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J. Biol. Chem., Vol. 282, Issue 40, 29201-29210, October 5, 2007

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G_q Directly Activates p63RhoGEF and Trio via a Conserved Extension of the Dbl Homology-associated Pleckstrin Homology Domain^*

Rafael J. Rojas¹, Marielle E. Yohe, Svetlana Gershburg, Takeharu Kawano, Tohru Kozasa^¶2, and John Sondek^||**3

From the Pharmacology and ^||Biochemistry and Biophysics, and ^**Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599 and the Departments of Anatomy and Cell Biology and ^¶Pharmacology, University of Illinois, Chicago, Illinois 60612

The coordinated cross-talk from heterotrimeric G proteins to Rho GTPases is essential during a variety of physiological processes. Emerging data suggest that members of the G_12/13 and G_q/11 families of heterotrimeric G proteins signal downstream to RhoA via distinct pathways. Although studies have elucidated mechanisms governing G_12/13-mediated RhoA activation, proteins that functionally couple G_q/11 to RhoA activation have remained elusive. Recently, the Dbl-family guanine nucleotide exchange factor (GEF) p63RhoGEF/GEFT has been described as a novel mediator of G_q/11 signaling to RhoA based on its ability to synergize with G_q/11 resulting in enhanced RhoA signaling in cells. We have used biochemical/biophysical approaches with purified protein components to better understand the mechanism by which activated G_q directly engages and stimulates p63RhoGEF. Basally, p63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated G_q relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain. This unique extension is conserved in the related Dbl-family members Trio and Kalirin and we show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by G_q.

Received for publication, April 25, 2007 , and in revised form, June 26, 2007.

^* 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.

¹ Supported by United States Army Medical Research and Materiel Command, Breast Cancer Research Program Grant DAMD17-03-1-0646.

² Supported by National Institutes of Health Grant R01 GM6145408.

³ Supported by National Institutes of Health Grants P01-GM65533 and R01-GM62299. To whom correspondence should be addressed: Dept. of Pharmacology, University of North Carolina, CB 7365, 1106 M.E.J. Bldg., Chapel Hill, NC 27599. Tel.: 919-966-7350; Fax: 919-966-5640; E-mail: sondek{at}med.unc.edu.

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