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Am J Physiol Cell Physiol 295: C130-C137, 2008. First published April 23, 2008; doi:10.1152/ajpcell.00168.2008
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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Collagen phagocytosis is regulated by the guanine nucleotide exchange factor Vav2

P. D. Arora,1 P. A. Marignani,2 and C. A. McCulloch1

1CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Ontario; 2Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada

Submitted 21 March 2008 ; accepted in final form 22 April 2008

Collagen phagocytosis is a crucial {alpha}2β1-integrin-dependent process that mediates extracellular matrix remodeling by fibroblasts. We showed previously that after initial contact with collagen, activated Rac1 accelerates collagen phagocytosis but the Rac guanine nucleotide exchange factors (GEFs) that regulate Rac are not defined. We examined here the GEFs that regulate collagen phagocytosis in mouse fibroblasts. Collagen binding enhanced Rac1 activity (5–20 min) but not Cdc42 or RhoA activity. Analysis of collagen bead-associated proteins showed enrichment with Vav2, which correlated temporally with increased Rac1 activity. Knockdown of Vav2 prevented Rac activation, recruitment of Rac1 to collagen bead binding sites, and collagen bead binding, but knockdown of Sos-1 or β-Pix had no effect on Rac activation or collagen binding. Vav2 was associated with the nucleotide-free Rac1 mutant (G15ARac1) after collagen binding. Collagen bead binding promoted phosphorylation of Vav2, which temporally correlated with Rac1 activation and which required Src kinase activity. Blockage of Src activity prevented collagen bead-induced Rac activation and collagen bead binding. Collectively these data indicate that Vav2 regulates the Rac1 activity associated with the binding step of collagen phagocytosis.

{alpha}2β1; integrin; Vav2; small GTPases


Address for reprint requests and other correspondence: CA McCulloch, Rm. 244, Fitzgerald Bldg, University of Toronto, 150 College St., Toronto, Ontario M5S 3E2, Canada (e-mail: christopher.mccculloch{at}utoronto.ca)






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