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J. Biol. Chem., Vol. 282, Issue 15, 11135-11143, April 13, 2007

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Role of CrkII in Fc Receptor-mediated Phagocytosis^*

Warren L. Lee¹, Gabriela Cosio², Keith Ireton^¶, and Sergio Grinstein³

From the Programme in Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, Interdepartmental Division of Critical Care Medicine and the Division of Respirology, Department of Medicine, University of Toronto, Ontario M5S 1A8, Canada, and ^¶Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32826

Phagocytosis of IgG-opsonized pathogens by Fc receptors requires extensive remodeling of the actin cytoskeleton, a process regulated by the small GTPase Rac. Vav was thought to be the guanine nucleotide exchange factor responsible for the activation of Rac, but recent evidence indicates that Fc receptor-mediated phagocytosis is unaffected in macrophages lacking all three isoforms of Vav. We therefore tested whether another GEF, DOCK180, participates in Fc receptor-initiated phagocytosis. DOCK180 associates with the adaptor protein Crk, which mediates recruitment of the GEF to sites of tyrosine phosphorylation. CrkII and DOCK180 were found to accumulate at the phagocytic cup. Knockdown of Crk or DOCK180 in murine macrophages using small interfering RNA inhibited phagocytosis of IgG-opsonized particles. Moreover, transfection of dominant negative CrkII prevented both recruitment of DOCK180 and the activation of Rac at the phagocytic cup. This is the first report of a role for either Crk or DOCK180 in Fc receptor-mediated phagocytosis. The Crk-DOCK180 complex is involved in the clearance of apoptotic cells, which unlike the ingestion of IgG-opsonized particles, is an anti-inflammatory process. The finding that CrkII-DOCK180 is also responsible, at least in part, for the effects of Fc receptors implies that additional, parallel pathways must account for the associated pro-inflammatory effect.

Received for publication, January 29, 2007

^* 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 the Canadian Institutes of Health Research and the Canadian Lung Association, the McLaughlin Centre for Molecular Medicine, and the University of Toronto Postgraduate Medical Education Awards.

² Supported by the McLaughlin Centre for Molecular Medicine.

³ Current holder of the Pitblado Chair in Cell Biology. To whom correspondence should be addressed: Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-5727; Fax: 416-813-5028; E-mail: sga{at}sickkids.ca.

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