Authors

W. L. Lee; G. Cosio; K. Ireton;S. Grinstein

Comments

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Abbreviated Journal Title

J. Biol. Chem.

Keywords

NUCLEOTIDE EXCHANGE FACTORS; ADAPTER PROTEINS; APOPTOTIC CELLS; RHO-GTPASES; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHATIDYLSERINE RECEPTOR; RAC-GEF; ACTIVATION; MEMBRANE; COMPLEX; Biochemistry & Molecular Biology

Abstract

Phagocytosis of IgG-opsonized pathogens by Fc gamma 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 gamma receptor-mediated phagocytosis is unaffected in macrophages lacking all three isoforms of Vav. We therefore tested whether another GEF, DOCK180, participates in Fc gamma 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 gamma 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 gamma receptors implies that additional, parallel pathways must account for the associated pro-inflammatory effect.

Journal Title

Journal of Biological Chemistry

Volume

282

Issue/Number

15

Publication Date

1-1-2007

Document Type

Article

Language

English

First Page

11135

Last Page

11143

WOS Identifier

WOS:000245941500034

ISSN

0021-9258

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