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Rap1 Activation Is Required for Fc Receptor-Dependent Phagocytosis¹

Jooho Chung^*,, Carlos H. Serezani^*, Steven K. Huang^*, Joel N. H. Stern, Derin B. Keskin, Rajesh Jagirdar^*, Thomas G. Brock^*, David M. Aronoff and Marc Peters-Golden^2,*

Divisions of ^* Pulmonary and Critical Care Medicine and Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138

Phagocytosis of IgG-opsonized microbes via the Fc receptor (FcR) requires the precise coordination of a number of signaling molecules, including the low-molecular mass GTPases. Little is known about the Ras-family GTPase Rap1 in this process. We therefore investigated its importance in mediating FcR-dependent phagocytosis in NR8383 rat alveolar macrophages. Pulldown of active Rap1 and fluorescence microscopic analysis of GFP-RalGDS (Ral guanine dissociation stimulator)-transfected macrophages revealed that Rap1 is indeed activated by FcR crosslinking. Inhibition of Rap1 activity, both by Rap1GAP (GTPase-activating protein) expression and liposome-delivered blocking Ab, severely impaired the ability of cells to ingest IgG-opsonized targets. FcR-induced Rap1 activation was found to be independent of both cAMP and Ca²⁺, suggesting a role for the second messenger-independent guanosine exchange factor, C3G. This was supported by the facts that 1) liposome-delivered blocking Ab against C3G inhibited both FcR-dependent phagocytosis and Rap1 activation, and 2) both active Rap1GTP and C3G were found to translocate to the phagosome. Taken together, our data demonstrate a novel role for Rap1 and its exchange factor C3G in mediating FcR-dependent phagocytosis.

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 This work was supported by National Institutes of Health Grant RO1-HL58897 (to M.P.-G.).

² Address correspondence and reprint requests to Dr. Marc Peters-Golden, University of Michigan Health System, 6301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5642. E-mail address: petersm{at}umich.edu

³ Abbreviations used in this paper: AM, alveolar macrophage; CalDAG, calcium diacylglycerol; GAP, GTPase-activating protein; GEF, guanosine exchange factor; Epac-1, exchange protein directly activated by cAMP; RalGDS, Ral guanine dissociation stimulator.