Regulation of phospholipase C-δ1 through direct interactions with the small GTPase Ral and calmodulin

Abstract

Second messengers generated from membrane lipids play a critical role in signaling and control diverse cellular processes. Despite being one of the most evolutionarily conserved of all the phosphoinositide-specific phospholipase C (PLC) isoforms, a family of enzymes responsible for hydrolysis of the membrane lipid phosphatidylinositol bisphosphate, the mechanism of PLC-δ1 activation is still poorly understood. Here we report a novel regulatory mechanism for PLC-δ1 activation that involves direct interaction of the small GTPase Ral and the universal calcium-signaling molecule calmodulin (CaM) with PLC-δ1. In addition, we have identified a novel IQ type CaM binding motif within the catalytic region of PLC-δ1 that is not found in other PLC isoforms. Binding of CaM at the IQ motif inhibits PLC-δ1 activity, while addition of Ral reverses the inhibition. The overexpression of various Ral mutants in cells potentiates PLC-δ1 activity. Thus, the Ral-CaM complex defines a multifaceted regulatory mechanism for PLC-δ1 activation. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.