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: A Shared Effector Protein in Ras-, Rho-, and G
ß
-Mediated Signaling
Department of Pharmacology University of North Carolina School of Medicine Chapel Hill, NC 27599
Correspondence: Address correspondence to TKH. E-mail tkh{at}med.unc.edu; fax 919-966-5640.
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-
, 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-ß isozymes, PLC- is activated by Gß
released upon activation of heterotrimeric G proteins. However, PLC- markedly differs from the PLC-ß isozymes in its capacity for activation by G
12/13 - but not Gq -coupled receptors. PLC- contains two Ras-associating domains located near the C terminus, and H-Ras regulates PLC- as a downstream effector. Rho also activates PLC- , 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- 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- is a multifunctional nexus protein that senses and mediates crosstalk between heterotrimeric and small GTPase signaling pathways.
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