 TCCAACTGCA CAGACTATCC GATGAAAAAT CCCCCGCACA TTCTGCCAAA AGTGAGATGG 2880 GATCCCAACT ATCACTGGCT AGCACGACAG CATATGGATC TCTCAATGAG AAGTACGAAC 2940 ATGCTATTCG GGACATGGCA CGTGACTTGG AGTGTTACAA GAACACTGTC GACTCACTAA 3000 CCAAGAAACA GGAGAACTAT GGAGCATTGT TTGATCTTTT TGAGCAAAAG CTTAGAAAAC 3060 TCACTCAACA CATTGATCGA TCCAACTTGA AGCCTGAAGA GGCAATACGA TTCAGGCAGG 3120 ACATTGCTCA TTTGAGGGAT ATTAGCAATC ATCTTGCATC CAACTCAGCT CATGCTAACG 3180 AAGGCGCTGG TGAGCTTCTT CGTCAACCAT CTCTGGAATC AGTTGCATCC CATCGATCAT 3240 CGATGTCATC GTCGTCGAAA AGCAGCAAGC AGGAGAAGAT CAGCTTGAGC TCGTTTGGCA 3300 AGAACAAGAA GAGCTGGATC CGCTCCTCAC TCTCCAAGTT CACCAAGAAG AAGAACAAGA 3360 ACTACGACGA AGCACATATG CCATCAATTT CCGGATCTCA AGGAACTCTT GACAACATTG 3420 ATGTGATTGA GTTGAAGCAA GAGCTCAAAG AACGCGATAG TGCACTTTAC GAAGTCCGCC 3480 TTGACAATCT GGATCGTGCC CGCGAAGTTG ATGTTCTGAG GGAGACAGTG AACAAGTTGA 3540 AAACCGAGAA CAAGCAATTA AAGAAAGAAG TGGACAAACT CACCAACGGT CCAGCCACTC 3600 GTGCTTCTTC CCGCGCCTCA ATTCCAGTTA TCTACGACGA TGAGCATGTC TATGATGCAG 3660 CGTGTAGCAG TACATCAGCT AGTCAATCTT CGAAACGATC CTCTGGCTGC AACTCAATCA 3720 AGGTTACTGT AAACGTGGAC ATCGCTGGAG AAATCAGTTC GATCGTTAAC CCGGACAAAG 3780 AGATAATCGT AGGATATCTT GCCATGTCAA CCAGTCAGTC ATGCTGGAAA GACATTGATG 3840 TTTCTATTCT AGGACTATTT GAAGTCTACC TATCCAGAAT TGATGTGGAG CATCAACTTG 3900 GAATCGATGC TCGTGATTCT ATCCTTGGCT ATCAAATTGG TGAACTTCGA CGCGTCATTG 3960 GAGACTCCAC AACCATGATA ACCAGCCATC CAACTGACAT TCTTACTTCC TCAACTACAA 4020 TCCGAATGTT CATGCACGGT GCCGCACAGA GTCGCGTAGA CAGTCTGGTC CTTGATATGC 4080 TTCTTCCAAA GCAAATGATT CTCCAACTCG TCAAGTCAAT TTTGACAGAG AGACGTCTGG 4140 TGTTAGCTGG AGCAACTGGA ATTGGAAAGA GCAAACTGGC GAAGACCCTG GCTGCTTATG 4200 TATCTATTCG AACAAATCAA TCCGAAGATA GTATTGTTAA TATCAGCATT CCTGAAAACA 4260 ATAAAGAAGA ATTGCTTCAA GTGGAACGAC GCCTGGAAAA GATCTTGAGA AGCAAAGAAT 4320 CATGCATCGT AATTCTAGAT AATATCCCAA AGAATCGAAT TGCATTTGTT GTATCCGTTT 4380 TTGCAAATGT CCCACTTCAA AACAACGAAG GTCCATTTGT AGTATGCACA GTCAACCGAT 4440 ATCAAATCCC TGAGCTTCAA ATTCACCACA ATTTCAAAAT GTCAGTAATG TCGAATCGTC 4500 TCGAAGGATT CATCCTACGT TACCTCCGAC GACGGGCGGT AGAGGATGAG TATCGTCTAA 4560 CTGTACAGAT GCCATCAGAG CTCTTCAAAA TCATTGACTT CTTCCCAATA GCTCTTCAGG 4620 CCGTCAATAA TTTTATTGAG AAAACGAATT CTGTTGATGT GACAGTTGGT CCAAGAGCAT 4680 GCTTGAACTG TCCTCTAACT GTCGATGGAT CCCGTGAATG GTTCATTCGA TTGTGGAATG 4740 AGAACTTCAT TCCATATTTG GAACGTGTTG CTAGAGATGG CAAAAAAACC TTCGGTCGCT 4800 GCACTTCCTT CGAGGATCCC ACCGACATCG TCTCTAAAAA ATGGCCGTGG TTCGATGGTG 4860 AAAACCCGGA GAATGTGCTC AAACGTCTTC AACTCCAAGA CCTCGTCCCG TCACCTGCCA 4920 ACTCATCCCG ACAACACTTC AATCCCCTCG AGTCGTTGAT CCAATTGCAT GCTACCAAGC 4980 ATCAGACCAT CGACAACATT TGAACAGAAG ACTCTAATCT TCTCTCGCCT CTCCCCCGCT 5040 TTCCTTATCT TCGTACCGGT ACCTGATGAT TCCCCATTTT CCCCCTTTTC CCCCCAATTT 5100 CCCAGAACCT CCTGTTCCCT TTGTTCCTAG TCCTCCCGGG TGCCGACGCC GAAGCGATTT 5160 AAAAACCTTT TTCTTTCCGA AACATTTCCC ATTGCTCATT AATAGTCAAA TTGAATAAAC 5220 AGTGTATGTA CTTAAAAAAA AAAAAAAAAA AACTCGAGGG GGGGCCCGGT ACCCAGCTTT 5280 TGTTCCCTTT AGTGAGGGTT AATTGCGCGC TTGGCGTAAT CATGGTCATA GCTGTTTCCT 5340 GTGTGAAATT GTTATCCGCT CACAATTCCA CACAACATAC GAGCCGGAAG CATAAAGTGT 5400 AAAGCCTGGG GTGCCTAATG AGTGAGCTAA CTCACATTAA TTGCGTTGCG CTCACTGCCC 5460 GCTTTCCAGT CGGGAAACCT GTCGTGCCAG CTGCATTAAT GAATCGGCCA ACGCGCGGGG 5520 AGAGGCGGTT TGCGTATTGG GCGCTCTTCC GCTTCCTCGC TCACTGACTC GCTGCGCTCG 5580 GTCGTTCGGC TGCGGCGAGC GGTATCAGCT CACTCAAAGG CGGTAATACG GTTATCCACA 5640 GAATCAGGGG ATAACGCAGG AAAGAACATG TGAGCAAAAG GCCAGCAAAA GGCCAGGAAC 5700 CGTAAAAAGG CCGCGTTGCT GGCGTTTTTC CATAGGCTCC GCCCCCCTGA CGAGCATCAC 5760 AAAAATCGAC GCTCAAGTCA GAGGTGGCGA AACCCGACAG GACTATAAAG ATACCAGGCG 5820 TTTCCCCCTG GAAGCTCCCT CGTGCGCTCT CCTGTTCCGA CCCTGCCGCT TACCGGATAC 5880 CTGTCCGCCT TTCTCCCTTC GGGAAGCGTG GCGCTTTCTC ATAGCTCACG CTGTAGGTAT 5940 CTCAGTTCGG TGTAGGTCGT TCGCTCCAAG CTGGGCTGTG TGCACGAACC CCCCGTTCAG 6000 CCCGACCGCT GCGCCTTATC CGGTAACTAT CGTCTTGAGT CCAACCCGGT AAGACACGAC 6060 TTATCGCCAC TGGCAGCAGC CACTGGTAAC AGGATTAGCA GAGCGAGGTA TGTAGGCGGT 6120 GCTACAGAGT TCTTGAAGTG GTGGCCTAAC TACGGCTACA CTAGAAGGAC AGTATTTGGT 6180 ATCTGCGCTC TGCTGAAGCC AGTTACCTTC GGAAAAAGAG TTGGTAGCTC TTGATCCGGC 6240 AAACAAACCA CCGCTGGTAG CGGTGGTTTT TTTGTTTGCA AGCAGCAGAT TACGCGCAGA 6300 AAAAAAGGAT CTCAAGAAGA TCCTTTGATC TTTTCTACGG GGTCTGACGC TCAGTGGAAC 6360 GAAAACTCAC GTTAAGGGAT TTTGGTCATG AGATTATCAA AAAGGATCTT CACCTAGATC 6420 CTTTTAAATT AAAAATGAAG TTTTAAATCA ATCTAAAGTA TATATGAGTA AACTTGGTCT 6480 GACAGTTACC AATGCTTAAT CAGTGAGGCA CCTATCTCAG CGATCTGTCT ATTTCGTTCA 6540 TCCATAGTTG CCTGACTCCC CGTCGTGTAG ATAACTACGA TACGGGAGGG CTTACCATCT 6600 GGCCCCAGTG CTGCAATGAT ACCGCGAGAC CCACGCTCAC CGGCTCCAGA TTTATCAGCA 6660 ATAAACCAGC CAGCCGGAAG GGCCGAGCGC AGAAGTGGTC CTGCAACTTT ATCCGCCTCC 6720 ATCCAGTCTA TTAATTGTTG CCGGGAAGCT AGAGTAAGTA GTTCGCCAGT TAATAGTTTG 6780 CGCAACGTTG TTGCCATTGC TACAGGCATC GTGGTGTCAC GCTCGTCGTT TGGTATGGCT 6840 TCATTCAGCT CCGGTTCCCA ACGATCAAGG CGAGTTACAT GATCCCCCAT GTTGTGCAAA 6900 AAAGCGGTTA GCTCCTTCGG TCCTCCGATC GTTGTCAGAA GTAAGTTGGC CGCAGTGTTA 6960 TCACTCATGG TTATGGCAGC ACTGCATAAT TCTCTTACTG TCATGCCATC CGTAAGATGC 7020 TTTTCTGTGA CTGGTGAGTA CTCAACCAAG TCATTCTGAG AATAGTGTAT GCGGCGACCG 7080 AGTTGCTCTT GCCCGGCGTC AATACGGGAT AATACCGCGC CACATAGCAG AACTTTAAAA 7140 GTGCTCATCA TTGGAAAACG TTCTTCGGGG CGAAAACTCT CAAGGATCTT ACCGCTGTTG 7200 AGATCCAGTT CGATGTAACC CACTCGTGCA CCCAACTGAT CTTCAGCATC TTTTACTTTC 7260 ACCAGCGTTT CTGGGTGAGC AAAAACAGGA AGGCAAAATG CCGCAAAAAA GGGAATAAGG 7320 GCGACACGGA AATGTTGAAT ACTCATACTC TTCCTTTTTC AATATTATTG AAGCATTTAT 7380 CAGGGTTATT GTCTCATGAG CGGATACATA TTTGAATGTA TTTAGAAAAA TAAACAAATA 7440 GGGGTTCCGC GCACATTTCC CCGAAAAGTG CCAC 7474 (2) INFORMATION FOR SEQ ID NO: 27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13414 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: circular (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "plasmid" (iii) HYPOTHETICAL: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION:11582 (D) OTHER INFORMATION:/note= "N is A,G, C or T" (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27: TATGACGACG TCAAATGTAG AATTGATACC ATTCTACACG GATTGGGCCA ATCGGCACCT 60 TTCGAAGGGC AGCTTATCAA AGTCGATTAG GGATATTTCC AATGATTTTC GCGACTATCG 120 ACTGGTTTCT CAGCTTATTA ATGTGATCGT TCCGATCAAC GAATTCTCGC CTGCATTCAC 180 GAAACGTTTG GCAAAAATCA CATCGAACCT GGATGGCCTC GAAACGTGTC TCGACTACCT 240 GAAAAATCTG GGTCTCGACT GCTCGAAACT CACCAAAACC GATATCGACA GCGGAAACTT 300 GGGTGCAGTT CTCCAGCTGC TCTTCCTGCT CTCCACCTAC AAGCAGAAGC TTCGGCAACT 360 GAAAAAAGAT CAGAAGAAAT TGGAGCAACT ACCCACATCC ATTATGCCAC CCGCGGTTTC 420 TAAATTACCC TCGCCACGTG TCGCCACGTC AGCAACCGCT TCAGCAACTA ACCCAAATTC 480 CAACTTTCCA CAAATGTCAA CATCCAGGCT TCAGACTCCA CAGTCAAGAA TATCGAAAAT 540 TGATTCATCA AAGATTGGTA TCAAGCCAAA GACGTCTGGA CTTAAACCAC CCTCATCATC 600 AACCACTTCA TCAAATAATA CAAATTCATT CCGTCCGTCG AGCCGTTCGA GTGGCAATAA 660 TAATGTTGGC TCGACGATAT CCACATCTGC GAAGAGCTTA GAATCATCAT CAACGTACAG 720 CTCTATTTCG AATCTAAACC GACCTACCTC CCAACTCCAA AAACCTTCTA GACCACAAAC 780 CCAGCTAGTT CGTGTTGCTA CAACTACAAA AATCGGAAGC TCAAAGCTAG CCGCTCCGAA 840 AGCCGTGAGC ACCCCAAAAC TTGCTTCTGT GAAGACTATT GGAGCAAAAC AAGAGCCCGA 900 TAACAGCGGT GGTGGTGGTG GTGGAATGCT GAAATTAAAG TTATTCAGTA GCAAAAACCC 960 ATCTTCCTCA TCGAATAGCC CACAACCTAC GAGAAAGGCG GCGGCGGTGC CTCAACAACA 1020 AACTTTGTCG AAAATCGCTG CCCCAGTGAA AAGTGGCCTG AAGCCGCCGA CCAGTAAGCT 1080 GGGAAGTGCC ACGTCTATGT CGAAGCTTTG TACGCCAAAA GTTTCCTACC GTAAAACGGA 1140 CGCCCCAATC ATATCTCAAC AAGACTCGAA ACGATGCTCA AAGAGCAGTG AAGAAGAGTC 1200 CGGATACGCT GGATTCAACA GCACGTCGCC AACGTCATCA TCGACGGAAG GTTCCCTAAG 1260 CATGCATTCC ACATCTTCCA AGAGTTCAAC GTCAGACGAA AAGTCTCCGT CATCAGACGA 1320 TCTTACTCTT AACGCCTCCA TCGTGACAGC TATCAGACAG CCGATAGCCG CAACACCGGT 1380 TTCTCCAAAT ATTATCAACA AGCCTGTTGA GGAAAAACCA ACACTGGCAG TGAAAGGAGT 1440 GAAAAGCACA GCGAAAAAAG ATCCACCTCC AGCTGTTCCG CCACGTGACA CCCAGCCAAC 1500 AATCGGAGTT GTTAGTCCAA TTATGGCACA TAAGAAGTTG ACAAATGACC CCGTGATATC 1560 TGAAAAACCA GAACCTGAAA AGCTCCAATC AATGAGCATC GACACGACGG ACGTTCCACC 1620 GCTTCCACCT CTAAAATCAG TTGTTCCACT TAAAATGACT TCAATCCGAC AACCACCAAC 1680 GTACGATGTT CTTCTAAAAC AAGGAAAAAT CACATCGCCT GTCAAGTCGT TTGGATATGA 1740 GCAGTCGTCC GCGTCTGAAG ACTCCATTGT GGCTCATGCG TCGGCTCAGG TGACTCCGCC 1800 GACAAAAACT TCTGGTAATC ATTCGCTGGA GAGAAGGATG GGAAAGAATA AGACATCAGA 1860 ATCCAGCGGC TACACCTCTG ACGCCGGTGT TGCGATGTGC GCCAAAATGA GGGAGAAGCT 1920 GAAAGAATAC GATGACATGA CTCGTCGAGC ACAGAACGGC TATCCTGACA ACTTCGAAGA 1980 CAGTTCCTCC TTGTCGTCTG GAATATCCGA TAACAACGAG CTCGACGACA TATCCACGGA 2040 CGATTTGTCC GGAGTAGACA TGGCAACAGT CGCCTCCAAA CATAGCGACT ATTCCCACTT 2100 TGTTCGCCAT CCCACGTCTT CTTCCTCAAA GCCCCGAGTC CCCAGTCGGT CCTCCACATC 2160 AGTCGATTCT CGATCTCGAG CAGAACAGGA GAATGTGTAC AAACTTCTGT CCCAGTGCCG 2220 AACGAGCCAA CGTGGCGCCG CTGCCACCTC AACCTTCGGA CAACATTCGC TAAGATCCCC 2280 GGGATACTCA TCCTATTCTC CACACTTATC AGTGTCAGCT GATAAGGACA CAATGTCTAT 2340 GCACTCACAG ACTAGTCGAC GACCTTCTTC ACAAAAACCA AGCTATTCAG GCCAATTTCA 2400 TTCACTTGAT CGTAAATGCC ACCTTCAAGA GTTCACATCC ACCGAGCACA GAATGGCGGC 2460 TCTCTTGAGC CCGAGACGGG TGCCGAACTC GATGTCGAAA TATGATTCTT CAGGATCCTA 2520 CTCGGCGCGT TCCCGAGGTG GAAGCTCTAC TGGTATCTAT GGAGAGACGT TCCAACTGCA 2580 CAGACTATCC GATGAAAAAT CCCCCGCACA TTCTGCCAAA AGTGAGATGG GATCCCAACT 2640 ATCACTGGCT AGCACGACAG CATATGGATC TCTCAATGAG AAGTACGAAC ATGCTATTCG 2700 GGACATGGCA CGTGACTTGG AGTGTTACAA GAACACTGTC GACTCACTAA CCAAGAAACA 2760 GGAGAACTAT GGAGCATTGT TTGATCTTTT TGAGCAAAAG CTTAGAAAAC TCACTCAACA 2820 CATTGATCGA TCCAACTTGA AGCCTGAAGA GGCAATACGA TTCAGGCAGG ACATTGCTCA 2880 TTTGAGGGAT ATTAGCAATC ATCTTGCATC CAACTCAGCT CATGCTAACG AAGGCGCTGG 2940 TGAGCTTCTT CGTCAACCAT CTCTGGAATC AGTTGCATCC CATCGATCAT CGATGTCATC 3000 GTCGTCGAAA AGCAGCAAGC AGGAGAAGAT CAGCTTGAGC TCGTTTGGCA AGAACAAGAA 3060 GAGCTGGATC CGCTCCTCAC TCTCCAAGTT CACCAAGAAG AAGAACAAGA ACTACGACGA 3120 AGCACATATG CCATCAATTT CCGGATCTCA AGGAACTCTT GACAACATTG ATGTGATTGA 3180 GTTGAAGCAA GAGCTCAAAG AACGCGATAG TGCACTTTAC GAAGTCCGCC TTGACAATCT 3240 GGATCGTGCC CGCGAAGTTG ATGTTCTGAG GGAGACAGTG AACAAGTTGA AAACCGAGAA 3300 CAAGCAATTA AAGAAAGAAG TGGACAAACT CACCAACGGT CCAGCCACTC GTGCTTCTTC 3360 CCGCGCCTCA ATTCCAGTTA TCTACGACGA TGAGCATGTC TATGATGCAG CGTGTAGCAG 3420 TACATCAGCT AGTCAATCTT CGAAACGATC CTCTGGCTGC AACTCAATCA AGGTTACTGT 3480 AAACGTGGAC ATCGCTGGAG AAATCAGTTC GATCGTTAAC CCGGACAAAG