ACTIVATION OF PHOSPHOLIPASE C-GAMMA BY PI 3-KINASE-INDUCED PH DOMAIN-MEDIATED MEMBRANE TARGETING

Signaling via growth factor receptors frequently results in the concom itant activation of phospholipase Cy (PLC gamma) and phosphatidylinosi tol (PI) 3-kinase. While it is well established that tyrosine phosphor ylation of PLC gamma is necessary for its activation, we show here tha t PLC gamma is regulated additionally by the lipid products of PI 3-ki nase, We demonstrate that the pleckstrin homology (PH) domain of PLC g amma binds to phosphatidylinositol 3,4,5-trisphosphate [PdtIns(3,4,5)P -3], and is targeted to the membrane in response to growth factor stim ulation, while a mutated version of this PH domain that does not bind PdtIns(3,4,5)P-3 is not membrane targeted. Consistent with these obser vations, activation of PI 3-kinase causes PLC gamma PH domain-mediated membrane targeting and PLC gamma activation. By contrast, either the inhibition of PI 3-kinase by overexpression of a dominant-negative mut ant or the prevention of PLC gamma membrane targeting by overexpressio n of the PLC gamma PH domain prevents growth factor-induced PLC gamma activation. These experiments reveal a novel mechanism for cross-talk and mutual regulation of activity between two enzymes that participate in the control of phosphoinositide metabolism.