Phosphoinositide 3-Kinase Regulates Phospholipase Cγ-mediated Calcium Signaling

• Published in: The Journal of biological chemistry Vol. 273; no. 37; pp. 23750 - 23757
• Main Authors: Rameh, Lucia E., Rhee, Sue Goo, Spokes, Katherine, Kazlauskas, Andrius, Cantley, Lewis C., Cantley, Lloyd G.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 11.09.1998
• ISSN: 0021-9258; 1083-351X
• 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 Cγ (PLCγ) with an apparent Kd of 2.4 μm and to displace the C-terminal SH2 domain from the activated platelet-derived growth factor receptor (PDGFR). To investigate the in vivorelevance of this observation, intracellular inositol trisphosphate (IP3) generation and calcium release were examined in HepG2 cells expressing a series of PDGFR mutants that activate PLCγ with or without receptor association with PI3K. Coactivation of PLCγ and PI3K resulted in an ∼40% increase in both intracellular IP3generation and intracellular calcium release as compared with selective activation of PLCγ. 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-P3by receptor-associated PI3K causes an increase in IP3production and intracellular calcium release, potentially via enhanced PtdIns-4,5-P2 substrate availability due to PtdIns-3,4,5-P3-mediated recruitment of PLCγ to the lipid bilayer.