AGATAATCGT 3540 AGGATATCTT GCCATGTCAA CCAGTCAGTC ATGCTGGAAA GACATTGATG TTTCTATTCT 3600 AGGACTATTT GAAGTCTACC TATCCAGAAT TGATGTGGAG CATCAACTTG GAATCGATGC 3660 TCGTGATTCT ATCCTTGGCT ATCAAATTGG TGAACTTCGA CGCGTCATTG GAGACTCCAC 3720 AACCATGATA ACCAGCCATC CAACTGACAT TCTTACTTCC TCAACTACAA TCCGAATGTT 3780 CATGCACGGT GCCGCACAGA GTCGCGTAGA CAGTCTGGTC CTTGATATGC TTCTTCCAAA 3840 GCAAATGATT CTCCAACTCG TCAAGTCAAT TTTGACAGAG AGACGTCTGG TGTTAGCTGG 3900 AGCAACTGGA ATTGGAAAGA GCAAACTGGC GAAGACCCTG GCTGCTTATG TATCTATTCG 3960 AACAAATCAA TCCGAAGATA GTATTGTTAA TATCAGCATT CCTGAAAACA ATAAAGAAGA 4020 ATTGCTTCAA GTGGAACGAC GCCTGGAAAA GATCTTGAGA AGCAAAGAAT CATGCATCGT 4080 AATTCTAGAT AATATCCCAA AGAATCGAAT TGCATTTGTT GTATCCGTTT TTGCAAATGT 4140 CCCACTTCAA AACAACGAAG GTCCATTTGT AGTATGCACA GTCAACCGAT ATCAAATCCC 4200 TGAGCTTCAA ATTCACCACA ATTTCAAAAT GTCAGTAATG TCGAATCGTC TCGAAGGATT 4260 CATCCTACGT TACCTCCGAC GACGGGCGGT AGAGGATGAG TATCGTCTAA CTGTACAGAT 4320 GCCATCAGAG CTCTTCAAAA TCATTGACTT CTTCCCAATA GCTCTTCAGG CCGTCAATAA 4380 TTTTATTGAG AAAACGAATT CTGTTGATGT GACAGTTGGT CCAAGAGCAT GCTTGAACTG 4440 TCCTCTAACT GTCGATGGAT CCCGTGAATG GTTCATTCGA TTGTGGAATG AGAACTTCAT 4500 TCCATATTTG GAACGTGTTG CTAGAGATGG CAAAAAAACC TTCGGTCGCT GCACTTCCTT 4560 CGAGGATCCC ACCGACATCG TCTCTAAAAA ATGGCCGTGG TTCGATGGTG AAAACCCGGA 4620 GAATGTGCTC AAACGTCTTC AACTCCAAGA CCTCGTCCCG TCACCTGCCA ACTCATCCCG 4680 ACAACACTTC AATCCCCTCG AGTCGTTGAT CCAATTGCAT GCTACCAAGC ATCAGACCAT 4740 CGACAACATT TGAACAGAAG ACTCTAATCT TCTCTCGCCT CTCCCCCGCT TTCCTTATCT 4800 TCGTACCGGT ACCTGATGAT TCCCCATTTT CCCCCTTTTC CCCCCAATTT CCCAGAACCT 4860 CCTGTTCCCT TTGTTCCTAG TCCTCCCGGG TGCCGACGCC GAAGCGATTT AAAAACCTTT 4920 TTCTTTCCGA AACATTTCCC ATTGCTCATT AATAGTCAAA TTGAATAAAC AGTGTATGTA 4980 CTTAAAAAAA AAAAAAAAAA AAAAAAAAAA GGCCTATGCG GCCGGGCCAT GGAGGCCGAA 5040 TTCCCGGGGA TCCGTCGACC TGCAGCCAAG CTAATTCCGG GCGAATTTCT TATGATTTAT 5100 GATTTTTATT ATTAAATAAG TTATAAAAAA AATAAGTGTA TACAAATTTT AAAGTGACTC 5160 TTAGGTTTTA AAACGAAAAT TCTTGTTCTT GAGTAACTCT TTCCTGTAGG TCAGGTTGCT 5220 TTCTCAGGTA TAGCATGAGG TCGCTCTTAT TGACCACACC TCTACCGGCA TGCAAGCTTG 5280 GCGTAATCAT GGTCATAGCT GTTTCCTGTG TGAAATTGTT ATCCGCTCAC AATTCCACAC 5340 AACATACGAG CCGGAAGCAT AAAGTGTAAA GCCTGGGGTG CCTAATGAGT GAGGTAACTC 5400 ACATTAATTG CGTTGCGCTC ACTGCCCGCT TTCCAGTCGG GAAACCTGTC GTGCCAGCTG 5460 GATTAATGAA TCGGCCAACG CGCGGGGAGA GGCGGTTTGC GTATTGGGCG CTCTTCCGCT 5520 TCCTCGCTCA CTGACTCGCT GCGCTCGGTC GTTCGGCTGC GGCGAGCGGT ATCAGCTCAC 5580 TCAAAGGCGG TAATACGGTT ATCCACAGAA TCAGGGGATA ACGCAGGAAA GAACATGTGA 5640 GCAAAAGGCC AGCAAAAGGC CAGGAACCGT AAAAAGGCCG CGTTGCTGGC GTTTTTCCAT 5700 AGGCTCCGCC CCCCTGACGA GCATCACAAA AATCGACGCT CAAGTCAGAG GTGGCGAAAC 5760 CCGACAGGAC TATAAAGATA CCAGGCGTTT CCCCCTGGAA GCTCCCTCGT GCGCTCTCCT 5820 GTTCCGACCC TGCCGCTTAC CGGATACCTG TCCGCCTTTC TCCCTTCGGG AAGCGTGGCG 5880 CTTTCTCATA GCTCACGCTG TAGGTATCTC AGTTCGGTGT AGGTCGTTCG CTCCAAGCTG 5940 GGCTGTGTGC ACGAACCCCC CGTTCAGCCC GACCGCTGCG CCTTATCCGG TAACTATCGT 6000 CTTGAGTCCA ACCCGGTAAG ACACGACTTA TCGCCACTGG CAGCAGCCAC TGGTAACAGG 6060 ATTAGCAGAG CGAGGTATGT AGGCGGTGCT ACAGAGTTCT TGAAGTGGTG GCCTAACTAC 6120 GGCTACACTA GAAGGACAGT ATTTGGTATC TGCGCTCTGC TGAAGCCAGT TACCTTCGGA 6180 AAAAGAGTTG GTAGCTCTTG ATCCGGCAAA CAAACCACCG CTGGTAGCGG TGGTTTTTTT 6240 GTTTGCAAGC AGCAGATTAC GCGCAGAAAA AAAGGATCTC AAGAAGATCC TTTGATCTTT 6300 TCTACGGGGT CTGACGCTCA GTGGAACGAA AACTCACGTT AAGGGATTTT GGTCATGAGA 6360 TTATCAAAAA GGATCTTCAC CTAGATCCTT TTAAATTAAA AATGAAGTTT TAAATCAATC 6420 TAAAGTATAT ATGAGTAAAC TTGGTCTGAC AGTTACCAAT GCTTAATCAG TGAGGCACCT 6480 ATCTCAGCGA TCTGTCTATT TCGTTCATCC ATAGTTGCCT GACTCCCCGT CGTGTAGATA 6540 ACTACGATAC GGGAGGGCTT ACCATCTGGC CCCAGTGCTG CAATGATACC GCGAGACCCA 6600 CGCTCACCGG CTCCAGATTT ATCAGCAATA AACCAGCCAG CCGGAAGGGC CGAGCGCAGA 6660 AGTGGTCCTG CAACTTTATC CGCCTCCATC CAGTCTATTA ATTGTTGCCG GGAAGCTAGA 6720 GTAAGTAGTT CGCCAGTTAA TAGTTTGCGC AACGTTGTTG CCATTGCTAC AGGCATCGTG 6780 GTGTCACGCT CGTCGTTTGG TATGGCTTCA TTCAGCTCCG GTTCCCAACG ATCAAGGCGA 6840 GTTACATGAT CCCCCATGTT GTGCAAAAAA GCGGTTAGCT CCTTCGGTCC TCCGATCGTT 6900 GTCAGAAGTA AGTTGGCCGC AGTGTTATCA CTCATGGTTA TGGCAGCACT GCATAATTCT 6960 CTTACTGTCA TGCCATCCGT AAGATGCTTT TCTGTGACTG GTGAGTACTC AACCAAGTCA 7020 TTCTGAGAAT AGTGTATGCG GCGACCGAGT TGCTCTTGCC CGGCGTCAAT ACGGGATAAT 7080 ACCGCGCCAC ATAGCAGAAC TTTAAAAGTG CTCATCATTG GAAAACGTTC TTCGGGGCGA 7140 AAACTCTCAA GGATCTTACC GCTGTTGAGA TCCAGTTCGA TGTAACCCAC TCGTGCACCC 7200 AACTGATCTT CAGCATCTTT TACTTTCACC AGCGTTTCTG GGTGAGCAAA AACAGGAAGG 7260 CAAAATGCCG CAAAAAAGGG AATAAGGGCG ACACGGAAAT GTTGAATACT CATACTCTTC 7320 CTTTTTCAAT ATTATTGAAG CATTTATCAG GGTTATTGTC TCATGAGCGG ATACATATTT 7380 GAATGTATTT AGAAAAATAA ACAAATAGGG GTTCCGCGCA CATTTCCCCG AAAAGTGCCA 7440 CCTGAACGAA GCATCTGTGC TTCATTTTGT AGAACAAAAA TGCAACGCGA GAGCGCTAAT 7500 TTTTCAAACA AAGAATCTGA GCTGCATTTT TACAGAACAG AAATGCAACG CGAAAGCGCT 7560 ATTTTACCAA CGAAGAATCT GTGCTTCATT TTTGTAAAAC AAAAATGCAA CGCGAGAGCG 7620 CTAATTTTTC AAACAAAGAA TCTGAGCTGC ATTTTTACAG AACAGAAATG CAACGCGAGA 7680 GCGCTATTTT ACCAACAAAG AATCTATACT TCTTTTTTGT TCTACAAAAA TGCATCCCGA 7740 GAGCGCTATT TTTCTAACAA AGCATCTTAG ATTACTTTTT TTCTCCTTTG TGCGCTCTAT 7800 AATGCAGTCT CTTGATAACT TTTTGCACTG TAGGTCCGTT AAGGTTAGAA GAAGGCTACT 7860 TTGGTGTCTA TTTTCTCTTC CATAAAAAAA GCCTGACTCC ACTTCCCGCG TTTACTGATT 7920 ACTAGCGAAG CTGCGGGTGC ATTTTTTCAA GATAAAGGCA TCCCCGATTA TATTCTATAC 7980 CGATGTGGAT TGCGCATACT TTGTGAACAG AAAGTGATAG CGTTGATGAT TCTTCATTGG 8040 TCAGAAAATT ATGAACGGTT TCTTCTATTT TGTCTCTATA TACTACGTAT AGGAAATGTT 8100 TACATTTTCG TATTGTTTTC GATTCACTCT ATGAATAGTT CTTACTACAA TTTTTTTGTC 8160 TAAAGAGTAA TACTAGAGAT AAACATAAAA AATGTAGAGG TCGAGTTTAG ATGCAAGTTC 8220 AAGGAGCGAA AGGTGGATGG GTAGGTTATA TAGGGATATA GCACAGAGAT ATATAGCAAA 8280 GAGATACTTT TGAGCAATGT TTGTGGAAGC GGTATTCGCA ATATTTTAGT AGCTCGTTAC 8340 AGTCCGGTGC GTTTTTGGTT TTTTGAAAGT GCGTCTTCAG AGCGCTTTTG GTTTTCAAAA 8400 GCGCTCTGAA GTTCCTATAC TTTCTAGAGA ATAGGAACTT CGGAATAGGA ACTTCAAAGC 8460 GTTTCCGAAA ACGAGCGCTT CCGAAAATGC AACGCGAGCT GCGCACATAC AGCTCACTGT 8520 TCACGTCGCA CCTATATCTG CGTGTTGCCT GTATATATAT ATACATGAGA AGAACGGCAT 8580 AGTGCGTGTT TATGCTTAAA TGCGTACTTA TATGCGTCTA TTTATGTAGG ATGAAAGGTA 8640 GTCTAGTACC TCCTGTGATA TTATCCCATT CCATGCGGGG TATCGTATGC TTCCTTCAGC 8700 ACTACCCTTT AGCTGTTCTA TATGCTGCCA CTCCTCAATT GGATTAGTCT CATCCTTCAA 8760 TGCTATCATT TCCTTTGATA TTGGATCATA TTAAGAAACC ATTATTATCA TGACATTAAC 8820 CTATAAAAAT AGGCGTATCA CGAGGCCCTT TCGTCTCGCG CGTTTCGGTG ATGACGGTGA 8880 AAACCTCTGA CACATGCAGC TCCCGGAGAC GGTCACAGCT TGTCTGTAAG CGGATGCCGG 8940 GAGCAGACAA GCCCGTCAGG GCGCGTCAGC GGGTGTTGGC GGGTGTCGGG GCTGGCTTAA 9000 CTATGCGGCA TCAGAGCAGA TTGTACTGAG AGTGCACCAT AGATCAACGA CATTACTATA 9060 TATATAATAT AGGAAGCATT TAATAGACAG CATCGTAATA TATGTGTACT TTGCAGTTAT 9120 GACGCCAGAT GGCAGTAGTG GAAGATATTC TTTATTGAAA AATAGCTTGT CACCTTACGT 9180 ACAATCTTGA TCCGGAGCTT TTCTTTTTTT GCCGATTAAG AATTAATTCG GTCGAAAAAA 9240 GAAAAGGAGA GGGCCAAGAG GGAGGGCATT GGTGACTATT GAGCACGTGA GTATACGTGA 9300 TTAAGCACAC AAAGGCAGCT TGGAGTATGT CTGTTATTAA TTTCACAGGT AGTTCTGGTC 9360 CATTGGTGAA AGTTTGCGGC TTGCAGAGCA CAGAGGCCGC AGAATGTGCT CTAGATTCCG 9420 ATGCTGACTT GCTGGGTATT ATATGTGTGC CCAATAGAAA GAGAACAATT GACCCGGTTA 9480 TTGCAAGGAA AATTTCAAGT CTTGTAAAAG CATATAAAAA TAGTTCAGGC ACTCCGAAAT 9540 ACTTGGTTGG CGTGTTTCGT AATCAACCTA AGGAGGATGT TTTGGCTCTG GTCAATGATT 9600 ACGGCATTGA TATCGTCCAA CTGCATGGAG ATGAGTCGTG GCAAGAATAC CAAGAGTTCC 9660 TCGGTTTGCC AGTTATTAAA AGACTCGTAT TTCCAAAAGA CTGCAACATA CTACTCAGTG 9720 CAGCTTCACA GAAACCTCAT TCGTTTATTC CCTTGTTTGA TTCAGAAGCA GGTGGGACAG 9780 GTGAACTTTT GGATTGGAAC TCGATTTCTG ACTGGGTTGG AAGGCAAGAG AGCCCCGAAA 9840 GCTTACATTT TATGTTAGCT GGTGGACTGA CGCCAGAAAA TGTTGGTGAT GCGCTTAGAT 9900 TAAATGGCGT TATTGGTGTT GATGTAAGCG GAGGTGTGGA GACAAATGGT GTAAAAGACT 9960 CTAACAAAAT AGCAAATTTC GTCAAAAATG CTAAGAAATA GGTTATTACT GAGTAGTATT 10020 TATTTAAGTA TTGTTTGTGC ACTTGCCGAT CTATGCGGTG TGAAATACCG CACAGATGCG 10080 TAAGGAGAAA ATACCGCATC AGGAAATTGT AAACGTTAAT ATTTTGTTAA AATTCGCGTT 10140 AAATTTTTGT TAAATCAGCT CATTTTTTAA CCAATAGGCC GAAATCGGCA AAATCCCTTA 10200 TAAATCAAAA GAATAGACCG AGATAGGGTT GAGTGTTGTT CCAGTTTGGA ACAAGAGTCC 10260 ACTATTAAAG AACGTGGACT CCAACGTCAA AGGGCGAAAA ACCGTCTATC AGGGCGATGG 10320 CCCACTACGT GAACCATCAC CCTAATCAAG TTTTTTGGGG TCGAGGTGCC GTAAAGCACT 10380 AAATCGGAAC CCTAAAGGGA GCCCCCGATT TAGAGCTTGA CGGGGAAAGC CGGCGAACGT 10440 GGCGAGAAAG GAAGGGAAGA AAGCGAAAGG AGCGGGCGCT AGGGCGCTGG CAAGTGTAGC 10500 GGTCACGCTG CGCGTAACCA CCACACCCGC CGCGCTTAAT GCGCCGCTAC AGGGCGCGTC 10560 GCGCCATTCG CCATTCAGGC TGCGCAACTG TTGGGAAGGG CGATCGGTGC GGGCCTCTTC 10620 GCTATTACGC CAGCTGGCGA AAGGGGGATG TGCTGCAAGG CGATTAAGTT GGGTAACGCC 10680 AGGGTTTTCC CAGTCACGAC GTTGTAAAAC GACGGCCAGT CGTCCAAGCT TTCGCGAGCT 10740 CGAGATCCCG AGCTTTGCAA ATTAAAGCCT TCGAGCGTCC CAAAACCTTC TCAAGCAAGG 10800 TTTTCAGTAT AATGTTACAT GCGTACACGC GTCTGTACAG AAAAAAAAGA AAAATTTGAA 10860 ATATAAATAA CGTTCTTAAT ACTAACATAA CTATAAAAAA ATAAATAGGG ACCTAGACTT 10920 CAGGTTGTCT AACTCCTTCC TTTTCGGTTA GAGCGGATGT GGGGGGAGGG CGTGAATGTA 10980 AGCGTGACAT AACTAATTAC ATGATATCGA CAAAGGAAAA GGGGCCTGTT TACTCACAGG 11040 CTTTTTTCAA GTAGGTAATT AAGTCGTTTC TGTCTTTTTC CTTCTTCAAC CCACCAAAGG 11100 CCATCTTGGT ACTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT 11160 TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTCATA GAAATAATAC 11220 AGAAGTAGAT GTTGAATTAG ATTAAACTGA AGATATATAA TTTATTGGAA AATACATAGA 11280 GCTTTTTGTT GATGCGCTTA AGCGATCAAT TCAACAACAC CACCAGCAGC TCTGATTTTT 11340 TCTTCAGCCA ACTTGGAGAC GAATCTAGCT TTGACGATAA CTGGAACATT TGGGATTCTA 11400 CCCTTACCCA AGATCTTACC GTAACCGGCT GCCAAAGTGT CAATAACTGG AGCAGTTTCC 11460 TTAGAAGCAG ATTTCAAGTA TTGGTCTCTC TTGTCTTCTG GGATCAATGT CCACAATTTG 11520 TCCAAGTTCA AGACTGGCTT CCAGAAATGA GCTTGTTGCT TGTGGAAGTA TCTCATACCA 11580 ANCCTTACCG AAATAACCTG GATGGTATTT ATCCATGTTA ATTCTGTGGT GATGTTGACC 11640 ACCGGCCATA CCTCTACCAC CGGGGTGCTT TCTGTGCTTA CCGATACGAC CTTTACCGGC 11700 TGAGACGTGA CCTCTGTGCT TTCTAGTCTT AGTGAATCTG GAAGGCATTC TTGATTAGTT 11760 GGATGATTGT TCTGGGATTT AATGCAAAAA AATCACTAAG AAGGAAAAAA ATCAACGGAG 11820 AAAGCAAACG CCATCTTAAA TATACGGGAT ACAGATGAAA GGTTTGAACC TATCTGGGAA 11880 AATACGCATT AAACAAGCGA AAAACTGCGA GGAAAATTGT TTGCGTCTCT GCGGGCTATT 11940 CACGCGCCAG AGGAAAATAG GAAAAATAAC AGGGCATTAG AAAAATAATT TTGATTTTGG 12000 