Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1994-04-18
1997-10-07
Walsh, Stephen
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 76, 435 791, G01N 3353
Patent
active
056746911
DESCRIPTION:
BRIEF SUMMARY
The present invention relates generally to a novel receptor-type tyrosine kinase and to genetic sequences encoding same.
Tyrosine kinases form an important class of molecules involved in the regulation of growth and differentiation (1). One mode of proof for this role came from the identification of receptors which bind known soluble growth factors. The receptors for epidermal growth factor (EGF) (2), platelet derived growth factor (PDGF) (3) and colony stimulating factor-1 (CSF-1)(4) were all shown to be transmembrane molecules with the cytoplasmic regions encoding a tyrosine kinase catalytic domain. The CSF-1 receptor is homologous to the PDGF receptor in both the catalytic and extracellular domains (1,5). The extra cellular domain of these proteins is distinguished from other tyrosine kinases by the presence of immunoglobulin-like repeats (1,6). Based on structural properties of the kinase domain, the c-kit protein was identified as another member of this family (7). The c-kit gene locus appears to underpin the defects in the congenitally anaemic W/W mouse (8-10). The ligand has now been identified (11-14) as shown to be encoded by the Sl locus. The locus is abnormal in the Steel mouse (15) which has identical defects to the W/W mouse but encodes a normal c-kit gene.
The other line of evidence for a critical role of tyrosine kinase proteins in growth control came from the study of vital oncogenes (16-17). These genes were shown to be directly involved in growth dysregulation by observations of a change in cell growth following introduction of DNA encoding these genes into fibroblasts. All oncogenes have been shown to have close cellular homologues (proto-oncogenes). One of the first identified oncogenes was v-src, the cellular homologue (c-src) is the prototypical representative of the family of cytoplasmic tyrosine kinases which, following myristylation, become associated with the inner leaf of the cell membrane (18). Within the haemopoietic system a number of lineage-restricted src-like kinases have been defined (19).
The T cell-associated src-like kinase, lck, has been shown to associate independently with both the CD4 and CD8 transmembrane glycoproteins to form a signalling complex (20,21). By contrast, v-erb-B and v-fms, like their cellular homologues the EGF receptor and CSF 1 receptor, respectively, are transmembrane molecules encoding the entire signal transduction machinery in a single polypeptide (1,17).
Detailed analysis of the amino acid sequences of these proteins has revealed conserved structural motifs within the catalytic domains (5). Both tyrosine and serine-threonine kinases have a consensus GXGXXG sequence (SEQ ID NO:12) which is found in many nucleotide binding proteins (5). Other conserved sequence motifs are shared by both types of kinase while others are specific for the tyrosine or the threonine-serine kinase subgroups (5). The tyrosine kinases, while having regions of sequence conservation specific to this family, can be further subdivided according to the structural features of the regions 5' to the catalytic domain (1,4-7). The novel tyrosine kinase of the present invention exhibits the same general characteristics as previously known tyrosine kinases.
In accordance with the present invention, a new receptor-type tyrosine kinase is provided and which is identified as a member of the eph/elk family of tyrosine kinases (22,23). The novel tyrosine kinase receptor is designated HEK ("human eph/elk-like kinase"). As the present inventors have identified expression of HEK in both pre-B and T cell lines, the receptor molecule of the present invention and/or its ligand is contemplated herein to have particular applicability for use as agents in the in vivo modulation of the production and/or function of pre-B, B and T cells.
Accordingly, one aspect of the present invention provides an isolated receptor-type tyrosine kinase, said tyrosine kinase characterised by, in its naturally occurring form, being reactive to the monoclonal antibody III.A4, having an apparent molecular weight of ap
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Lhotak et al, "Characterization of Elk . . . "Mol. Cell, Biol. 11:2496-2502 (May 1991).
Hirai et al, "A Novel Putative Tyrosine Kinase Receptor . . . " Science 238:1717-1720 (Dec. 1987).
Pasquale et al, "Identification of chicken embryo kinase 5 . . . " Cell Reg. 2:523-534 (Jul. 1991).
Lindberg et al, "cDNA Cloning and Characterization . . . " Mol. Cell. Biol. 10(12):6316-6324 (Dec. 1990).
Sajjadi et al "Identification of a New eph-Related . . . " New Biologist 3(8):769-778 (Aug. 1991).
Flanagan et al "The kit Ligand: A Cell Surface Molecule . . . " Cell 63 63:185-194 (Oct. 1990).
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Boyd Andrew W.
Simpson Richard John
Ward Larry David
Wicks Ian
Wilkinson David
Amrad Corporation Limited
Basham Daryl A.
Walsh Stephen
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