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Human p63RhoGEF, a novel RhoA-specific guanine nucleotide exchange factor, is localized in cardiac sarcomere

Michel Souchet^1,*, Elodie Portales-Casamar^2,*, David Mazurais¹, Susanne Schmidt², Isabelle Léger¹, Jean-Luc Javré¹, Philippe Robert¹, Isabelle Berrebi-Bertrand¹, Antoine Bril¹, Bernard Gout¹, Anne Debant^2, and Thierry P. G. Calmels^1,

¹ SmithKline Beecham Laboratoires Pharmaceutiques, Unité de Biologie Cardiovasculaire, 4 rue du Chesnay Beauregard, BP 96205, 35760 Saint-Grégoire, France
² Centre de Recherches en Biochimie Macromoléculaire-Centre National de la Recherche Scientifique, UPR 1086, 1919 Route de Mende, 34293 Montpellier Cedex 05, France

Authors for correspondence (e-mail: t.calmels{at}bioprojet.com ; debant{at}crbm.cnrs-mop.fr)

Accepted 26 October 2001

The Rho small GTPases are crucial proteins involved in regulation of signal transduction cascades from extracellular stimuli to cell nucleus and cytoskeleton. It has been reported that these GTPases are directly associated with cardiovascular disorders. In this context, we have searched for novel modulators of Rho GTPases, and here we describe p63RhoGEF a new Db1-like guanine nucleotide exchange factor (GEF). P63RhoGEF encodes a 63 kDa protein containing a Db1 homology domain in tandem with a pleckstrin homology domain and is most closely related to the second Rho GEF domain of Trio. Northern blot and in situ analysis have shown that p63RhoGEF is mainly expressed in heart and brain. In vitro guanine nucleotide exchange assays have shown that p63RhoGEF specifically acts on RhoA. Accordingly, p63RhoGEF expression induces RhoA-dependent stress fiber formation in fibroblasts and in H9C2 cardiac myoblasts. Moreover, we show that p63RhoGEF activation of RhoA in intact cells is dependent on the presence of the PH domain. Using a specific anti-p63RhoGEF antibody, we have detected the p63RhoGEF protein by immunocytochemistry in human heart and brain tissue sections. Confocal microscopy shows that p63RhoGEF is located in the sarcomeric I-band mainly constituted of cardiac sarcomeric actin. Together, these results show that p63RhoGEF is a RhoA-specific GEF that may play a key role in actin cytoskeleton reorganization in different tissues, especially in heart cellular morphology.

Key words: GEF, RhoA, Cardiac sarcomere

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