TAATGTGTGG GTCCCTGGTG TACAGATGTT ACATTGGTTA CAGTACTCTT GTTTTTGCTG 12060 TGTTTTTCGA TGAATCTCCA AAATGGTTGT TAGCACATGG AAGAGTCACC GATGCTAAGT 12120 TATCTCTATG TAAGCTACGT GGCGTGACTT TTGATGAAGC CGCACAAGAG ATACAGGATT 12180 GGCAACTGCA AATAGAATCT GGGGATCTAG ATATCCTTTT GTTGTTTCCG GGTGTACAAT 12240 ATGGACTTCC TCTTTTCTGG CAACCAAACC CATACATCGG GATTCCTATA ATACCTTCGT 12300 TGGTCTCCCT AACATGTAGG TGGCGGAGGG GAGATATACA ATAGAACAGA TACCAGACAA 12360 GACATAATGG GCTAAACAAG ACTACACCAA TTACACTGCC TCATTGATGG TGGTACATAA 12420 CGAACTAATA CTGTAGCCCT AGACTTGATA GCCATCATCA TATCGAAGTT TCACTACCCT 12480 TTTTCCATTT GCCATCTATT GAAGTAATAA TAGGCGCATG CAACTTCTTT TCTTTTTTTT 12540 TCTTTTCTCT CTCCCCCGTT GTTGTCTCAC CATATCCGCA ATGACAAAAA AAATGATGGA 12600 AGACACTAAA GGAAAAAATT AACGACAAAG ACAGCACCAA CAGATGTCGT TGTTCCAGAG 12660 CTGATGAGGG GTATCTTCGA ACACACGAAA CTTTTTCCTT CCTTCATTCA CGCACACTAC 12720 TCTCTAATGA GCAACGGTAT ACGGCCTTCC TTCCAGTTAC TTGAATTTGA AATAAAAAAA 12780 GTTTGCCGCT TTGCTATCAA GTATAAATAG ACCTGCAATT ATTAATCTTT TGTTTCCTCG 12840 TCATTGTTCT CGTTCCCTTT CTTCCTTGTT TCTTTTTCTG CACAATATTT CAAGCTATAC 12900 CAAGCATACA ATCAACTCCA AGCTTGAAGC AAGCCTCCTG AAAGATGAAG CTACTGTCTT 12960 CTATCGAACA AGCATGCGAT ATTTGCCGAC TTAAAAAGCT CAAGTGCTCC AAAGAAAAAC 13020 CGAAGTGCGC CAAGTGTCTG AAGAACAACT GGGAGTGTCG CTACTCTCCC AAAACCAAAA 13080 GGTCTCCGCT GACTAGGGCA CATCTGACAG AAGTGGAATC AAGGCTAGAA AGACTGGAAC 13140 AGCTATTTCT ACTGATTTTT CCTCGAGAAG ACCTTGACAT GATTTTGAAA ATGGATTCTT 13200 TACAGGATAT AAAAGCATTG TTAACAGGAT TATTTGTACA AGATAATGTG AATAAAGATG 13260 CCGTCACAGA TAGATTGGCT TCAGTGGAGA CTGATATGCC TCTAACATTG AGACAGCATA 13320 GAATAAGTGC GACATCATCA TCGGAAGAGA GTAGTAACAA AGGTCAAAGA CAGTTGACTG 13380 TATCGCCGGA ATTGCAATAC CCAGCTTTGA CTCA 13414 (2) INFORMATION FOR SEQ ID NO: 28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 10288 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: circular (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "plasmid" (iii) HYPOTHETICAL: NO (ix) FEATURE: (A) NAME/KEY: misc_feature (B) LOCATION: 8456 (D) OTHER INFORMATION: /note= "N is A, C, G, or T" (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28: TATGCCATCA ATTTCCGGAT CTCAAGGAAC TCTTGACAAC ATTGATGTGA TTGAGTTGAA 60 GCAAGAGCTC AAAGAACGCG ATAGTGCACT TTACGAAGTC CGCCTTGACA ATCTGGATCG 120 TGCCCGCGAA GTTGATGTTC TGAGGGAGAC AGTGAACAAG TTGAAAACCG AGAACAAGCA 180 ATTAAAGAAA GAAGTGGACA AACTCACCAA CGGTCCAGCC ACTCGTGCTT CTTCCCGCGC 240 CTCAATTCCA GTTATCTACG ACGATGAGCA TGTCTATGAT GCAGCGTGTA GCAGTACATC 300 AGCTAGTCAA TCTTCGAAAC GATCCTCTGG CTGCAACTCA ATCAAGGTTA CTGTAAACGT 360 GGACATCGCT GGAGAAATCA GTTCGATCGT TAACCCGGAC AAAGAGATAA TCGTAGGATA 420 TCTTGCCATG TCAACCAGTC AGTCATGCTG GAAAGACATT GATGTTTCTA TTCTAGGACT 480 ATTTGAAGTC TACCTATCCA GAATTGATGT GGAGCATCAA CTTGGAATCG ATGCTCGTGA 540 TTCTATCCTT GGCTATCAAA TTGGTGAACT TCGACGCGTC ATTGGAGACT CCACAACCAT 600 GATAACCAGC CATCCAACTG ACATTCTTAC TTCCTCAACT ACAATCCGAA TGTTCATGCA 660 CGGTGCCGCA CAGAGTCGCG TAGACAGTCT GGTCCTTGAT ATGCTTCTTC CAAAGCAAAT 720 GATTCTCCAA CTCGTCAAGT CAATTTTGAC AGAGAGACGT CTGGTGTTAG CTGGAGCAAC 780 TGGAATTGGA AAGAGCAAAC TGGCGAAGAC CCTGGCTGCT TATGTATCTA TTCGAACAAA 840 TCAATCCGAA GATAGTATTG TTAATATCAG CATTCCTGAA AACAATAAAG AAGAATTGCT 900 TCAAGTGGAA CGACGCCTGG AAAAGATCTT GAGAAGCAAA GAATCATGCA TCGTAATTCT 960 AGATAATATC CCAAAGAATC GAATTGCATT TGTTGTATCC GTTTTTGCAA ATGTCCCACT 1020 TCAAAACAAC GAAGGTCCAT TTGTAGTATG CACAGTCAAC CGATATCAAA TCCCTGAGCT 1080 TCAAATTCAC CACAATTTCA AAATGTCAGT AATGTCGAAT CGTCTCGAAG GATTCATCCT 1140 ACGTTACCTC CGACGACGGG CGGTAGAGGA TGAGTATCGT CTAACTGTAC AGATGCCATC 1200 AGAGCTCTTC AAAATCATTG ACTTCTTCCC AATAGCTCTT CAGGCCGTCA ATAATTTTAT 1260 TGAGAAAACG AATTCTGTTG ATGTGACAGT TGGTCCAAGA GCATGCTTGA ACTGTCCTCT 1320 AACTGTCGAT GGATCCCGTG AATGGTTCAT TCGATTGTGG AATGAGAACT TCATTCCATA 1380 TTTGGAACGT GTTGCTAGAG ATGGCAAAAA AACCTTCGGT CGCTGCACTT CCTTCGAGGA 1440 TCCCACCGAC ATCGTCTCTA AAAAATGGCC GTGGTTCGAT GGTGAAAACC CGGAGAATGT 1500 GCTCAAACGT CTTCAACTCC AAGACCTCGT CCCGTCACCT GCCAACTCAT CCCGACAACA 1560 CTTCAATCCC CTCGAGTCGT TGATCCAATT GCATGCTACC AAGCATCAGA CCATCGACAA 1620 CATTTGAACA GAAGACTCTA ATCTTCTCTC GCCTCTCCCC CGCTTTCCTT ATCTTCGTAC 1680 CGGTACCTGA TGATTCCCCA TTTTCCCCCT TTTCCCCCCA ATTTCCCAGA ACCTCCTGTT 1740 CCCTTTGTTC CTAGTCCTCC CGGGTGCCGA CGCCGAAGCG ATTTAAAAAC CTTTTTCTTT 1800 CCGAAACATT TCCCATTGCT CATTAATAGT CAAATTGAAT AAACAGTGTA TGTACTTAAA 1860 AAAAAAAAAA AAAAAAAAAA AAAAGGCCTA TGCGGCCGGG CCATGGAGGC CGAATTCCCG 1920 GGGATCCGTC GACCTGCAGC CAAGCTAATT CCGGGCGAAT TTCTTATGAT TTATGATTTT 1980 TATTATTAAA TAAGTTATAA AAAAAATAAG TGTATACAAA TTTTAAAGTG ACTCTTAGGT 2040 TTTAAAACGA AAATTCTTGT TCTTGAGTAA CTCTTTCCTG TAGGTCAGGT TGCTTTCTCA 2100 GGTATAGCAT GAGGTCGCTC TTATTGACCA CACCTCTACC GGCATGCAAG CTTGGCGTAA 2160 TCATGGTCAT AGCTGTTTCC TGTGTGAAAT TGTTATCCGC TCACAATTCC ACACAACATA 2220 CGAGCCGGAA GCATAAAGTG TAAAGCCTGG GGTGCCTAAT GAGTGAGGTA ACTCACATTA 2280 ATTGCGTTGC GCTCACTGCC CGCTTTCCAG TCGGGAAACC TGTCGTGCCA GCTGGATTAA 2340 TGAATCGGCC AACGCGCGGG GAGAGGCGGT TTGCGTATTG GGCGCTCTTC CGCTTCCTCG 2400 CTCACTGACT CGCTGCGCTC GGTCGTTCGG CTGCGGCGAG CGGTATCAGC TCACTCAAAG 2460 GCGGTAATAC GGTTATCCAC AGAATCAGGG GATAACGCAG GAAAGAACAT GTGAGCAAAA 2520 GGCCAGCAAA AGGCCAGGAA CCGTAAAAAG GCCGCGTTGC TGGCGTTTTT CCATAGGCTC 2580 CGCCCCCCTG ACGAGCATCA CAAAAATCGA CGCTCAAGTC AGAGGTGGCG AAACCCGACA 2640 GGACTATAAA GATACCAGGC GTTTCCCCCT GGAAGCTCCC TCGTGCGCTC TCCTGTTCCG 2700 ACCCTGCCGC TTACCGGATA CCTGTCCGCC TTTCTCCCTT CGGGAAGCGT GGCGCTTTCT 2760 CATAGCTCAC GCTGTAGGTA TCTCAGTTCG GTGTAGGTCG TTCGCTCCAA GCTGGGCTGT 2820 GTGCACGAAC CCCCCGTTCA GCCCGACCGC TGCGCCTTAT CCGGTAACTA TCGTCTTGAG 2880 TCCAACCCGG TAAGACACGA CTTATCGCCA CTGGCAGCAG CCACTGGTAA CAGGATTAGC 2940 AGAGCGAGGT ATGTAGGCGG TGCTACAGAG TTCTTGAAGT GGTGGCCTAA CTACGGCTAC 3000 ACTAGAAGGA CAGTATTTGG TATCTGCGCT CTGCTGAAGC CAGTTACCTT CGGAAAAAGA 3060 GTTGGTAGCT CTTGATCCGG CAAACAAACC ACCGCTGGTA GCGGTGGTTT TTTTGTTTGC 3120 AAGCAGCAGA TTACGCGCAG AAAAAAAGGA TCTCAAGAAG ATCCTTTGAT CTTTTCTACG 3180 GGGTCTGACG CTCAGTGGAA CGAAAACTCA CGTTAAGGGA TTTTGGTCAT GAGATTATCA 3240 AAAAGGATCT TCACCTAGAT CCTTTTAAAT TAAAAATGAA GTTTTAAATC AATCTAAAGT 3300 ATATATGAGT AAACTTGGTC TGACAGTTAC CAATGCTTAA TCAGTGAGGC ACCTATCTCA 3360 GCGATCTGTC TATTTCGTTC ATCCATAGTT GCCTGACTCC CCGTCGTGTA GATAACTACG 3420 ATACGGGAGG GCTTACCATC TGGCCCCAGT GCTGCAATGA TACCGCGAGA CCCACGCTCA 3480 CCGGCTCCAG ATTTATCAGC AATAAACCAG CCAGCCGGAA GGGCCGAGCG CAGAAGTGGT 3540 CCTGCAACTT TATCCGCCTC CATCCAGTCT ATTAATTGTT GCCGGGAAGC TAGAGTAAGT 3600 AGTTCGCCAG TTAATAGTTT GCGCAACGTT GTTGCCATTG CTACAGGCAT CGTGGTGTCA 3660 CGCTCGTCGT TTGGTATGGC TTCATTCAGC TCCGGTTCCC AACGATCAAG GCGAGTTACA 3720 TGATCCCCCA TGTTGTGCAA AAAAGCGGTT AGCTCCTTCG GTCCTCCGAT CGTTGTCAGA 3780 AGTAAGTTGG CCGCAGTGTT ATCACTCATG GTTATGGCAG CACTGCATAA TTCTCTTACT 3840 GTCATGCCAT CCGTAAGATG CTTTTCTGTG ACTGGTGAGT ACTCAACCAA GTCATTCTGA 3900 GAATAGTGTA TGCGGCGACC GAGTTGCTCT TGCCCGGCGT CAATACGGGA TAATACCGCG 3960 CCACATAGCA GAACTTTAAA AGTGCTCATC ATTGGAAAAC GTTCTTCGGG GCGAAAACTC 4020 TCAAGGATCT TACCGCTGTT GAGATCCAGT TCGATGTAAC CCACTCGTGC ACCCAACTGA 4080 TCTTCAGCAT CTTTTACTTT CACCAGCGTT TCTGGGTGAG CAAAAACAGG AAGGCAAAAT 4140 GCCGCAAAAA AGGGAATAAG GGCGACACGG AAATGTTGAA TACTCATACT CTTCCTTTTT 4200 CAATATTATT GAAGCATTTA TCAGGGTTAT TGTCTCATGA GCGGATACAT ATTTGAATGT 4260 ATTTAGAAAA ATAAACAAAT AGGGGTTCCG CGCACATTTC CCCGAAAAGT GCCACCTGAA 4320 CGAAGCATCT GTGCTTCATT TTGTAGAACA AAAATGCAAC GCGAGAGCGC TAATTTTTCA 4380 AACAAAGAAT CTGAGCTGCA TTTTTACAGA ACAGAAATGC AACGCGAAAG CGCTATTTTA 4440 CCAACGAAGA ATCTGTGCTT CATTTTTGTA AAACAAAAAT GCAACGCGAG AGCGCTAATT 4500 TTTCAAACAA AGAATCTGAG CTGCATTTTT ACAGAACAGA AATGCAACGC GAGAGCGCTA 4560 TTTTACCAAC AAAGAATCTA TACTTCTTTT TTGTTCTACA AAAATGCATC CCGAGAGCGC 4620 TATTTTTCTA ACAAAGCATC TTAGATTACT TTTTTTCTCC TTTGTGCGCT CTATAATGCA 4680 GTCTCTTGAT AACTTTTTGC ACTGTAGGTC CGTTAAGGTT AGAAGAAGGC TACTTTGGTG 4740 TCTATTTTCT CTTCCATAAA AAAAGCCTGA CTCCACTTCC CGCGTTTACT GATTACTAGC 4800 GAAGCTGCGG GTGCATTTTT TCAAGATAAA GGCATCCCCG ATTATATTCT ATACCGATGT 4860 GGATTGCGCA TACTTTGTGA ACAGAAAGTG ATAGCGTTGA TGATTCTTCA TTGGTCAGAA 4920 AATTATGAAC GGTTTCTTCT ATTTTGTCTC TATATACTAC GTATAGGAAA TGTTTACATT 4980 TTCGTATTGT TTTCGATTCA CTCTATGAAT AGTTCTTACT ACAATTTTTT TGTCTAAAGA 5040 GTAATACTAG AGATAAACAT AAAAAATGTA GAGGTCGAGT TTAGATGCAA GTTCAAGGAG 5100 CGAAAGGTGG ATGGGTAGGT TATATAGGGA TATAGCACAG AGATATATAG CAAAGAGATA 5160 CTTTTGAGCA ATGTTTGTGG AAGCGGTATT CGCAATATTT TAGTAGCTCG TTACAGTCCG 5220 GTGCGTTTTT GGTTTTTTGA AAGTGCGTCT TCAGAGCGCT TTTGGTTTTC AAAAGCGCTC 5280 TGAAGTTCCT ATACTTTCTA GAGAATAGGA ACTTCGGAAT AGGAACTTCA AAGCGTTTCC 5340 GAAAACGAGC GCTTCCGAAA ATGCAACGCG AGCTGCGCAC ATACAGCTCA CTGTTCACGT 5400 CGCACCTATA TCTGCGTGTT GCCTGTATAT ATATATACAT GAGAAGAACG GCATAGTGCG 5460 TGTTTATGCT TAAATGCGTA CTTATATGCG TCTATTTATG TAGGATGAAA GGTAGTCTAG 5520 TACCTCCTGT GATATTATCC CATTCCATGC GGGGTATCGT ATGCTTCCTT CAGCACTACC 5580 CTTTAGCTGT TCTATATGCT GCCACTCCTC AATTGGATTA GTCTCATCCT TCAATGCTAT 5640 CATTTCCTTT GATATTGGAT CATATTAAGA AACCATTATT ATCATGACAT TAACCTATAA 5700 AAATAGGCGT ATCACGAGGC CCTTTCGTCT CGCGCGTTTC GGTGATGACG GTGAAAACCT 5760 CTGACACATG CAGCTCCCGG AGACGGTCAC AGCTTGTCTG TAAGCGGATG CCGGGAGCAG 5820 ACAAGCCCGT CAGGGCGCGT CAGCGGGTGT TGGCGGGTGT CGGGGCTGGC TTAACTATGC 5880 GGCATCAGAG CAGATTGTAC TGAGAGTGCA CCATAGATCA ACGACATTAC TATATATATA 5940 ATATAGGAAG CATTTAATAG ACAGCATCGT AATATATGTG TACTTTGCAG TTATGACGCC 6000 AGATGGCAGT AGTGGAAGAT ATTCTTTATT GAAAAATAGC TTGTCACCTT ACGTACAATC 6060 TTGATCCGGA GCTTTTCTTT TTTTGCCGAT TAAGAATTAA TTCGGTCGAA AAAAGAAAAG 6120 GAGAGGGCCA AGAGGGAGGG CATTGGTGAC TATTGAGCAC GTGAGTATAC GTGATTAAGC 6180 ACACAAAGGC AGCTTGGAGT ATGTCTGTTA TTAATTTCAC AGGTAGTTCT GGTCCATTGG 6240 TGAAAGTTTG CGGCTTGCAG AGCACAGAGG CCGCAGAATG TGCTCTAGAT TCCGATGCTG 6300 ACTTGCTGGG TATTATATGT GTGCCCAATA GAAAGAGAAC AATTGACCCG GTTATTGCAA 6360 GGAAAATTTC AAGTCTTGTA AAAGCATATA AAAATAGTTC AGGCACTCCG AAATACTTGG 6420 TTGGCGTGTT TCGTAATCAA CCTAAGGAGG ATGTTTTGGC TCTGGTCAAT GATTACGGCA 6480 TTGATATCGT CCAACTGCAT GGAGATGAGT CGTGGCAAGA ATACCAAGAG TTCCTCGGTT 6540 TGCCAGTTAT TAAAAGACTC GTATTTCCAA AAGACTGCAA CATACTACTC AGTGCAGCTT 6600 CACAGAAACC TCATTCGTTT ATTCCCTTGT TTGATTCAGA AGCAGGTGGG ACAGGTGAAC 6660 TTTTGGATTG GAACTCGATT TCTGACTGGG TTGGAAGGCA AGAGAGCCCC GAAAGCTTAC 6720 ATTTTATGTT AGCTGGTGGA CTGACGCCAG