Vav regulates activation of Rac but not Cdc42 during FcgammaR-mediated phagocytosis.
Phagocytosis is the process whereby cells direct the spatially localized, receptor-driven engulfment of particulate materials. It proceeds via remodeling of the actin cytoskeleton and shares many of the core cytoskeletal components involved in adhesion and migration. Small GTPases of the Rho family have been widely implicated in coordinating actin dynamics in response to extracellular signals and during diverse cellular processes, including phagocytosis, yet the mechanisms controlling their recruitment and activation are not known. We show herein that in response to ligation of Fc receptors for IgG (FcgammaR), the guanine nucleotide exchange factor Vav translocates to nascent phagosomes and catalyzes GTP loading on Rac, but not Cdc42. The Vav-induced Rac activation proceeds independently of Cdc42 function, suggesting distinct roles for each GTPase during engulfment. Moreover, inhibition of Vav exchange activity or of Cdc42 activity does not prevent Rac recruitment to sites of particle attachment. We conclude that Rac is recruited to Fcgamma membrane receptors in its inactive, GDP-bound state and that Vav regulates phagocytosis through subsequent catalysis of GDP/GTP exchange on Rac.
Patel
Jayesh C
JC
Medical Research Council Laboratory for Molecular Cell Biology, Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
Hall
Alan
A
Caron
Emmanuelle
E
D000818:Animals; D019556:COS Cells; D002384:Catalysis; D002460:Cell Line; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D015513:Oncogene Proteins / Q000378:metabolism*; D010587:Phagocytosis; D011485:Protein Binding; D011487:Protein Conformation; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D015513:Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D017452:Receptors, IgG; C496619:Vav1 protein, mouse; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins