Activation of phospholipase Cgamma by PI 3-kinase-induced PH domain-mediated membrane targeting

Abstract

Signaling via growth factor receptors frequently results in the concomitant activation of phospholipase Cγ (PLCγ) and phosphatidylinositol (PI) 3‐kinase. While it is well established that tyrosine phosphorylation of PLCγ is necessary for its activation, we show here that PLCγ is regulated additionally by the lipid products of PI 3‐kinase. We demonstrate that the pleckstrin homology (PH) domain of PLCγ binds to phosphatidylinositol 3,4,5‐trisphosphate [PdtIns(3,4,5)P3], and is targeted to the membrane in response to growth factor stimulation, while a mutated version of this PH domain that does not bind PdtIns(3,4,5)P3 is not membrane targeted. Consistent with these observations, activation of PI 3‐kinase causes PLCγ PH domain‐mediated membrane targeting and PLCγ activation. By contrast, either the inhibition of PI 3‐kinase by overexpression of a dominant‐negative mutant or the prevention of PLCγ membrane targeting by overexpression of the PLCγ PH domain prevents growth factor‐induced PLCγ 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.