AAAATGTTGG TGATGCGCTT AGATTAAATG 6780 GCGTTATTGG TGTTGATGTA AGCGGAGGTG TGGAGACAAA TGGTGTAAAA GACTCTAACA 6840 AAATAGCAAA TTTCGTCAAA AATGCTAAGA AATAGGTTAT TACTGAGTAG TATTTATTTA 6900 AGTATTGTTT GTGCACTTGC CGATCTATGC GGTGTGAAAT ACCGCACAGA TGCGTAAGGA 6960 GAAAATACCG CATCAGGAAA TTGTAAACGT TAATATTTTG TTAAAATTCG CGTTAAATTT 7020 TTGTTAAATC AGCTCATTTT TTAACCAATA GGCCGAAATC GGCAAAATCC CTTATAAATC 7080 AAAAGAATAG ACCGAGATAG GGTTGAGTGT TGTTCCAGTT TGGAACAAGA GTCCACTATT 7140 AAAGAACGTG GACTCCAACG TCAAAGGGCG AAAAACCGTC TATCAGGGCG ATGGCCCACT 7200 ACGTGAACCA TCACCCTAAT CAAGTTTTTT GGGGTCGAGG TGCCGTAAAG CACTAAATCG 7260 GAACCCTAAA GGGAGCCCCC GATTTAGAGC TTGACGGGGA AAGCCGGCGA ACGTGGCGAG 7320 AAAGGAAGGG AAGAAAGCGA AAGGAGCGGG CGCTAGGGCG CTGGCAAGTG TAGCGGTCAC 7380 GCTGCGCGTA ACCACCACAC CCGCCGCGCT TAATGCGCCG CTACAGGGCG CGTCGCGCCA 7440 TTCGCCATTC AGGCTGCGCA ACTGTTGGGA AGGGCGATCG GTGCGGGCCT CTTCGCTATT 7500 ACGCCAGCTG GCGAAAGGGG GATGTGCTGC AAGGCGATTA AGTTGGGTAA CGCCAGGGTT 7560 TTCCCAGTCA CGACGTTGTA AAACGACGGC CAGTCGTCCA AGCTTTCGCG AGCTCGAGAT 7620 CCCGAGCTTT GCAAATTAAA GCCTTCGAGC GTCCCAAAAC CTTCTCAAGC AAGGTTTTCA 7680 GTATAATGTT ACATGCGTAC ACGCGTCTGT ACAGAAAAAA AAGAAAAATT TGAAATATAA 7740 ATAACGTTCT TAATACTAAC ATAACTATAA AAAAATAAAT AGGGACCTAG ACTTCAGGTT 7800 GTCTAACTCC TTCCTTTTCG GTTAGAGCGG ATGTGGGGGG AGGGCGTGAA TGTAAGCGTG 7860 ACATAACTAA TTACATGATA TCGACAAAGG AAAAGGGGCC TGTTTACTCA CAGGCTTTTT 7920 TCAAGTAGGT AATTAAGTCG TTTCTGTCTT TTTCCTTCTT CAACCCACCA AAGGCCATCT 7980 TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT TTTTTTTTTT CATAGAAATA ATACAGAAGT 8100 AGATGTTGAA TTAGATTAAA CTGAAGATAT ATAATTTATT GGAAAATACA TAGAGCTTTT 8160 TGTTGATGCG CTTAAGCGAT CAATTCAACA ACACCACCAG CAGCTCTGAT TTTTTCTTCA 8220 GCCAACTTGG AGACGAATCT AGCTTTGACG ATAACTGGAA CATTTGGGAT TCTACCCTTA 8280 CCCAAGATCT TACCGTAACC GGCTGCCAAA GTGTCAATAA CTGGAGCAGT TTCCTTAGAA 8340 GCAGATTTCA AGTATTGGTC TCTCTTGTCT TCTGGGATCA ATGTCCACAA TTTGTCCAAG 8400 TTCAAGACTG GCTTCCAGAA ATGAGCTTGT TGCTTGTGGA AGTATCTCAT ACCAANCCTT 8460 ACCGAAATAA CCTGGATGGT ATTTATCCAT GTTAATTCTG TGGTGATGTT GACCACCGGC 8520 CATACCTCTA CCACCGGGGT GCTTTCTGTG CTTACCGATA CGACCTTTAC CGGCTGAGAC 8580 GTGACCTCTG TGCTTTCTAG TCTTAGTGAA TCTGGAAGGC ATTCTTGATT AGTTGGATGA 8640 TTGTTCTGGG ATTTAATGCA AAAAAATCAC TAAGAAGGAA AAAAATCAAC GGAGAAAGCA 8700 AACGCCATCT TAAATATACG GGATACAGAT GAAAGGTTTG AACCTATCTG GGAAAATACG 8760 CATTAAACAA GCGAAAAACT GCGAGGAAAA TTGTTTGCGT CTCTGCGGGC TATTCACGCG 8820 CCAGAGGAAA ATAGGAAAAA TAACAGGGCA TTAGAAAAAT AATTTTGATT TTGGTAATGT 8880 GTGGGTCCCT GGTGTACAGA TGTTACATTG GTTACAGTAC TCTTGTTTTT GCTGTGTTTT 8940 TCGATGAATC TCCAAAATGG TTGTTAGCAC ATGGAAGAGT CACCGATGCT AAGTTATCTC 9000 TATGTAAGCT ACGTGGCGTG ACTTTTGATG AAGCCGCACA AGAGATACAG GATTGGCAAC 9060 TGCAAATAGA ATCTGGGGAT CTAGATATCC TTTTGTTGTT TCCGGGTGTA CAATATGGAC 9120 TTCCTCTTTT CTGGCAACCA AACCCATACA TCGGGATTCC TATAATACCT TCGTTGGTCT 9180 CCCTAACATG TAGGTGGCGG AGGGGAGATA TACAATAGAA CAGATACCAG ACAAGACATA 9240 ATGGGCTAAA CAAGACTACA CCAATTACAC TGCCTCATTG ATGGTGGTAC ATAACGAACT 9300 AATACTGTAG CCCTAGACTT GATAGCCATC ATCATATCGA AGTTTCACTA CCCTTTTTCC 9360 ATTTGCCATC TATTGAAGTA ATAATAGGCG CATGCAACTT CTTTTCTTTT TTTTTCTTTT 9420 CTCTCTCCCC CGTTGTTGTC TCACCATATC CGCAATGACA AAAAAAATGA TGGAAGACAC 9480 TAAAGGAAAA AATTAACGAC AAAGACAGCA CCAACAGATG TCGTTGTTCC AGAGCTGATG 9540 AGGGGTATCT TCGAACACAC GAAACTTTTT CCTTCCTTCA TTCACGCACA CTACTCTCTA 9600 ATGAGCAACG GTATACGGCC TTCCTTCCAG TTACTTGAAT TTGAAATAAA AAAAGTTTGC 9660 CGCTTTGCTA TCAAGTATAA ATAGACCTGC AATTATTAAT CTTTTGTTTC CTCGTCATTG 9720 TTCTCGTTCC CTTTCTTCCT TGTTTCTTTT TCTGCACAAT ATTTCAAGCT ATACCAAGCA 9780 TACAATCAAC TCCAAGCTTG AAGCAAGCCT CCTGAAAGAT GAAGCTACTG TCTTCTATCG 9840 AACAAGCATG CGATATTTGC CGACTTAAAA AGCTCAAGTG CTCCAAAGAA AAACCGAAGT 9900 GCGCCAAGTG TCTGAAGAAC AACTGGGAGT GTCGCTACTC TCCCAAAACC AAAAGGTCTC 9960 CGCTGACTAG GGCACATCTG ACAGAAGTGG AATCAAGGCT AGAAAGACTG GAACAGCTAT 10020 TTCTACTGAT TTTTCCTCGA GAAGACCTTG ACATGATTTT GAAAATGGAT TCTTTACAGG 10080 ATATAAAAGC ATTGTTAACA GGATTATTTG TACAAGATAA TGTGAATAAA GATGCCGTCA 10140 CAGATAGATT GGCTTCAGTG GAGACTGATA TGCCTCTAAC ATTGAGACAG CATAGAATAA 10200 GTGCGACATC ATCATCGGAA GAGAGTAGTA ACAAAGGTCA AAGACAGTTG ACTGTATCGC 10260 CGGAATTGCA ATACCCAGCT TTGACTCA 10288 (2) INFORMATION FOR SEQ ID NO: 29: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7625 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: circular (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "plasmid" (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29: GCTTGCATGC AACTTCTTTT CTTTTTTTTT CTTTTCTCTC TCCCCCGTTG TTGTCTCACC 60 ATATCCGCAA TGACAAAAAA AATGATGGAA GACACTAAAG GAAAAAATTA ACGACAAAGA 120 CAGCACCAAC AGATGTCGTT GTTCCAGAGC TGATGAGGGG TATCTTCGAA CACACGAAAC 180 TTTTTCCTTC CTTCATTCAC GCACACTACT CTCTAATGAG CAACGGTATA CGGCCTTCCT 240 TCCAGTTACT TGAATTTGAA ATAAAAAAAG TTTGCCGCTT TGCTATCAAG TATAAATAGA 300 CCTGCAATTA TTAATCTTTT GTTTCCTCGT CATTGTTCTC GTTCCCTTTC TTCCTTGTTT 360 CTTTTTCTGC ACAATATTTC AAGCTATACC AAGCATACAA TCAACTCCAA GCTTTGCAAA 420 GATGGATAAA GCGGAATTAA TTCCCGAGCC TCCAAAAAAG AAGAGAAAGG TCGAATTGGG 480 TACCGCCGCC AATTTTAATC AAAGTGGGAA TATTGCTGAT AGCTCATTGT CCTTCACTTT 540 CACTAACAGT AGCAACGGTC CGAACCTCAT AACAACTCAA ACAAATTCTC AAGCGCTTTC 600 ACAACCAATT GCCTCCTCTA ACGTTCATGA TAACTTCATG AATAATGAAA TCACGGCTAG 660 TAAAATTGAT GATGGTAATA ATTCAAAACC ACTGTCACCT GGTTGGACGG ACCAAACTGC 720 GTATAACGCG TTTGGAATCA CTACAGGGAT GTTTAATACC ACTACAATGG ATGATGTATA 780 TAACTATCTA TTCGATGATG AAGATACCCC ACCAAACCCA AAAAAAGAGA TCGAATTCCC 840 GGGGATCCGC TCCTCACTCT CCAAGTTCAC CAAGAAGAAG AACAAGAACT ACGACGAAGC 900 ACATATGCCA TCAATTTCCG GATCTCAAGG AACTCTTGAC AACATTGATG TGATTGAGTT 960 GAAGCAAGAG CTCAAAGAAC GCGATAGTGC ACTTTACGAA GTCCGCCTTG ACAATCTGGA 1020 TCGTGCCCGC GAAGTTGATG TTCTGAGGGA GACAGTGAAC AAGTTGAAAA CCGAGAACAA 1080 GCAATTAAAG AAAGAAGTGG ACAAACTCAC CAACGGTCCA GCCACTCGTG CTTCTTCCCG 1140 CGCCTCAATT CCAGTTATCT ACGACGATGA GCATGTCTAT GATGCAGCGT GTAGCAGTAC 1200 ATCAGCTAGT CAATCTTCGA AACGATCCTC TGGCTGCAAC TCAATCAAGG TTACTGTAAA 1260 CGTGGACATC GCTGGAGAAA TCAGTTCGAT CGTTAACCCG GACAAAGAGA TAATCGTAGG 1320 ATATCTTGCC ATGTCAACCA GTCAGTCATG CTGGAAAGAC ATTGATGTTT CTATTCTAGG 1380 ACTATTTGAA GTCTACCTAT CCAGAATTGA TGTGGAGCAT CAACTTGGAA TCGATGCTCG 1440 TGATTCTATC CTTGGCTATC AAATTGGTGA ACTTCGACGC GTCATTGGAG ACTCCACAAC 1500 CATGATAACC AGCCATCCAA CTGACATTCT TACTTCCTCA ACTACAATCC GAATGTTCAT 1560 GCACGGTGCC GCACAGAGTC GCGTAGACAG TCTGGTCCTT GATATGCTTC TTCCAAAGCA 1620 AATGATTCTC CAACTCGTCA AGTCAATTTT GACAGAGAGA CGTCTGGTGT TAGCTGGAGC 1680 AACTGGAATT GGAAAGAGCA AACTGGCGAA GACCCTGGCT GCTTATGTAT CTATTCGAAC 1740 AAATCAATCC GAAGATAGTA TTGTTAATAT CAGCATTCCT GAAAACAATA AAGAAGAATT 1800 GCTTCAAGTG GAACGACGCC TGGAAAAGAT CTATGAATCG TAGATACTGA AAAACCCCGC 1860 AAGTTCACTT CAACTGTGCA TCGTGCACCA TCTCAATTTC TTTCATTTAT ACATCGTTTT 1920 GCCTTCTTTT ATGTAACTAT ACTCCTCTAA GTTTCAATCT TGGCCATGTA ACCTCTGATC 1980 TATAGAATTT TTTAAATGAC TAGAATTAAT GCCCATCTTT TTTTTGGACC TAAATTCTTC 2040 ATGAAAATAT ATTACGAGGG CTTATTCAGA AGCTTTGGAC TTCTTCGCCA GAGGTTTGGT 2100 CAAGTCTCCA ATCAAGGTTG TCGGCTTGTC TACCTTGCCA GAAATTTACG AAAAGATGGA 2160 AAAGGGTCAA ATCGTTGGTA GATACGTTGT TGACACTTCT AAATAAGCGA ATTTCTTATG 2220 ATTTATGATT TTTATTATTA AATAAGTTAT AAAAAAAATA AGTGTATACA AATTTTAAAG 2280 TGACTCTTAG GTTTTAAAAC GAAAATTCTT GTTCTTGAGT AACTCTTTCC TGTAGGTCAG 2340 GTTGCTTTCT CAGGTATAGC ATGAGGTCGC TCTTATTGAC CACACCTCTA CCGGCATGCC 2400 CGAAATTCCC CTACCCTATG AACATATTCC ATTTTGTAAT TTCGTGTCGT TTCTATTATG 2460 AATTTCATTT ATAAAGTTTA TGTACAAATA TCATAAAAAA AGAGAATCTT TTTAAGCAAG 2520 GATTTTCTTA ACTTCTTCGG CGACAGCATC ACCGACTTCG GTGGTACTGT TGGAACCACC 2580 TAAATCACCA GTTCTGATAC CTGCATCCAA AACCTTTTTA ACTGCATCTT CAATGGCCTT 2640 ACCTTCTTCA GGCAAGTTCA ATGACAATTT CAACATCATT GCAGCAGACA AGATAGTGGC 2700 GATAGGGTCA ACCTTATTCT TTGGCAAATC TGGAGCAGAA CCGTGGCATG GTTCGTACAA 2760 ACCAAATGCG GTGTTCTTGT CTGGCAAAGA GGCCAAGGAC GCAGATGGCA ACAAACCCAA 2820 GGAACCTGGG ATAACGGAGG CTTCATCGGA GATGATATCA CCAAACATGT TGCTGGTGAT 2880 TATAATACCA TTTAGGTGGG TTGGGTTCTT AACTAGGATC ATGGCGGCAG AATCAATCAA 2940 TTGATGTTGA ACCTTCAATG TAGGAAATTC GTTCTTGATG GTTTCCTCCA CAGTTTTTCT 3000 CCATAATCTT GAAGAGGCCA AAACATTAGC TTTATCCAAG GACCAAATAG GCAATGGTGG 3060 CTCATGTTGT AGGGCCATGA AAGCGGCCAT TCTTGTGATT CTTTGCACTT CTGGAACGGT 3120 GTATTGTTCA CTATCCCAAG CGACACCATC ACCATCGTCT TCCTTTCTCT TACCAAAGTA 3180 AATACCTCCC ACTAATTCTC TGACAACAAC GAAGTCAGTA CCTTTAGCAA ATTGTGGCTT 3240 GATTGGAGAT AAGTCTAAAA GAGAGTCGGA TGCAAAGTTA CATGGTCTTA AGTTGGCGTA 3300 CAATTGAAGT TCTTTACGGA TTTTTAGTAA ACCTTGTTCA GGTCTAACAC TACCTGTACC 3360 CCATTTAGGA CCACCCACAG CACCTAACAA AACGGCATCA ACCTTCTTGG AGGCTTCCAG 3420 CGCCTCATCT GGAAGTGGGA CACCTGTAGC ATCGATAGCA GCACCACCAA TTAAATGATT 3480 TTCGAAATCG AACTTGACAT TGGAACGAAC ATCAGAAATA GCTTTAAGAA CCTTAATGGC 3540 TTCGGCTGTG ATTTCTTGAC CAACGTGGTC ACCTGGCAAA ACGACGATCT TCTTAGGGGC 3600 AGACATTAGA ATGGTATATC CTTGAAATAT ATATATATAT TGCTGAAATG TAAAAGGTAA 3660 GAAAAGTTAG AAAGTAAGAC GATTGCTAAC CACCTATTGG AAAAAACAAT AGGTCCTTAA 3720 ATAATATTGT CAACTTCAAG TATTGTGATG CAAGCATTTA GTCATGAACG CTTCTCTATT 3780 CTATATGAAA AGCCGGTTCC GGCCTCTCAC CTTTCCTTTT TCTCCCAATT TTTCAGTTGA 3840 AAAAGGTATA TGCGTCAGGC GACCTCTGAA ATTAACAAAA AATTTCCAGT CATCGAATTT 3900 GATTCTGTGC GATAGCGCCC CTGTGTGTTC TCGTTATGTT GAGGAAAAAA ATAATGGTTG 3960 CTAAGAGATT CGAACTCTTG CATCTTACGA TACCTGAGTA TTCCCACAGT TGGGGATCTC 4020 GACTCTAGCT AGAGGATCAA TTCGTAATCA TGGTCATAGC TGTTTCCTGT GTGAAATTGT 4080 TATCCGCTCA CAATTCCACA CAACATACGA GCCGGAAGCA TAAAGTGTAA AGCCTGGGGT 4140 GCCTAATGAG TGAGGTAACT CACATTAATT GCGTTGCGCT CACTGCCCGC TTTCCAGTCG 4200 GGAAACCTGT CGTGCCAGCT GGATTAATGA ATCGGCCAAC GCGCGGGGAG AGGCGGTTTG 4260 CGTATTGGGC GCTCTTCCGC TTCCTCGCTC ACTGACTCGC TGCGCTCGGT CGTTCGGCTG 4320 CGGCGAGCGG TATCAGCTCA CTCAAAGGCG GTAATACGGT TATCCACAGA ATCAGGGGAT 4380 AACGCAGGAA AGAACATGTG AGCAAAAGGC CAGCAAAAGG CCAGGAACCG TAAAAAGGCC 4440 GCGTTGCTGG CGTTTTTCCA TAGGCTCCGC CCCCCTGACG AGCATCACAA AAATCGACGC 4500 TCAAGTCAGA GGTGGCGAAA CCCGACAGGA CTATAAAGAT ACCAGGCGTT TCCCCCTGGA 4560 AGCTCCCTCG TGCGCTCTCC TGTTCCGACC CTGCCGCTTA CCGGATACCT GTCCGCCTTT 4620 CTCCCTTCGG GAAGCGTGGC GCTTTCTCAT AGCTCACGCT GTAGGTATCT CAGTTCGGTG 4680 TAGGTCGTTC GCTCCAAGCT GGGCTGTGTG CACGAACCCC CCGTTCAGCC CGACCGCTGC 4740 GCCTTATCCG GTAACTATCG TCTTGAGTCC AACCCGGTAA GACACGACTT