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J. Biol. Chem., Vol. 281, Issue 13, 8756-8764, March 31, 2006

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Dissociation of Recruitment and Activation of the Small G-protein Rac during Fc Receptor-mediated Phagocytosis^*

From the Centre for Molecular Microbiology and Infection, and Division of Cell and Molecular Cell biology, Faculty of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom

Rho-family proteins play a central role in most actin-dependent processes, including the control and maintenance of cell shape, adhesion, motility, and phagocytosis. Activation of these GTP-binding proteins is tightly regulated spatially and temporally; however, very little is known of the mechanisms involved in their recruitment and activation in vivo. Because of its inducible, restricted signaling, phagocytosis offers an ideal physiological system to delineate the pathways linking surface receptors to actin remodeling via Rho GTPases. In this study, we investigated the involvement of early regulators of Fc receptor signaling in Rac recruitment and activation. Using a combination of receptor mutagenesis, cellular, molecular, and pharmacological approaches, we show that Src family and Syk kinases control Rac and Vav function during phagocytosis. Importantly, both the immunoreceptor tyrosine-based activation motif within Fc receptor cytoplasmic domain and Src kinase control the recruitment of Vav and Rac. However, Syk activity is dispensable for Vav and Rac recruitment. Moreover, we show that Rac and Cdc42 activities coordinate F-actin accumulation at nascent phagosomes. Our results provide new insights in the understanding of the spatiotemporal regulation of Rho-family GTPase function, and of Rac in particular, during phagocytosis. We believe they will contribute to a better understanding of more complex cellular processes, such as cell adhesion and migration.

Received for publication, December 27, 2005

^* This work was supported in part by grants from the Wellcome Trust (068556/Z/02/Z) and Biotechnology and Biological Sciences Research Council (28/C18637). 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 a fellowship from the French foundation "La Fondation pour la Recherche Médicale" (SPE20030627107).

² To whom correspondence should be addressed: CMMI2, Flowers Bldg., Armstrong Rd., Imperial College London, London SW7 2AZ United Kingdom. Tel.: 44-207-594-3089; Fax: 44-207-594-3076; E-mail: e.caron{at}imperial.ac.uk.

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