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J. Biol. Chem., Vol. 283, Issue 31, 21588-21598, August 1, 2008

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RhoA-GDP Regulates RhoB Protein Stability

POTENTIAL INVOLVEMENT OF RhoGDI^*

T. T. Giang Ho¹, Sofia D. Merajver², Charles M. Lapière, Betty V. Nusgens, and Christophe F. Deroanne, Research Associate of the Belgian FNRS³

From the Laboratory of Connective Tissues Biology, GIGA-R, University of Liège, Tour de Pathologie, B23/3, B-4000 Sart Tilman, Belgium and the Breast and Ovarian Cancer Risk Evaluation Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0948

RhoA plays a significant role in actin stress fibers formation. However, silencing RhoA alone or RhoA and RhoC did not completely suppress the stress fibers suggesting a residual "Rho-like" activity. RhoB, the third member of the Rho subclass, is a shortlived protein barely detectable in basal conditions. In various cell types, the silencing of RhoA induced a strong up-regulation of both total and active RhoB protein levels that were rescued by re-expressing RhoA and related to an enhanced half-life of the protein. The RhoA-dependent regulation of RhoB does not depend on the activity of RhoA but is mediated by its GDP-bound form. The stabilization of RhoB was not dependent on isoprenoid biosynthesis, Rho kinase, extracellular signal-regulated kinase, p38 mitogen-activated kinase, or phosphatidylinositol 3'-OH kinase pathways but required RhoGDI. The forced expression of RhoGDI increased RhoB half-life, whereas its knock-down antagonized the induction of RhoB following RhoA silencing. Moreover, a RhoA mutant (RhoAR68E) unable to bind RhoGDI was significantly less efficient as compared with wild-type RhoA in reversing RhoB up-regulation upon RhoA silencing. These results suggest that, in basal conditions, RhoGDI is rate-limiting and the suppression of RhoA makes it available to stabilize RhoB. Our results highlight RhoGDI-dependent cross-talks that regulate the stability of RhoGTPases.

Received for publication, December 10, 2007 , and in revised form, April 14, 2008.

^* This work was supported in part by grants from the Belgian Fonds de la Recherche Scientifique (FNRS) (1.5.188.0 [EC] 6) and Fonds de la Recherche Scientifique Medicale (FRSM) (3.4514.07) (to C. F. D.), the "Belgian Federation against Cancer, Nonprofit Organization," and the Belspo/Prodex Agency at the European Space Agency (to C. M. L. and B. V. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6.

¹ Fellow of the Belgian F.N.R.S (FRIA).

² Supported by the Burroughs Wellcome Fund and the Breast Cancer Research Foundation.

³ To whom correspondence should be addressed. Tel.: 32-0-4-366-24-59; Fax: 32-0-4-366-24-57; E-mail: c.deroanne{at}ulg.ac.be.

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