Previous research supported by this grant led to the discovery of phosphoinositide 3-kinase (PI 3-kinase), and the realization that five different phosphoinositides exist in mammalian cells (PtdIns-4-P, PtdIns-4- P, Ptdins-3,4-P2, Ptdins-4,5-P2 and Ptdins-3,4,5-P3) rather than two as previously thought. During the past granting period, cDNA clones of several of the enzymes that make these lipids have been cloned and these enzymes have been found to play unexpected critical roles in a host of cellular functions. The hypothesis guiding this proposal is that subdomains of the Ptdins kinases unique to specific isoforms allow independent control of production of these phosphoinositides at distinct compartments of the cell for distinct purposes. The goal of this proposal is to compare the structures of the different PtdIns kinases and dissect the domain structures that give them their unique properties.
The specific aims are to 1) characterize a PtdIns 4-kinase we recently cloned, 2) obtain a cDNA clone of a PtdIns-4-P 5-kinase that associates with rac, 3) determine the structural basis for association of PI 3- kinase, PtdIns 4-kinase and PtdIns-4-P 5-kinase with cellular regulators, 4) determine the structural basis for lipid kinase activity and for an unexpected protein kinase activity intrinsic to PI 3-kinase and 5) determine the enzymatic activities intrinsic to a family of PI 3-kinase homologues that includes the recently- discovered Ataxia-Telangiectasia gene.
|Wong, Kwok-Kin; Engelman, Jeffrey A; Cantley, Lewis C (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87-90|
|Myers, Andrea P; Meyerhardt, Jeffrey A; Cantley, Lewis C (2009) Getting knit-PI3Ky: PIK3CA mutation status to direct multimodality therapy? Clin Cancer Res 15:6748-50|
|Engelman, Jeffrey A; Chen, Liang; Tan, Xiaohong et al. (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351-6|
|Chang, James D; Field, Seth J; Rameh, Lucia E et al. (2004) Identification and characterization of a phosphoinositide phosphate kinase homolog. J Biol Chem 279:11672-9|
|Nishikawa, K; Toker, A; Wong, K et al. (1998) Association of protein kinase Cmu with type II phosphatidylinositol 4-kinase and type I phosphatidylinositol-4-phosphate 5-kinase. J Biol Chem 273:23126-33|
|Kapeller, R; Prasad, K V; Janssen, O et al. (1994) Identification of two SH3-binding motifs in the regulatory subunit of phosphatidylinositol 3-kinase. J Biol Chem 269:1927-33|
|Yoakim, M; Hou, W; Songyang, Z et al. (1994) Genetic analysis of a phosphatidylinositol 3-kinase SH2 domain reveals determinants of specificity. Mol Cell Biol 14:5929-38|
|Liscovitch, M; Chalifa, V; Pertile, P et al. (1994) Novel function of phosphatidylinositol 4,5-bisphosphate as a cofactor for brain membrane phospholipase D. J Biol Chem 269:21403-6|
|Wong, K; Cantley, L C (1994) Cloning and characterization of a human phosphatidylinositol 4-kinase. J Biol Chem 269:28878-84|
|Prasad, K V; Janssen, O; Kapeller, R et al. (1993) Src-homology 3 domain of protein kinase p59fyn mediates binding to phosphatidylinositol 3-kinase in T cells. Proc Natl Acad Sci U S A 90:7366-70|
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