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Vol. 18, Issue 4, 1242-1252, April 2007

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Gem Associates with Ezrin and Acts via the Rho-GAP Protein Gmip to Down-Regulate the Rho Pathway

Anastassia Hatzoglou^*,,, Isabelle Ader^*,,, Anne Splingard^*,, James Flanders^*,,||, Evelyne Saade^*,, Ingrid Leroy^*,, Sabine Traver^*,, Sandra Aresta^*,,¶, and Jean de Gunzburg^*,

*Institut Curie–Centre de Recherche and Inserm U528, Paris F-75248, France

Submitted June 9, 2006; Revised December 7, 2006; Accepted January 18, 2007
Monitoring Editor: J. Silvio Gutkind

Gem is a protein of the Ras superfamily that plays a role in regulating voltage-gated Ca²⁺ channels and cytoskeletal reorganization. We now report that GTP-bound Gem interacts with the membrane–cytoskeleton linker protein Ezrin in its active state, and that Gem binds to active Ezrin in cells. The coexpression of Gem and Ezrin induces cell elongation accompanied by the disappearance of actin stress fibers and collapse of most focal adhesions. The same morphological effect is elicited when cells expressing Gem alone are stimulated with serum and requires the expression of ERM proteins. We show that endogenous Gem down-regulates the level of active RhoA and actin stress fibers. The effects of Gem downstream of Rho, i.e., ERM phosphorylation as well as disappearance of actin stress fibers and most focal adhesions, require the Rho-GAP partner of Gem, Gmip, a protein that is enriched in membranes under conditions in which Gem induced cell elongation. Our results suggest that Gem binds active Ezrin at the plasma membrane–cytoskeleton interface and acts via the Rho-GAP protein Gmip to down-regulate the processes dependent on the Rho pathway.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present addresses: LBCMCP, CNRS UMR5088, Université Paul Sabatier–Toulouse III, 118 Route de Narbonne, 31062 Toulouse Cedex 9, France;

INSERM U563, Institut Claudius Regaud, 20-24 Rue du Pont St Pierre, 31052 Toulouse Cedex, France;

^|| Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853;

^¶ Inserm UMR599, 27 Bd. Leï Roure, 13009 Marseille, France.

Address correspondence to: Anastassia Hatzoglou (hatzoglo{at}cict.fr) or Jean de Gunzburg (gunzburg{at}curie.fr)

Abbreviations used: ERM, Ezrin, Radixin, Moesin; N-ERMAD, N-terminal ERM association domain; C-ERMAD, C-terminal ERM association domain; PIP2, phosphatidylinositol 4,5 bisphosphate; GAP, GTPase-activating protein; GST, glutathione S-transferase; TEV, tobacco etch virus.