ATCGCCACTG 4800 GCAGCAGCCA CTGGTAACAG GATTAGCAGA GCGAGGTATG TAGGCGGTGC TACAGAGTTC 4860 TTGAAGTGGT GGCCTAACTA CGGCTACACT AGAAGGACAG TATTTGGTAT CTGCGCTCTG 4920 CTGAAGCCAG TTACCTTCGG AAAAAGAGTT GGTAGCTCTT GATCCGGCAA ACAAACCACC 4980 GCTGGTAGCG GTGGTTTTTT TGTTTGCAAG CAGCAGATTA CGCGCAGAAA AAAAGGATCT 5040 CAAGAAGATC CTTTGATCTT TTCTACGGGG TCTGACGCTC AGTGGAACGA AAACTCACGT 5100 TAAGGGATTT TGGTCATGAG ATTATCAAAA AGGATCTTCA CCTAGATCCT TTTAAATTAA 5160 AAATGAAGTT TTAAATCAAT CTAAAGTATA TATGAGTAAA CTTGGTCTGA CAGTTACCAA 5220 TGCTTAATCA GTGAGGCACC TATCTCAGCG ATCTGTCTAT TTCGTTCATC CATAGTTGCC 5280 TGACTCCCCG TCGTGTAGAT AACTACGATA CGGGAGGGCT TACCATCTGG CCCCAGTGCT 5340 GCAATGATAC CGCGAGACCC ACGCTCACCG GCTCCAGATT TATCAGCAAT AAACCAGCCA 5400 GCCGGAAGGG CCGAGCGCAG AAGTGGTCCT GCAACTTTAT CCGCCTCCAT CCAGTCTATT 5460 AATTGTTGCC GGGAAGCTAG AGTAAGTAGT TCGCCAGTTA ATAGTTTGCG CAACGTTGTT 5520 GCCATTGCTA CAGGCATCGT GGTGTCACGC TCGTCGTTTG GTATGGCTTC ATTCAGCTCC 5580 GGTTCCCAAC GATCAAGGCG AGTTACATGA TCCCCCATGT TGTGCAAAAA AGCGGTTAGC 5640 TCCTTCGGTC CTCCGATCGT TGTCAGAAGT AAGTTGGCCG CAGTGTTATC ACTCATGGTT 5700 ATGGCAGCAC TGCATAATTC TCTTACTGTC ATGCCATCCG TAAGATGCTT TTCTGTGACT 5760 GGTGAGTACT CAACCAAGTC ATTCTGAGAA TAGTGTATGC GGCGACCGAG TTGCTCTTGC 5820 CCGGCGTCAA TACGGGATAA TACCGCGCCA CATAGCAGAA CTTTAAAAGT GCTCATCATT 5880 GGAAAACGTT CTTCGGGGCG AAAACTCTCA AGGATCTTAC CGCTGTTGAG ATCCAGTTCG 5940 ATGTAACCCA CTCGTGCACC CAACTGATCT TCAGCATCTT TTACTTTCAC CAGCGTTTCT 6000 GGGTGAGCAA AAACAGGAAG GCAAAATGCC GCAAAAAAGG GAATAAGGGC GACACGGAAA 6060 TGTTGAATAC TCATACTCTT CCTTTTTCAA TATTATTGAA GCATTTATCA GGGTTATTGT 6120 CTCATGAGCG GATACATATT TGAATGTATT TAGAAAAATA AACAAATAGG GGTTCCGCGC 6180 ACATTTCCCC GAAAAGTGCC ACCTGACGTC TAAGAAACCA TTATTATCAT GACATTAACC 6240 TATAAAAATA GGCGTATCAC GAGGCCCTTT CGTCTCGCGC GTTTCGGTGA TGACGGTGAA 6300 AACCTCTGAC ACATGCAGCT CCCGGAGACG GTCACAGCTT GTCTGTAAGC GGATGCCGGG 6360 AGCAGACAAG CCCGTCAGGG CGCGTCAGCG GGTGTTGGCG GGTGTCGGGG CTGGCTTAAC 6420 TATGCGGCAT CAGAGCAGAT TGTACTGAGA GTGCACCATA ACGCATTTAA GCATAAACAC 6480 GCACTATGCC GTTCTTCTCA TGTATATATA TATACAGGCA ACACGCAGAT ATAGGTGCGA 6540 CGTGAACAGT GAGCTGTATG TGCGCAGCTC GCGTTGCATT TTCGGAAGCG CTCGTTTTCG 6600 GAAACGCTTT GAAGTTCCTA TTCCGAAGTT CCTATTCTCT AGCTAGAAAG TATAGGAACT 6660 TCAGAGCGCT TTTGAAAACC AAAAGCGCTC TGAAGACGCA CTTTCAAAAA ACCAAAAACG 6720 CACCGGACTG TAACGAGCTA CTAAAATATT GCGAATACCG CTTCCACAAA CATTGCTCAA 6780 AAGTATCTCT TTGCTATATA TCTCTGTGCT ATATCCCTAT ATAACCTACC CATCCACCTT 6840 TCGCTCCTTG AACTTGCATC TAAACTCGAC CTCTACATTT TTTATGTTTA TCTCTAGTAT 6900 TACTCTTTAG ACAAAAAAAT TGTAGTAAGA ACTATTCATA GAGTGAATCG AAAACAATAC 6960 GAAAATGTAA ACATTTCCTA TACGTAGTAT ATAGAGACAA AATAGAAGAA ACCGTTCATA 7020 ATTTTCTGAC CAATGAAGAA TCATCAACGC TATCACTTTC TGTTCACAAA GTATGCGCAA 7080 TCCACATCGG TATAGAATAT AATCGGGGAT GCCTTTATCT TGAAAAAATG CACCCGCAGC 7140 TTCGCTAGTA ATCAGTAAAC GCGGGAAGTG GAGTCAGGCT TTTTTTATGG AAGAGAAAAT 7200 AGACACCAAA GTAGCCTTCT TCTAACCTTA ACGGACCTAC AGTGCAAAAA GTTATCAAGA 7260 GACTGCATTA TAGAGCGCAC AAAGGAGAAA AAAAGTAATC TAAGATGCTT TGTTAGAAAA 7320 ATAGCGCTCT CGGGATGCAT TTTTGTAGAA CAAAAAAGAA GTATAGATTC TTTGTTGGTA 7380 AAATAGCGCT CTCGCGTTGC ATTTCTGTTC TGTAAAAATG CAGCTCAGAT TCTTTGTTTG 7440 AAAAATTAGC GCTCTCGCGT TGCATTTTTG TTTTACAAAA ATGAAGCACA GATTCTTCGT 7500 TGGTAAAATA GCGCTTTCGC GTTGCATTTC TGTTCTGTAA AAATGCAGCT CAGATTCTTT 7560 GTTTGAAAAA TTAGCGCTCT CGCGTTGCAT TTTTGTTCTA CAAAATGAAG CACAGATGCT 7620 TCGTT 7625 (2) INFORMATION FOR SEQ ID NO: 30: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9642 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: circular (ii) MOLECULE TYPE: other nucleic acid (A) DESCRIPTION: /desc = "plasmid" (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: ATGACCATGA TTACGCCAAG CTTGTCTTCT TCTAAATTCC CATAAAATCC CGAAACTCCT 60 TCCCTCTATC TTCTTTTTCT TCTCGTTTTC AAATGTTTCT CTCTATCCCA TTCTCTCATC 120 AATTGAGTGG GATGAGGCTA TCTCTGCCTC TCTTCTGAAT CTCTGAACCA TCTTACATTA 180 CACTGTGGAT GACGAGCCCC ACAGGCTCCC TTGCATCAGA TACTGCCATT GGGGATGGCA 240 AAGAAGAGAG AAGGTATTGT GAGGATATAT TTTTCTAAGA AAAAACGTTT GAAGAAAAGA 300 AGATGAAGAA GATCTGCTTG ATTCATTGCA CAAGTTAGAA GTAACAGGGG TCTATATTTC 360 GAAGAACTTA AAGGGAATGC AACTGAACAT AAAATTAAAC AAAGGGATTG AATCCTGCAG 420 TGAGTATTTT CGGTTTTTCA CTGGTTCTCT GTAAAAAGAG TAATGCAAAG GGCAAGTTAA 480 CTTAGGTCGT AAATGTATTG AATTTGCTTA AAATCTGAAG ATCTAGTGGT GAACCGTGGA 540 AGATTATCAA GAGGAGGCTG AAGATCTGTT TAAGAACCAT TAATCAAACT GGTATTCTAT 600 TTTCACTGGT TGTATGTAAA CATTCTATCT TATTCCTTTT ATCACTGTTC TGCACTTTCC 660 TATAAAAAAA GTTGACCGAC CGTACTCTCT GAATTCATTT TTCCCGATCT TACCAACTCC 720 CGATCTATCT CTATCCCTGG TTTTTTCTTC GTGCTCCAAT GGAATTCTTG AGACTTCCAC 780 TATCTTCTCT GGCACCCTCC ACTACGCGTA GGCGTCTCTC GCTTCGTGTA TTCCCGGGAA 840 GCCGGTTCCC GTCTCTCCCG CCGCTGCCGC TGCCGCACAC AGCTTTACAC CTCGTAGAAT 900 CCCCAAAGAG GGGCGTGGCT TGCGGGTGCC AACATCCTCC TGCCGAGGAA GAAGCAGGCA 960 CTCATCACTC GCATCATCAA CCTCGGGATT GGCCAAAGGA CCCAAAGGTA TGTTTCGAAT 1020 GATACTAACA TAACATAGAA CATTTTCAGG AGGACCCTTG GCTAGAACTA GTGGATCCGA 1080 GCTCTCCCAT ATGACGACGT CAAATGTAGA ATTGATACCA ATCTACACGG ATTGGGCCAA 1140 TCGGCACCTT TCGAAGGGCA GCTTATCAAA GTCGATTAGG GATATTTCCA ATGATTTTCG 1200 CGACTATCGA CTGGTTTCTC AGCTTATTAA TGTGATCGTT CCGATCAACG AATTCTCGCC 1260 TGCATTCACG AAACGTTTGG CAAAAATCAC ATCGAACCTG GATGGCCTCG AAACGTGTCT 1320 CGACTACCTG AAAAATCTGG GTCTCGACTG CTCGAAACTC ACCAAAACCG ATATCGACAG 1380 CGGAAACTTG GGTGCAGTTC TCCAGCTGCT CTTCCTGCTC TCCACCTACA AGCAGAAGCT 1440 TCGGCAACTG AAAAAAGATC AGAAGAAATT GGAGCAACTA CCCACATCCA TTATGCCACC 1500 CGCGGTTTCT AAATTACCCT CGCCACGTGT CGCCACGTCA GCAACCGCTT CAGCAACTAA 1560 CCCAAATTCC AACTTTCCAC AAATGTCAAC ATCCAGGCTT CAGACTCCAC AGTCAAGAAT 1620 ATCGAAAATT GATTCATCAA AGATTGGTAT CAAGCCAAAG ACGTCTGGAC TTAAACCACC 1680 CTCATCATCA ACCACTTCAT CAAATAATAC AAATTCATTC CGTCCGTCGA GCCGTTCGAG 1740 TGGCAATAAT AATGTTGGCT CGACGATATC CACATCTGCG AAGAGCTTAG AATCATCATC 1800 AACGTACAGC TCTATTTCGA ATCTAAACCG ACCTACCTCC CAACTCCAAA AACCTTCTAG 1860 ACCACAAACC CAGCTAGTTC GTGTTGCTAC AACTACAAAA ATCGGAAGCT CAAAGCTAGC 1920 CGCTCCGAAA GCCGTGAGCA CCCCAAAACT TGCTTCTGTG AAGACTATTG GAGCAAAACA 1980 AGAGCCCGAT AACAGCGGTG GTGGTGGTGG TGGAATGCTG AAATTAAAGT TATTCAGTAG 2040 CAAAAACCCA TCTTCCTCAT CGAATAGCCC ACAACCTACG AGAAAGGCGG CGGCGGTGCC 2100 TCAACAACAA ACTTTGTCGA AAATCGCTGC CCCAGTGAAA AGTGGCCTGA AGCCGCCGAC 2160 CAGTAAGCTG GGAAGTGCCA CGTCTATGTC GAAGCTTTGT ACGCCAAAAG TTTCCTACCG 2220 TAAAACGGAC GCCCCAATCA TATCTCAACA AGACTCGAAA CGATGCTCAA AGAGCAGTGA 2280 AGAAGAGTCC GGATACGCTG GATTCAACAG CACGTCGCCA ACGTCATCAT CGACGGAAGG 2340 TTCCCTAAGC ATGCATTCCA CATCTTCCAA GAGTTCAACG TCAGACGAAA AGTCTCCGTC 2400 ATCAGACGAT CTTACTCTTA ACGCCTCCAT CGTGACAGCT ATCAGACAGC CGATAGCCGC 2460 AACACCGGTT TCTCCAAATA TTATCAACAA GCCTGTTGAG GAAAAACCAA CACTGGCAGT 2520 GAAAGGAGTG AAAAGCACAG CGAAAAAAGA TCCACCTCCA GCTGTTCCGC CACGTGACAC 2580 CCAGCCAACA ATCGGAGTTG TTAGTCCAAT TATGGCACAT AAGAAGTTGA CAAATGACCC 2640 CGTGATATCT GAAAAACCAG AACCTGAAAA GCTCCAATCA ATGAGCATCG ACACGACGGA 2700 CGTTCCACCG CTTCCACCTC TAAAATCAGT TGTTCCACTT AAAATGACTT CAATCCGACA 2760 ACCACCAACG TACGATGTTC TTCTAAAACA AGGAAAAATC ACATCGCCTG TCAAGTCGTT 2820 TGGATATGAG CAGTCGTCCG CGTCTGAAGA CTCCATTGTG GCTCATGCGT CGGCTCAGGT 2880 GACTCCGCCG ACAAAAACTT CTGGTAATCA TTCGCTGGAG AGAAGGATGG GAAAGAATAA 2940 GACATCAGAA TCCAGCGGCT ACACCTCTGA CGCCGGTGTT GCGATGTGCG CCAAAATGAG 3000 GGAGAAGCTG AAAGAATACG ATGACATGAC TCGTCGAGCA CAGAACGGCT ATCCTGACAA 3060 CTTCGAAGAC AGTTCCTCCT TGTCGTCTGG AATATCCGAT AACAACGAGC TCGACGACAT 3120 ATCCACGGAC GATTTGTCCG GAGTAGACAT GGCAACAGTC GCCTCCAAAC ATAGCGACTA 3180 TTCCCACTTT GTTCGCCATC CCACGTCTTC TTCCTCAAAG CCCCGAGTCC CCAGTCGGTC 3240 CTCCACATCA GTCGATTCTC GATCTCGAGC AGAACAGGAG AATGTGTACA AACTTCTGTC 3300 CCAGTGCCGA ACGAGCCAAC GTGGCGCCGC TGCCACCTCA ACCTTCGGAC AACATTCGCT 3360 AAGATCCCCG GGATACTCAT CCTATTCTCC ACACTTATCA GTGTCAGCTG ATAAGGACAC 3420 AATGTCTATG CACTCACAGA CTAGTCGACG ACCTTCTTCA CAAAAACCAA GCTATTCAGG 3480 CCAATTTCAT TCACTTGATC GTAAATGCCA CCTTCAAGAG TTCACATCCA CCGAGCACAG 3540 AATGGCGGCT CTCTTGAGCC CGAGACGGGT GCCGAACTCG ATGTCGAAAT ATGATTCTTC 3600 AGGATCCTAC TCGGCGCGTT CCCGAGGTGG AAGCTCTACT GGTATCTATG GAGAGACGTT 3660 CCAACTGCAC AGACTATCCG ATGAAAAATC CCCCGCACAT TCTGCCAAAA GTGAGATGGG 3720 ATCCCAACTA TCACTGGCTA GCACGACAGC ATATGGATCT CTCAATGAGA AGTACGAACA 3780 TGCTATTCGG GACATGGCAC GTGACTTGGA GTGTTACAAG AACACTGTCG ACTCACTAAC 3840 CAAGAAACAG GAGAACTATG GAGCATTGTT TGATCTTTTT GAGCAAAAGC TTAGAAAACT 3900 CACTCAACAC ATTGATCGAT CCAACTTGAA GCCTGAAGAG GCAATACGAT TCAGGCAGGA 3960 CATTGCTCAT TTGAGGGATA TTAGCAATCA TCTTGCATCC AACTCAGCTC ATGCTAACGA 4020 AGGCGCTGGT GAGCTTCTTC GTCAACCATC TCTGGAATCA GTTGCATCCC ATCGATCATC 4080 GATGTCATCG TCGTCGAAAA GCAGCAAGCA GGAGAAGATC AGCTTGAGCT CGTTTGGCAA 4140 GAACAAGAAG AGCTGGATCC GCTCCTCACT CTCCAAGTTC ACCAAGAAGA AGAACAAGAA 4200 CTACGACGAA GCACATATGC CATCAATTTC CGGATCTCAA GGAACTCTTG ACAACATTGA 4260 TGTGATTGAG TTGAAGCAAG AGCTCAAAGA ACGCGATAGT GCACTTTACG AAGTCCGCCT 4320 TGACAATCTG GATCGTGCCC GCGAAGTTGA TGTTCTGAGG GAGACAGTGA ACAAGTTGAA 4380 AACCGAGAAC AAGCAATTAA AGAAAGAAGT GGACAAACTC ACCAACGGTC CAGCCACTCG 4440 TGCTTCTTCC CGCGCCTCAA TTCCAGTTAT CTACGACGAT GAGCATGTCT ATGATGCAGC 4500 GTGTAGCAGT ACATCAGCTA GTCAATCTTC GAAACGATCC TCTGGCTGCA ACTCAATCAA 4560 GGTTACTGTA AACGTGGACA TCGCTGGAGA AATCAGTTCG ATCGTTAACC CGGACAAAGA 4620 GATAATCGTA GGATATCTTG CCATGTCAAC CAGTCAGTCA TGCTGGAAAG ACATTGATGT 4680 TTCTATTCTA GGACTATTTG AAGTCTACCT ATCCAGAATT GATGTGGAGC ATCAACTTGG 4740 AATCGATGCT CGTGATTCTA TCCTTGGCTA TCAAATTGGT GAACTTCGAC GCGTCATTGG 4800 AGACTCCACA ACCATGATAA CCAGCCATCC AACTGACATT CTTACTTCCT CAACTACAAT 4860 CCGAATGTTC ATGCACGGTG CCGCACAGAG TCGCGTAGAC AGTCTGGTCC TTGATATGCT 4920 TCTTCCAAAG CAAATGATTC TCCAACTCGT CAAGTCAATT TTGACAGAGA GACGTCTGGT 4980 GTTAGCTGGA GCAACTGGAA TTGGAAAGAG CAAACTGGCG AAGACCCTGG CTGCTTATGT 5040 ATCTATTCGA ACAAATCAAT CCGAAGATAG TATTGTTAAT ATCAGCATTC CTGAAAACAA 5100 TAAAGAAGAA TTGCTTCAAG TGGAACGACG CCTGGAAAAG ATCTTGAGAA GCAAAGAATC 5160 ATGCATCGTA ATTCTAGATA ATATCCCAAA GAATCGAATT GCATTTGTTG TATCCGTTTT 5220 TGCAAATGTC CCACTTCAAA ACAACGAAGG TCCATTTGTA GTATGCACAG TCAACCGATA 5280 TCAAATCCCT GAGCTTCAAA TTCACCACAA TTTCAAAATG TCAGTAATGT CGAATCGTCT 5340 CGAAGGATTC ATCCTACGTT ACCTCCGACG ACGGGCGGTA GAGGATGAGT ATCGTCTAAC 5400 TGTACAGATG CCATCAGAGC TCTTCAAAAT CATTGACTTC