Polypeptides having kinase activity, their preparation and use

Details Polypeptides having kinase activity, their preparation and use Polypeptides having kinase activity, their preparation and use

1994-02-07

1998-10-20

Wax, Robert A.

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving transferase

435 29, 435794, C12N 912, C12Q 148

Patent

active

058244921

DESCRIPTION:

BRIEF SUMMARY
This invention relates to new polypeptides which exhibit kinase activity. More specifically, the invention is concerned with polypeptides which show phosphoinositide (hereinafter "PI") 3-kinase activity, particularly molecules involved in pathways responsible for cellular growth and differentiation.
Major advances have taken place in our knowledge of the structure and function of the signal transducing molecules and second messenger systems coupled to cell surface receptors. Thus, a subset of polypeptide growth factor receptors belong to the family of protein-tyrosine kinases (hereinafter "PTK" and activation of these receptors following ligand binding involves autophosphorylation of the receptor as well as phosphorylation of a number of intracellular substrate proteins (reviewed in Ullrich, A et al., 1990). The importance of receptor autophosphorylation had been unclear until recently, when evidence from several laboratories has suggested that this event may mediate the formation of complexes between receptor proteins and putative growth regulatory proteins such as phospholipase C.gamma.(PLC.gamma.) (Meisenhelder et al, 1989), phosphatidylinositol PI3-kinase (Coughlin, S R et al, 1989), GTPase-activating protein (GAP) (Kaplan et al, 1990), the serine/theonine kinase Raf (Morrison et al, 1989), and members of the src-family of protein-tyrosine kinases (Kypta, R M et al., 1990) (reviewed in Cantley, L C et al., 1991).
The association of PI kinase activity with activated receptors is of particular interest since increased turnover of PI and its phosphorylated derivatives has been implicated in the action of hormones, growth factors and transformation of cells by DNA and RNA viruses (reviewed in Whitman, M et al., 1988; Cantley et al., 1991). Several species of PI kinase are known to exist, but up to now none of these enzymes have been characterised by cloning and expression and the demonstration of PI kinase activity. Fibroblasts contain at least two PI kinase activities which are distinguishable on the basis of their detergent sensitivity and kinetic properties (Whitman, M et al., 1987). These two activities were classified as Type I (inhibited by non-ionic detergents) and Type II (stimulated by non-ionic detergents and inhibited by adenosine). A third distinct species (Type III) has been identified in bovine brain but remains poorly characterised (Enderman, G et al., 1987). One species of PI kinase activity in particular has become of major interest in the search for second messenger systems linked to protein-tyrosine kinases because this activity was shown to co-immunoprecipitate with activated platelet-derived growth factor (PDGF) receptors (Kaplan, D R et al., 1987; Coughlin, S R et al., 1989) and with the polyoma middle T antigen/pp60.sup.c-scr (mT:pp60.sup.c-src) complex (Whitman, M et al., 1985). This activity has been shown to be due to a Type I PI kinase which produces novel inositol lipids phosphorylated at the D-3 position of the inositol ring (Whitman, M et al., 1988). More recently this enzyme has also been shown to associate with the CSF-1 receptor (Varticovski, L et al., 1989) kit (Lev et al, 1991), the epidermal growth factor (EGF) receptor (Bjorge et al, 1990), the PDGF .alpha.-receptor (Yu et al, 1991), the insulin receptor (Ruderman et al, 1990), the hepatocyte growth factor receptor, Met (Graziani et al, 1991), and with activated non-receptor protein-tyrosine kinases (Fukui & Hanafusa, 1989; Chan et al, 1990; Varticovski et al, 1991).
PI3 kinase activity has been closely linked to the presence of 81/85 kD proteins in these immunoprecipitates which can be phosphorylated on tyrosine residues by the associated protein-tyrosine kinase both in vitro and in vivo (Kaplan, D R et al., 1987; Courtneidge, S A et al., 1987; Cohen et al, 1990). Recently a 650 fold purification of PI3-kinase from bovine brain was described which, among other proteins present in the purest preparation, contained an 85 kD protein which was shown to be an in vitro substrate for the PDGF and EGF receptors (Morgan, S J et

REFERENCES:
Hiles et al., Cell 70:419-429 (1992).
Hu et al., Mol. Cell. Biol. 13:7677-7688 (1993).
Carpenter et al., J. Biol. Chem. 265:19704-19711 (1990).
Shibasaki et al., J. Biol. Chem. 266:8108-8114 (1991).
Cantley et al., Cell 64: 281-302 (1991).
Savitsky et al., Science 268: 1749-1753 (1995).

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