Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-01-19
2000-08-22
Allen, Marianne P.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
530350, C07K 14435, C07K 14705, C12N 1512, C12N 1554
Patent
active
061074721
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
The present invention relates to proteins having receptor-type tyrosine kinase-like properties hinch represent a novel family of proteins related to protein tyrosine kinases. The present invention relates to the full length proteins and to subunits, mutants, derivatives and/or analogues thereof and to nucleotide sequences encoding same. The present invention also extends to ligands for the above proteins and to pharmaceutical compositions comprising the proteins and/or mutants, derivatives and/or analogues thereof and/or ligands thereto.
BACKGROUND OF THE INVENTION
The phosphorylation of tyrosine residues on protein substrates is a pathway whereby signals of grow the and differentiation are transmitted by growth factor receptors and transforming onoogenes (1). Evidence for this role of tyrosine phosphorylation came from the identification of receptors which bind known soluble growth factors. For example, 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 defining a tyrosine kinase catalytic domain (5).
The other line of evidence for a critical role played by tyrosine phosphorylation in growth control came from the study of viral oncogenes (6-7). The sequences 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 ono genes 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 (8).
Protein-tyrosine kinases (PTKs) represent a family of phosphotransferases related by their conserved catalytic domains (reviewed in 7 and 25). Phylogenetic analysis of this family suggests that several subfamilies of the PTKs exist based on the organisation of their non-catalytic sequences. These families include i) The Src related PTKs such as c-yes, c-lyn and hck; ii) the JAK family, and iii) at least seven subfamilies of growth factor receptors.
In particular, these previously known PTKs contain the Rossman motif (32) which is putatively associated with ATP binding. The Rossman motif has three invariant glycine residues in a six amino acid cluster as follows: (SEQ ID NO:1) Gly-X-Gly-X-X-Gly, where X is an amino acid residue.
In accordance with the present invention, proteins having receptor-type PTK-like properties have been discovered representing a new family of proteins related to receptor-type PTKs but exhibiting one or more of the following characteristics: and/or an altered Rossman motif, a unique tri-amino acid sequence in the kinase catalytic domain and/or an extracellular region comprising leucine rich regions. The proteins having the receptor-type PTK-like properties of the present invention are designated herein "RYK" for "related to tyrosine kinases".
SUMMARY OF THE INVENTION
One aspect of the present invention is directed to an isolated protein having receptor-type protein tyrosine kinase (PTK)-like properties including ATP binding, wherein said protein has an Ala binding site comprising a sequence of amino acid residues with the proviso that said amino acid sequence is not Gly-X-Gly-X-X-Gly, where X is any amino acid residue, or a subunit, fragment, derivative or analogue of said protein.
More particularly, the present invention provides an isolated protein having PTK-like properties including ATP binding wherein said protein has an ATP binding site consisting of (SEQ ID NO:2) Gln-a-Gly-b-c-Gly, where a, b and c may be the same or different and each is an amino acid residue, or a subunit, fragment, derivative or analogue of said protein.
Another aspect of the present invention provides an isolated protein having PTK-like properties including ATP bin
REFERENCES:
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Partanen, J. et al., PNAS, 87: 8913-8919, 1990.
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Hovens Christopher M.
Stacker Steven A.
Wilks Andrew F.
Allen Marianne P.
Ludwig Institute for Cancer Research
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