TTCCCAATAG CTCTTCAGGC 5460 CGTCAATAAT TTTATTGAGA AAACGAATTC TGTTGATGTG ACAGTTGGTC CAAGAGCATG 5520 CTTGAACTGT CCTCTAACTG TCGATGGATC CCGTGAATGG TTCATTCGAT TGTGGAATGA 5580 GAACTTCATT CCATATTTGG AACGTGTTGC TAGAGATGGC AAAAAAACCT TCGGTCGCTG 5640 CACTTCCTTC GAGGATCCCA CCGACATCGT CTCTAAAAAA TGGCCGTGGT TCGATGGTGA 5700 AAACCCGGAG AATGTGCTCA AACGTCTTCA ACTCCAAGAC CTCGTCCCGT CACCTGCCAA 5760 CTCATCCCGA CAACACTTCA ATCCCCTCGA GTCGTTGATC CAATTGCATG CTACCAAGCA 5820 TCAGACCATC GACAACATTT GAACAGAAGA CTCTAATCTT CTCTCGCCTC TCCCCCGCTT 5880 TCCTTATCTT CGTACCGGTA CCATGGTATT GATATCTGAG CTCCGCATCG GCCGCTGTCA 5940 TCAGATCGCC ATCTCGCGCC CGTGCCTCTG ACTTCTAAGT CCAATTACTC TTCAACATCC 6000 CTACATGCTC TTTCTCCCTG TGCTCCCACC CCCTATTTTT GTTATTATCA AAAAAACTTC 6060 TTCTTAATTT CTTTGTTTTT TAGCTTCTTT TAAGTCACCT CTAACAATGA AATTGTGTAG 6120 ATTCAAAAAT AGAATTAATT CGTAATAAAA AGTCGAAAAA AATTGTGCTC CCTCCCCCCA 6180 TTAATAATAA TTCTATCCCA AAATCTACAC AATGTTCTGT GTACACTTCT TATGTTTTTT 6240 TTACTTCTGA TAAATTTTTT TTGAAACATC ATAGAAAAAA CCGCACACAA AATACCTTAT 6300 CATATGTTAC GTTTCAGTTT ATGACCGCAA TTTTTATTTC TTCGCACGTC TGGGCCTCTC 6360 ATGACGTCAA ATCATGCTCA TCGTGAAAAA GTTTTGGAGT ATTTTTGGAA TTTTTCAATC 6420 AAGTGAAAGT TTATGAAATT AATTTTCCTG CTTTTGCTTT TTGGGGGTTT CCCCTATTGT 6480 TTGTCAAGAG TTTCGAGGAC GGCGTTTTTC TTGCTAAAAT CACAAGTATT GATGAGCACG 6540 ATGCAAGAAA GATCGGAAGA AGGTTTGGGT TTGAGGCTCA GTGGAAGGTG AGTAGAAGTT 6600 GATAATTTGA AAGTGGAGTA GTGTCTATGG GGTTTTTGCC TTAAATGACA GAATACATTC 6660 CCAATATACC AAACATAACT GTTTAAAATT AAACATTTTT CTAAATTTTA TATGATTTCT 6720 TTTAAATTTG CAAAAATTAC TTAAATTTGA ATTCCCGCGC AAATGAGTGA CTTCATTTTC 6780 TGCATTATTG TGTTTTCCGG CTATATTAAT AGGTATTTGT TTGTGTTTTT CTTTATTTTA 6840 TGATTCGAAC TCCAATTTGT AAATTTTCGA ACATATTTCC CTAAAGAAAA AATATGATTA 6900 ATCTGGAAAA ATTGGAAAAT TATTTTTCAA ATAAAAAACA AAGAAAAAAA TGAAGAAAAA 6960 CCTATTAGTT TGGCCATAAA ACGCAAAAAT GTCGAAAATG ACGTCACTCA TCTGCGCGGG 7020 AAATCAAGAA TAATTCGGCC TTTTTTATTT TTTTGGAAAA TCGTAAAACA TTTAGAAAAA 7080 TTTTTTAATA GTTATAGTGG GACTGTATTC TGTCATTTAG GGCAAAAGCC AGAGACGCTA 7140 CTCCACCGTT GGGGGATCCA CTAGTCGGCC GTACGGGCCC TTTCGTCTCG CGCGTTTCGG 7200 TGATGACGGT GAAAACCTCT GACACATGCA GCTCCCGGAG ACGGTCACAG CTTGTCTGTA 7260 AGCGGATGCC GGGAGCAGAC AAGCCCGTCA GGGCGCGTCA GCGGGTGTTG GCGGGTGTCG 7320 GGGCTGGCTT AACTATGCGG CATCAGAGCA GATTGTACTG AGAGTGCACC ATATGCGGTG 7380 TGAAATACCG CACAGATGCG TAAGGAGAAA ATACCGCATC AGGCGGCCTT AAGGGCCTCG 7440 TGATACGCCT ATTTTTATAG GTTAATGTCA TGATAATAAT GGTTTCTTAG ACGTCAGGTG 7500 GCACTTTTCG GGGAAATGTG CGCGGAACCC CTATTTGTTT ATTTTTCTAA ATACATTCAA 7560 ATATGTATCC GCTCATGAGA CAATAACCCT GATAAATGCT TCAATAATAT TGAAAAAGGA 7620 AGAGTATGAG TATTCAACAT TTCCGTGTCG CCCTTATTCC CTTTTTTGCG GCATTTTGCC 7680 TTCCTGTTTT TGCTCACCCA GAAACGCTGG TGAAAGTAAA AGATGCTGAA GATCAGTTGG 7740 GTGCACGAGT GGGTTACATC GAACTGGATC TCAACAGCGG TAAGATCCTT GAGAGTTTTC 7800 GCCCCGAAGA ACGTTTTCCA ATGATGAGCA CTTTTAAAGT TCTGCTATGT GGCGCGGTAT 7860 TATCCCGTAT TGACGCCGGG CAAGAGCAAC TCGGTCGCCG CATACACTAT TCTCAGAATG 7920 ACTTGGTTGA GTACTCACCA GTCACAGAAA AGCATCTTAC GGATGGCATG ACAGTAAGAG 7980 AATTATGCAG TGCTGCCATA ACCATGAGTG ATAACACTGC GGCCAACTTA CTTCTGACAA 8040 CGATCGGAGG ACCGAAGGAG CTAACCGCTT TTTTGCACAA CATGGGGGAT CATGTAACTC 8100 GCCTTGATCG TTGGGAACCG GAGCTGAATG AAGCCATACC AAACGACGAG CGTGACACCA 8160 CGATGCCTGT AGCAATGGCA ACAACGTTGC GCAAACTATT AACTGGCGAA CTACTTACTC 8220 TAGCTTCCCG GCAACAATTA ATAGACTGGA TGGAGGCGGA TAAAGTTGCA GGACCACTTC 8280 TGCGCTCGGC CCTTCCGGCT GGCTGGTTTA TTGCTGATAA ATCTGGAGCC GGTGAGCGTG 8340 GGTCTCGCGG TATCATTGCA GCACTGGGGC CAGATGGTAA GCCCTCCCGT ATCGTAGTTA 8400 TCTACACGAC GGGGAGTCAG GCAACTATGG ATGAACGAAA TAGACAGATC GCTGAGATAG 8460 GTGCCTCACT GATTAAGCAT TGGTAACTGT CAGACCAAGT TTACTCATAT ATACTTTAGA 8520 TTGATTTAAA ACTTCATTTT TAATTTAAAA GGATCTAGGT GAAGATCCTT TTTGATAATC 8580 TCATGACCAA AATCCCTTAA CGTGAGTTTT CGTTCCACTG AGCGTCAGAC CCCGTAGAAA 8640 AGATCAAAGG ATCTTCTTGA GATCCTTTTT TTCTGCGCGT AATCTGCTGC TTGCAAACAA 8700 AAAAACCACC GCTACCAGCG GTGGTTTGTT TGCCGGATCA AGAGCTACCA ACTCTTTTTC 8760 CGAAGGTAAC TGGCTTCAGC AGAGCGCAGA TACCAAATAC TGTCCTTCTA GTGTAGCCGT 8820 AGTTAGGCCA CCACTTCAAG AACTCTGTAG CACCGCCTAC ATACCTCGCT CTGCTAATCC 8880 TGTTACCAGT GGCTGCTGCC AGTGGCGATA AGTCGTGTCT TACCGGGTTG GACTCAAGAC 8940 GATAGTTACC GGATAAGGCG CAGCGGTCGG GCTGAACGGG GGGTTCGTGC ACACAGCCCA 9000 GCTTGGAGCG AACGACCTAC ACCGAACTGA GATACCTACA GCGTGAGCAT TGAGAAAGCG 9060 CCACGCTTCC CGAAGGGAGA AAGGCGGACA GGTATCCGGT AAGCGGCAGG GTCGGAACAG 9120 GAGAGCGCAC GAGGGAGCTT CCAGGGGGAA ACGCCTGGTA TCTTTATAGT CCTGTCGGGT 9180 TTCGCCACCT CTGACTTGAG CGTCGATTTT TGTGATGCTC GTCAGGGGGG CGGAGCCTAT 9240 GGAAAAACGC CAGCAACGCG GCCTTTTTAC GGTTCCTGGC CTTTTGCTGG CCTTTTGCTC 9300 ACATGTTCTT TCCTGCGTTA TCCCCTGATT CTGTGGATAA CCGTATTACC GCCTTTGAGT 9360 GAGCTGATAC CGCTCGCCGC AGCCGAACGA CCGAGCGCAG CGAGTCAGTG AGCGAGGAAG 9420 CGGAAGAGCG CCCAATACGC AAACCGCCTC TCCCCGCGCG TTGGCCGATT CATTAATGCA 9480 GCTGGCACGA CAGGTTTCCC GACTGGAAAG CGGGCAGTGA GCGCAACGCA ATTAATGTGA 9540 GTTAGCTCAC TCATTAGGCA CCCCAGGCTT TACACTTTAT GCTTCCGGCT CGTATGTTGT 9600 GTGGAATTGT GAGCGGATAA CAATTTCACA CAGGAAACAG CT 9642 (2) INFORMATION FOR SEQ ID NO: 31: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 110 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: Met Thr Thr Ser Asn Val Glu Leu He Pro He Tyr Thr Asp Trp Ala 1 5 10 15 Asn Arg His Leu Ser Lys Gly Ser Leu Ser Lys Ser He Arg Asp He 20 25 30 Ser Asn Asp Phe Arg Asp Tyr Arg Leu Val Ser Gin Leu He Asn Val 35 40 45 He Val Pro He Asn Glu Phe Ser Pro Ala Phe Thr Lys Arg Leu Ala 50 55 60 Lys He Thr Ser Asn Leu Asp Gly Leu Glu Thr Cys Leu Asp Tyr Leu 65 70 75 80 Lys Asn Leu Gly Leu Asp Cys Ser Lys Leu Thr Lys Thr Asp He Asp 85 90 95 Ser Gly Asn Leu Gly Ala Val Leu Gin Leu Leu Phe Leu Leu 100 105 110 (2) INFORMATION FOR SEQ ID NO: 32: (i) SEQUENCE CHARACTERISTICS ' : (A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32: Lys Gin Lys Leu Arg Gin Leu Lys Lys Asp Gin Lys Lys Leu Glu Gin 1 5 10 15 Leu Pro Thr Ser 20 (2) INFORMATION FOR SEQ ID NO: 33: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33: Asp Pro Pro Pro Ala Val Pro Pro Arg 1 5 (2) INFORMATION FOR SEQ ID NO: 34: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34: Asp Val Pro Pro Leu Pro Pro Leu Lys 1 5 (2) INFORMATION FOR SEQ ID NO: 35: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35: Lys Lys Lys Asn Lys 1 5 (2) INFORMATION FOR SEQ ID NO: 36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: Lys Thr Glu Asn Lys Gin Leu Lys Lys Glu Val Asp Lys Leu Thr Asn 1 5 10 15 Gly Pro Ala Thr 20 (2) INFORMATION FOR SEQ ID NO: 37: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37: Gly Ala Thr Gly He Gly Lys Ser 1 5 (2) INFORMATION FOR SEQ ID NO: 38: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 58 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 38: Met Ser Glu Glu Pro Thr Pro Val Ser Gly Asn Asp Lys Gin Leu Leu 1 5 10 15 Asn Lys Ala Trp Glu He Thr Gin Lys Lys Thr Phe Thr Ala Trp Cys 20 25 30 Asn Ser His Leu Arg Lys Leu Gly Ser Ser He Glu Gin He Asp Thr 35 40 45 Asp Phe Thr Asp Gly He Lys Leu Ala Gin 50 55 (2) INFORMATION FOR SEQ ID NO: 39: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 44 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39: Met Thr Thr Ser Asn Val Glu Leu He Pro He Tyr Thr Asp Trp Ala 1 5 10 15 Asn Arg His Leu Ser Lys Gly Ser Leu Ser Lys Ser He Arg Asp He 20 25 30 Ser Asn Asp Phe Arg Asp Tyr Arg Leu Val Ser Gin 35 40 (2) INFORMATION FOR SEQ ID NO: 40: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40: Phe Glu Arg Ser Arg He Lys Ala Leu Ala Asp Glu Arg Glu Val Val 1 5 10 15 Gin Lys Lys Thr Phe Thr Lys Trp Val Asn Ser His Leu Ala Arg Val 20 25 30 Ser Cys Arg He Thr Asp Leu Tyr Lys Asp Leu Arg Asp Gly Arg Met 35 40 45 Leu He Lys 50 (2) INFORMATION FOR SEQ ID NO: 41: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 59 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41: Leu Leu Glu Val He Ser Asn Asp Pro Val Phe Lys Val Asn Lys Thr 1 5 10 15 Pro Lys Leu Arg Arg He His Asn He Gin Asn Val Gly Leu Cys Leu 20 25 30 Lys His He Glu Ser His Gly Val Lys Leu Val Gly He Gly Ala Glu 35 40 45 Glu Leu Val Asp Lys Asn Leu Lys Met Thr Leu 50 55 (2) INFORMATION FOR SEQ ID NO: 42: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 60 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42: Leu He Asn Val He Val Pro He Asn Glu Phe Ser Pro Ala Phe Thr 1 5 10 15 Lys Arg Leu Ala Lys He Thr Ser Asn Leu Asp Gly Leu Glu Thr Cys 20 25 30 Leu Asp Tyr Leu Lys Asn Leu Gly Leu Asp Cys Ser Lys Leu Thr Lys 35 40 45 Thr Asp He Asp Ser Gly Asn Leu Gly Ala Val Leu 50 55 60 (2) INFORMATION FOR SEQ ID NO: 43: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 57 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43: Leu Leu Glu Val Leu Ser Gly Glu Met Leu Pro Lys Pro Thr Lys Gly 1 5 10 15 Lys Met Arg He His Cys Leu Glu Asn Val Asp Lys Ala Leu Gin Phe 20 25 30 Leu Lys Glu Gin Arg Val His Leu Glu Asn Met Gly Ser His Asp He 35 40 45 Val Asp Gly Asn His Arg Leu Val Leu 50 55 (2) INFORMATION FOR SEQ ID NO: 44: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 42 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44: Gly Met He Trp Thr He He Leu Arg Phe Ala He Gin Asp He Ser 1 5 10 15 He Glu Glu Leu Ser Ala Lys Glu Ala Leu Leu Leu Trp Cys Gin Arg 20 25 30 Lys Thr Glu Gly Tyr Asp Arg Val Lys Val 35 40 (2) INFORMATION FOR SEQ ID NO: 45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45: Gin Leu Leu Phe Leu Leu Ser Thr Tyr Lys Gin Lys Leu Arg Gin Leu 1 5 10 15 Lys Lys Asp Gin Lys Lys Leu Glu Gin Leu Pro Thr Ser He Met Pro 20 25 30 Pro Ala Val Ser Lys Leu Pro Ser Pro Arg Val Ala Thr Ser 35 40 45 (2) INFORMATION FOR SEQ ID NO: 46: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 48 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46: Gly Leu He Trp Thr He He Leu Arg Phe Gin He Gin Asp He Val 1 5 10 15 Val Gin Thr Gin Glu Gly Arg Glu Thr Arg Ser Ala Lys Asp Ala Leu 20 25 30 Leu Gin Phe Leu Lys Glu Gin Arg Val His Leu Glu Asn Met Gly Ser 35 40 45 (2) INFORMATION FOR SEQ ID NO: 47: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 100 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cosmid DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47: GATCAGAAGA AATTGGAGCA ACTACCCACA TCCATTATGC CACCCGCGGT TTCTAAGTGA 60 GTTTAATTTT GAGTTTACGA CTACAAAAAT GTGTTCTTTA 100 (2) INFORMATION FOR SEQ ID NO: 48: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 91 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: cosmid DNA (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48: CCGCCTTCTG ACTTCGTGAC GACAGTCTCG ACACGTGGGG TTGCAGGTAG GAGTGGATGA 60 GTCGAAACTG ATAAGATAGT CATTTGAGAT C 91

