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J. Biol. Chem., Vol. 281, Issue 47, 36360-36368, November 24, 2006

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The Rab4A Effector Protein Rabip4 Is Involved in Migration of NIH 3T3 Fibroblasts^*

Jelena Vukmirica¹, Pascale Monzo², Yannick Le Marchand-Brustel, and Mireille Cormont³

From the INSERM U568, UFR Médecine, 06107 Nice Cedex 02 and Université de Nice-Sophia-Antipolis, UFR Sciences, 06002 Nice, France

The small GTP-binding protein Rab4 has been involved in the recycling of v3 integrins in response to platelet-derived growth factor (PDGF) stimulation suggesting a role for Rab4 in cell adhesion and migration. In this study, we explored the role of Rabip4 and Rabip4', two Rab4 effector proteins, in migration of NIH 3T3 fibroblasts. In these cells, Rabip4 and Rabip4', collectively named Rabip4s, were partially co-localized with the early endosomal marker EEA1. PDGF treatment re-distributed endogenous Rabip4s toward the cell periphery where they colocalized with F-actin. In cells expressing green fluorescent protein (GFP)-Rabip4 or GFP-Rabip4', constitutive appearance of GFP-Rabip4s at the cell periphery was accompanied by local increase in cortical F-actin in membrane ruffles at the leading edge. The expression of GFP-Rabip4 induced an increased migration compared with control cells expressing GFP alone, even in the absence of PDGF stimulation. On the contrary, in cells expressing a mutated form of Rabip4s unable to interact with Rab4, lack of typical leading edge was observed. Furthermore, PDGF treatment did not stimulate the migration of these cells. Furthermore, down-regulation of the expression of Rabip4s inhibited PDGF-stimulated cell migration. Endogenous Rabip4s were localized with v integrins at the leading edge following PDGF treatment, whereas in cells expressing GFP-Rabip4s, v integrins, together with GFP-Rabip4s, were constitutively localized at the leading edge. In contrast, reduction in Rabip4s expression levels using small interfering RNA was associated with impaired PDGF-induced translocation of v integrins toward the leading edge. Taken together, our data provide evidence that Rabip4s, possibly via their interaction with Rab4, regulate integrin trafficking and are involved in the migration of NIH 3T3 fibroblasts.

Received for publication, March 28, 2006 , and in revised form, August 25, 2006.

^* This work was supported in part by the Institut National de la Santé etdela Recherche Médicale, the University of Nice-Sophia Antipolis, the Association pour la Recherche contre le Cancer Grant 3240, the Région Provence Alpes Côte d'Azur, the Conseil Général des Alpes Maritimes and Association Contre le Cancer (ARC 7823) supported the purchase of the confocal microscope. 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 Videos 1-6 and Fig. S1.

¹ Supported by the Institut National de la Santé et de la Recherche Médicale (Poste Vert) and Fondation Pour la Recherche Médicale.

² Supported by the Ligue contre le Cancer, the Association pour la Recherche contre le Cancer, and the Fondation Bettencourt-Schueller. Present address: Dept. of Pathology, Columbia University, 630 W 168th St., P&S 15-410, New York, NY 10032.

³ To whom correspondence should be addressed. Tel.: 33-4-93-37-77-98; Fax: 33-4-93-37-77-01; E-mail: cormont{at}unice.fr.

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