Phosphoinositide 3-kinase regulates phospholipase Cgamma-mediated calcium signaling.

Rameh LE, Rhee SG, Spokes K, Kazlauskas A, Cantley LC, Cantley LG
J Biol Chem. 1998 273 (37): 23750-7

PMID: 9726983 · DOI:10.1074/jbc.273.37.23750

It has been demonstrated that the lipid products of the phosphoinositide 3-kinase (PI3K) can associate with the Src homology 2 (SH2) domains of specific signaling molecules and modify their actions. In the current experiments, phosphatidylinositol 3,4, 5-trisphosphate (PtdIns-3,4,5-P3) was found to bind to the C-terminal SH2 domain of phospholipase Cgamma (PLCgamma) with an apparent Kd of 2.4 microM and to displace the C-terminal SH2 domain from the activated platelet-derived growth factor receptor (PDGFR). To investigate the in vivo relevance of this observation, intracellular inositol trisphosphate (IP3) generation and calcium release were examined in HepG2 cells expressing a series of PDGFR mutants that activate PLCgamma with or without receptor association with PI3K. Coactivation of PLCgamma and PI3K resulted in an approximately 40% increase in both intracellular IP3 generation and intracellular calcium release as compared with selective activation of PLCgamma. Similarly, the addition of wortmannin or LY294002 to cells expressing the wild-type PDGFR inhibited the release of intracellular calcium. Thus, generation of PtdIns-3,4,5-P3 by receptor-associated PI3K causes an increase in IP3 production and intracellular calcium release, potentially via enhanced PtdIns-4, 5-P2 substrate availability due to PtdIns-3,4,5-P3-mediated recruitment of PLCgamma to the lipid bilayer.

MeSH Terms (20)

Androstadienes Binding Sites Calcium Chromones Enzyme Inhibitors Humans Isoenzymes Kinetics Morpholines Phosphatidylinositol 3-Kinases Phosphatidylinositol Phosphates Phospholipase C gamma Platelet-Derived Growth Factor Receptors, Platelet-Derived Growth Factor Recombinant Fusion Proteins Signal Transduction Transfection Tumor Cells, Cultured Type C Phospholipases Wortmannin

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