Claims: CLAIMS : 1. A cDNA encoding an UNC-53 protein of C. elegans or a functional equivalent derivative fragment or bioprecursor of said protein, which cDNA comprises at least from nucleotide position 431 to nucleotide position 4647 of the sequence shown in Figure 1. 2. A cDNA as claimed in claim 1 comprising at least from nucleotide position 431 to the 3' end of the sequence shown in Figure 1. 3. A cDNA as claimed in Claim 1 comprising at least from nucleotide position 64 to nucleotide position 4647 of the sequence as shown in Figure 1. 4. A cDNA as claimed in claim 3 comprising at least from nucleotide position 64 to the 3' end of the sequence shown in Figure 1. 5. A cDNA as claimed in Claims 1 to 4 comprising the nucleotide sequence shown in Figure 1. 6. A cDNA encoding an UNC-53 protein of C. elegans or a functional equivalent, derivative, fragment or bioprecursor of said protein, which cDNA comprises at least from nucleotide position 431 to nucleotide position 4812 of the 7A variant of the sequence shown in Figure 2. 7. A cDNA as claimed in claim 6 comprising at least from nucleotide position 431 to the 3' end of the 7A variant of the sequences shown in figure 2. 8. A cDNA as claimed in Claim 6 comprising at least from nucleotide position 64 to nucleotide position 4812 of the sequence shown in Figure 2. 9. A cDNA as claimed in claim 8 comprising at least from nucleotide position 64 to the 3' end of the 7A variant of the sequence shown in figure 2. 10. A cDNA as claimed in any of claims 6 to 9 comprising the nucleotide sequence of the 7A variant of the sequence shown in Figure 2. 11. A DNA expression vector which comprises a cDNA as claimed in any one of Claims 1 to 10. 12. A host cell transformed or transfected with the vector of Claim 11. 13. A host cell as claimed in Claim 12 which is a bacterial, an animal, a plant or an insect cell. 14. A transgenic cell comprising a transgene capable of expressing UNC-53 protein of C. elegans or a functional equivalent, derivative, fragment or bioprecursor of said protein. 15. A transgenic cell as claimed in Claim 14 which cell is a C. elegans cell, an N4 neuroblastoma cell or an MCF-7 breast carcinoma cell. 16. A transgenic organism comprising a transgene capable of expressing UNC-53 protein of C. elegans or a functional equivalent, derivative, fragment or bioprecursor of said protein. 17. A transgenic organism as claimed in Claim 16 wherein said organism is C. elegans. 18. A transgenic organism as claimed in Claim 16 wherein said organism is an insect, a non-human mammal or a plant. 19. A mutant of C. elegans which comprises an induced mutation in the wild-type unc-53 gene, which mutation affects the regulation of cell motility or the shape or direction of cell migration. 20. An UNC-53 protein encoded by the cDNA of Claim 1 and which protein has the amino acid sequence shown in Figure 4 from amino acid position 135 to amino acid position 1528. 21. An UNC-53 protein encoded by the cDNA sequence of any of Claims 2 to 5 and which protein has the amino acid sequence shown in Figure 4. 22. An UNC-53 protein encoded by the cDNA sequence of Claim 6 and which protein has the amino acid sequence shown in Figure 6 from amino acid position 135 to amino acid position 1583. 23. An UNC-53 protein encoded by the cDNA sequence according to any of Claims 7 to 10 and which protein has the amino acid sequence shown in Figure 6. 24. An UNC-53 protein of C. elegans. or a functional equivalent, derivative, fragment or bioprecursor of said protein, for use as a medicament to promote neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro- degenerative diseases or acute traumatic injuries. 25. An UNC-53 protein as claimed in any one of Claims 20 to 23 for use as a medicament to promote neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro- degenerative diseases or acute traumatic injuries. 26. Use of an UNC-53 protein of C. elegans. or a functional equivalent, derivative, fragment or bioprecursor of said protein in the manufacture of a medicament for promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. 27. Use of an UNC-53 protein as claimed in any one of Claims 20 to 23 in the manufacture of a medicament for promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro- degenerative or acute traumatic injuries. 28. A pharmaceutical composition comprising an UNC- 53 protein of C. elegans. a functional equivalent, derivative, bioprecursor or fragment of said protein and an acceptable carrier, diluent or excipient therefor. 29. A pharmaceutical composition as claimed in Claim 28 which comprises an UNC-53 protein as claimed in any one of Claims 20 to 23. 30. A nucleic acid sequence encoding an UNC-53 protein of C. elegans or a functional fragment, equivalent, derivative or bioprecursor of said protein, for use as a medicament to promote neuronal regeneration, vascularisation or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. 31. A nucleic acid sequence for use as claimed in Claim 27 wherein said sequence is a cDNA sequence as claimed in any one of Claims 1 to 10 or a functional fragment of said nucleic acid sequence. 32. Use of a nucleic acid sequence encoding and UNC- 53 protein of C. elegans or a functional equivalent fragment, derivative or bioprecursor of said protein, in the manufacture of a medicament to promote neuronal regeneration, vascularization or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. 33. Use of a nucleic acid sequence as claimed in Claim 32 wherein said sequence is a cDNA sequence as claimed in any one of Claims 1 to 10 or a functional fragment of said nucleic acid sequence. 34. A pharmaceutical composition comprising a nucleic sequence acid encoding an UNC-53 protein of C. elegans or a functional equivalent, derivative fragment or bioprecursor of said protein and an acceptable carrier, diluent, or excipient therefor. 35. A pharmaceutical composition as claimed in Claim 34 wherein said nucleic acid sequence is a cDNA sequence as claimed in any one of Claims 1 to 10. 36. A method of determining whether a compound is an inhibitor or an enhancer of the regulation of cell shape or motility or the direction of cell migration, which method comprises contacting said compound with a transgenic cell as claimed in Claims 14 or 15 and screening for a phenotypic change in said cell. 37. A method as claimed in Claim 36 wherein said compound is an inhibitor or an enhancer of a protein of the signal transduction pathway of said transgenic cell of which pathway UNC-53 protein or a functional equivalent, fragment or bioprecursor thereof is a component or said compound is an inhibitor or an enhancer of a parallel or redundant signal transduction pathway in said cell. 38. A method as claimed in Claim 36 or 37 wherein said protein is UNC-53 protein or a functional equivalent, fragment, derivative or bioprecursor thereof. 39. A method as claimed in any of Claims 36 to 38 wherein said phenotypic change to be screened is a change in cell shape or a change in cell motility. 40. A method as claimed in any of claims 36 to 38 wherein said phenotypic change to be screened is a change in filipodia outgrowth, ruffling behaviour, cell adhesion or the length of neurite growth. 41. A method as claimed in any of Claims 36 to 40 wherein said transgenic cell is an N4 neuroblastoma cell and the phenotypic change to be screened is the length of neurite growth. 42. A method as claimed in any of Claims 36 to 40 wherein said transgenic cell is an MCF-7 breast carcinoma cell and the phenotypic change to be screened is the extent of phagokinesis. 43. A method of determining whether a compound is an inhibitor or an enhancer of the regulation of cell shape or motility or of the direction of cell migration which method comprises administering said compound to a transgenic organism as claimed in any one of Claims 16 to 20, or a mutant organism as claimed in Claim 19, and screening for a phenotypic change in said organism. 44. A method as claimed in Claim 43 wherein said compound is an inhibitor or enhancer of a protein of the signal transduction pathway of said transgenic or mutant organisms, of which pathway UNC-53 protein or a functional equivalent, derivative or bioprecursor thereof is a component or said compound is an inhibitor or an enhancer of a parallel or redundant signal transduction pathway in said cell. 45. A method as claimed in Claim 44 wherein said protein of the signal transduction pathway is UNC-53 protein itself or a functional equivalent, fragment, derivative or bioprecursor of said protein. 46. A compound which is identifiable by the method according to any one of Claims 36 to 45 as an enhancer of the regulation of cell shape or motility or the direction of cell migration for use as a medicament for promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro- degenerative diseases or acute traumatic injuries. 47. Use of a compound identifiable by the method of any one of Claims 36 to 45 as an enhancer of the regulation of cell shape or motility or the direction of cell migration in C. elegans in the manufacture of a medicament for promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. 48. A pharmaceutical composition comprising the compound as claimed in Claim 46 and an acceptable carrier, diluent or excipient therefor. 49. A compound which is identifiable by the method according to any one of Claims 36 to 45 as an inhibitor of the regulation of cell motility or shape or the direction of cell migration of C. elegans for use as a medicament for alleviating the spread of disease inducing cells or metastasis. 