Phospholipase C isozymes as effectors of Ras superfamily GTPases

John Sondek,T. Kendall Harden,Stephanie N. Hicks

doi:10.1194/jlr.r800045-jlr200

Abstract

The physiological effects of many extracellular stimuli are initiated through receptor-promoted activation of phospholipase C and inositol lipid signaling pathways. The historical view that phospholipase C-promoted signaling primarily occurs through activation of heterotrimeric G proteins or tyrosine kinases has expanded in recent years with the realization that at least three different mammalian phospholipase C isozymes are directly activated by members of the Ras superfamily of GTPases. Thus, Ras, Rap, Rac, and Rho GTPases all specifically regulate certain phospholipase C isozymes, and insight into the physiological significance of these signaling responses is beginning to accrue. High resolution three-dimensional structures of phospholipase C isozymes also are beginning to shed light on their mechanism of activation.

Highlights

The physiological effects of many extracellular stimuli are initiated through receptor-promoted activation of phospholipase C and inositol lipid signaling pathways
The historically designated X and Y domains comprise the two halves of a highly conserved catalytic triose phosphate isomerase (TIM) barrel flanked on the N-terminal side by a series of elongation factor (EF)-hand domains and by a C2 domain at the C terminus
The catalytic core of most of the 13 mammalian Phospholipase C (PLC) isozymes is elaborated with unique domains that underlie the evolution of unique modes of regulation in these signaling proteins

Summary

Introduction

The physiological effects of many extracellular stimuli are initiated through receptor-promoted activation of phospholipase C and inositol lipid signaling pathways. Polypeptide growth factors promote inositol lipid signaling through a second major mechanism involving receptor autophosphorylation and generation of phosphotyrosine binding sites for PLC-g isozymes on the activated receptor [10].

Results

Conclusion