PLC-ε: A Shared Effector Protein in Ras-, Rho-, and Gαβγ-Mediated Signaling

  1. Michele R. Wing,
  2. David M. Bourdon and
  3. T. Kendall Harden
  1. Department of Pharmacology University of North Carolina School of Medicine Chapel Hill, NC 27599
  1. Address correspondence to TKH. E-mail tkh{at}med.unc.edu; fax 919-966-5640.

Abstract

The conceptual segregation of G protein–stimulated cell signaling responses into those mediated by heterotrimeric G proteins versus those promoted by small GTPases of the Ras superfamily is no longer vogue. PLC-ε , an isozyme of the phospholipase C (PLC) family, has been identified recently and dramatically extends our understanding of the crosstalk that occurs between heterotrimeric and small monomeric GTPases. Like the widely studied PLC-β isozymes, PLC-ε is activated by Gβγ released upon activation of heterotrimeric G proteins. However, PLC-ε markedly differs from the PLC-β isozymes in its capacity for activation by Gα12/13 - but not Gαq -coupled receptors. PLC-ε contains two Ras-associating domains located near the C terminus, and H-Ras regulates PLC-ε as a downstream effector. Rho also activates PLC-ε , but in a mechanism independent of the C-terminal Ras-associating domains. Therefore, Ca2+ mobilization and activation of protein kinase C are signaling responses associated with activation of both H-Ras and Rho. A guanine nucleotide exchange domain conserved in the N terminus of PLC-ε potentially confers a capacity for activators of this isozyme to cast signals into additional signaling pathways mediated by GTPases of the Ras superfamily. Thus, PLC-ε is a multifunctional nexus protein that senses and mediates crosstalk between heterotrimeric and small GTPase signaling pathways.

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