50. Use of a compound identifiable by the method according to any one of Claims 36 to 45 in the manufacture of a medicament for alleviating the spread of disease inducing cells or metastasis. 51. A pharmaceutical composition comprising the compound as claimed in Claim 49 and an acceptable carrier diluent or excipient therefor. 52. A transgenic cell which has been constructed to comprise a promoter sequence of an unc-53 gene of C. elegans fused to a nucleic acid sequence encoding a reporter molecule. 53. A transgenic cell as claimed in Claim 52 wherein said reporter molecule is green fluorescent protein (GFP) . 54. A method of determining whether a compound is an inhibitor or an enhancer of transcription of an unc-53 gene in C. elegans or a functional fragment of said gene, which method comprises the steps of (a) contacting said compound with a transgenic cell according to Claim 52 and (b) monitoring of said reporter molecule and comparing the results obtained from said monitoring step with a control comprising a transgenic cell as claimed in Claim 48, which cell has not been contacted with said compound. 55. A method as claimed in Claim 54 wherein said reporter molecule detected is mRNA. 56. A method as claimed in Claim 54 wherein said reporter molecule detected is green fluorescent protein (GFP) . 57. A compound which is identifiable by the method according to any one of Claims 54 to 56, as an enhancer of transcription of an unc-53 gene of C. elegans or a functional fragment of said gene for use in promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. 58. Use of a compound which is identifiable by the method of any one of Claims 54 to 56 as an enhancer of transcription of an unc-53 gene of C. elegans or a functional fragment of said gene in the manufacture of a medicament for promoting neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro-degenerative diseases or acute traumatic injuries. 59. A pharmaceutical composition which comprises the compound of Claim 57 and an acceptable carrier, diluent or excipient therefor. 60. A compound which is identifiable by the method of any one of Claims 54 to 56 as an inhibitor of transcription of an unc-53 gene of C. elegans or a functional fragment of said gene for use in alleviating the spread of disease inducing cells or metastasis. 61. Use of a compound which is identifiable by the method of any one of Claims 54 to 56 as an inhibitor of transcription of an unc-53 gene of C. elegans or a functional fragment of said gene in the manufacture of a medicament for alleviating spread of disease inducing cells or metastasis. 62. A pharmaceutical composition which comprises the compound of Claim 60 and an acceptable carrier, diluent or excipient therefor. 63. A kit for determining whether a compound is an enhancer or an inhibitor of the regulation of cell motility or shape or the direction of cell migration which kit comprises at least a plurality of transgenic cells as claimed in any one of Claims 14 or 15 and a plurality of wild-type cells of the same cell or cell- line. 64. A kit for determining whether a compound is an inhibitor or an enhancer of transcription of an unc-53 gene of C. elegans or a functional fragment of said gene which kit comprises at least a plurality of transgenic cells as claimed in Claims 52 or 53 and means for monitoring the reporter molecule. 65. A kit for determining whether a compound is an enhancer or an inhibitor of the activity of UNC-53 protein or a functional equivalent, derivative, fragment or bioprecusor of said protein, which kit comprises at least, one mutant organism of C. elegans as claimed in claim 10 or a transgenic organism as claimed in any of claims 16 to 18 and a wild type organism of C. elegans. 66. An oligonucleotide probe which comprises the carboxy-ter inal 1.5 kb of the coding nucleic acid sequence shown in Figure 1 or a fragment thereof comprising between 18 and 24 base pairs. 67. An oligonucleotide probe comprising a nucleic acid sequence encoding the amino acid sequence as numbered 1 to 110, 114 to 133, 487 to 495, 537 to 545, 1032 to 1037, 1097 to 1116 or 1300 to 1307 shown in Figure 3 or a fragment thereof. 68. A probe as claimed in Claim 66 or 67 which is labelled for detection. 69. A method of identifying homologues of a C. elegans unc-53 gene or a functional fragment thereof which method comprises hybridizing to a C. elegans DNA library an oligonucleotide probe as claimed in any one of Claims 66 to 68 under appropriate conditions of stringency to identify genes having statistically significant homology with the cDNA of any one of Claims 1 to 10. 70. A method of identifying a protein which is active in the signal transduction pathway of a cell of which an UNC-53 protein or a functional equivalent, fragment or bioprecursor of said UNC-53 protein is a component, which method comprises: component, which method comprises: (a) contacting an extract of said cell with an antibody to the UNC-53 protein of C.elegans or a functional equivalent, fragment, derivative ^ or bioprecursor of said protein, (b) identifying the antibody/UNC-53 complex, and (c) analysing the complex to identify any protein bound to the UNC-53 protein other than the antibody. 71. A method of identifying a further protein which is active in the signal transduction pathway of a cell of which an UNC-53 protein or a functional equivalent, fragment or bioprecursor of said UNC-53 protein is a component which method comprises: (a) forming an antibody to the identified protein bound to the UNC-53 protein in Claim 65, (b) contacting a cell extract with said antibody and identifying the antibody/protein complex, (c) analysing the complex to identify any further protein bound to the first protein other than the antibody, and (d) optionally repeating steps (a) to (c) to identify further proteins in said pathway. 72. A method of identifying a protein which is active in the signal transduction pathway of a cell of which an UNC-53 protein or a functional equivalent, fragment or bioprecursor of said UNC-53 protein is a component, which method comprises (a) contacting an extract of said cell with UNC-53 protein of C. elegans or a functional eguivalent, derivative or bioprecursor of said UNC-53 protein (b) identifying UNC-53 protein/protein complex formed and (c) analysing the complex to identify any protein bound to the UNC-53 protein other than another UNC-53 protein. 73. A method according to claim 72 which further comprises contacting a cell extract with any protein identified from step (c) not being UNC-53 protein and repeating steps (b) and (c) so as to identify any further protein involved in the signal transduction pathway of said cell. 74. A method of identifying a protein involved in the signal transduction pathway of C. elegans which method comprises: (a) constructing at least two nucleotide vectors, the first of which comprises a nucleotide segment encoding for a DNA binding domain of GAL4 protein fused to a sequence encoding UNC-53 protein of C. elegans or a functional eguivalent, derivative, fragment or bioprecursor thereof, the second vector comprising a nucleotide sequence encoding a protein binding domain of GAL4 protein fused to a nucleotide sequence encoding a protein to be tested, (b) co-transforming each of said vectors into a yeast cell being deficient for transcription of genes encoding galactose metabolites, wherein interaction between said test protein and said UNC-53 protein leads to transcription of said galactose metabolite genes. 75. A protein identified by the method, of any one of claims 70 to 74 for use as a medicament to promote neuronal regeneration, revascularisation or wound healing, or for treatment of chronic neuro- degeroactive diseases or acute traumatic injuries. 76. Use of a protein identified by the methods of any one of claims 70 to 74 in the manufacture of a medicament for promoting neuronal regeneration, revasculerisation or wound healing, or for treatment of chronic neurodegenerative diseases or acute traumatic injuries. 77. A pharmaceutical composition comprising a protein identified by the methods of any one of Claims 70 to 74 and an acceptable carrier diluent, or excipient therefor. 78. A process for producing an UNC-53 protein of C. elegans or a functional equivalent fragment, derivative or bioprecursor of said UNC-53 protein which process comprises culturing the transfected or transformed cells of Claim 12 or Claim 13 and recovering the expressed UNC-53 protein. 79. A process for producing an UNC-53 protein of C. elegans or a functional eguivalent fragment, derivative or bioprecursor of said protein which process comprises culturing an insect cell transfected with a recombinant Baculovirus vector, said vector comprising a DNA insert encoding said UNC-53 protein or a functional equivalent, fragment or bioprecursor thereof, downstream of the Baculovirus polyhedrin promoter, and recovering the expressed UNC-53 protein. 80. A hybridoma cell line deposited under the LMBP Accession No. 1383CB. 81. Monoclonal antibody 16-48-2 obtainable from the hybridoma deposited under the LMBP Accession No. 1383CB. 82. Plasmid pTB54 deposited under the LMBP Accession No. 3296. 83. Plasmid pBT112 deposited under the Accession No. 3295. 84. Plasmid pTB72 deposited under the LMBP Accession No. 3486. 85. Transgenic cell-line of C.elegans designated TB4EX25 and deposited under the LMBP Accession No. 1384CB. 86. Transgenic cell-line of C. elegans designated TBAIn76 and deposited under the Accession No. 1385CB. 87. A transgenic cell-line of MCF-7 breast carcinoma cells deposited under the LMBP Accession No. 1550CB. 88. A transgenic cell-line of N4 neuroblastoma cells deposited under LMBP Accession No. 1549CB.

Inventors: BOGAERT THIERRY, STRINGHAM EVE, VANDEKERCKHOVE JOEL, BOGAERT, THIERRY, STRINGHAM, EVE, VANDEKERCKHOVE, JOEL
Applicants: BOGAERT THIERRY, STRINGHAM EVE, VANDEKERCKHOVE JOEL, BOGAERT, THIERRY, STRINGHAM, EVE, VANDEKERCKHOVE, JOEL
Application year: 1996
Main classification: C12N15
IPC codes: A61K38, A61K48, C07K14, C12N15