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J. Biol. Chem., Vol. 280, Issue 47, 38923-38931, November 25, 2005

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Isozyme-specific Stimulation of Phospholipase C-₂ by Rac GTPases^*

From the Department of Pharmacology and Toxicology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany

The regulation of the two isoforms of phospholipase C-, PLC₁ and PLC₂, by cell surface receptors involves protein tyrosine phosphorylation as well as interaction with adapter proteins and phosphatidylinositol 3,4,5-trisphosphate (PtdInsP₃) generated by inositol phospholipid 3-kinases (PI3Ks). All three processes may lead to recruitment of the PLC isozymes to the plasma membrane and/or stimulation of their catalytic activity. Recent evidence suggests that PLC may also be regulated by Rho GTPases. In this study, PLC₁ and PLC₂ were reconstituted in intact cells and in a cell-free system with Rho GTPases to examine their influence on PLC activity. PLC₂, but not PLC₁, was markedly activated in intact cells by constitutively active Rac1^G12V, Rac2^G12V, and Rac3^G12V but not by Cdc42^G12V and RhoA^G14V. The mechanism of PLC₂ activation was apparently independent of phosphorylation of tyrosine residues known to be modified by PLC₂-activating protein-tyrosine kinases. Activation of PLC₂ by Rac2^G12V in intact cells coincided with a translocation of PLC₂ from the soluble to the particulate fraction. PLC isozyme-specific activation of PLC₂ by Rac GTPases (Rac1 Rac2 > Rac3), but not by Cdc42 or RhoA, was also observed in a cell-free system. Herein, activation of wild-type Rac GTPases with guanosine 5'-(3-O-thio)triphosphate caused a marked stimulation of PLC₂ but had no effect on the activity of PLC₁. PLC₁ and PLC₂ have previously been shown to be indiscriminately activated by PtdInsP₃ in vitro. Thus, the results suggest a novel mechanism of PLC₂ activation by Rac GTPases involving neither protein tyrosine phosphorylation nor PI3K-mediated generation of PtdInsP₃.

Received for publication, August 25, 2005 , and in revised form, September 12, 2005.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft and the German-Israeli Foundation for Scientific Research and Development. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 49-731-5002-3870; Fax: 49-731-5002-3872; E-Mail: peter.gierschik{at}uni-ulm.de.

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