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R-Mediated Signaling to Rac GTPases and Nicotinamide Adenine Dinucleotide Phosphate Oxidase Component p40(phox)1
* Center of Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; and
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
Phagocytes generate reactive oxygen species, the regulation of which is important in eliminating ingested microbes while limiting tissue damage. Clustering of Fc
Rs results in the activation of Vav proteins, Rho/Rac guanine nucleotide exchange factors, and results in robust superoxide generation through the NADPH oxidase. In this study, studies in neutrophils isolated from mice deficient in Vav or Rac isoforms demonstrate a critical role for Vav3 in Rac2-dependent activation of the NADPH oxidase following FcR clustering. However, studies in cytokine-primed cells revealed a strict requirement for Vav1 and Vav3 and Rac1 and Rac2 in the FcR-mediated oxidative burst. In comparison, Vav was not essential for PMA or G protein-coupled receptor-mediated superoxide generation. The FcR-mediated oxidative burst defect in Vav-deficient cells was linked to aberrant Rac activation as well as Rac- and actin-polymerization-independent, but PI3K-dependent, phosphorylation of the NADPH oxidase component p40(phox). In macrophages, Vav regulation of Rac GTPases was required specifically in FcR-mediated activation of the oxidative burst, but not in phagocytosis. Thus, Vav proteins specifically couple FcR signaling to NADPH oxidase function through a Rac-dependent as well as an unexpected Rac-independent signal that is proximal to NADPH oxidase activation and does not require actin polymerization.
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 Grants R01HL65095 and AR050800 (to T.N.M.) and a senior research fellowship from the American Lung Association (to A.U.).
2 A.U. and X.C. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Tanya N. Mayadas, Department of Pathology, Center of Excellence in Vascular Biology, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, New Research Building 07520, Boston, MA 02115. E-mail address: tmayadas{at}rics.bwh.harvard.edu
4 Abbreviations used in this paper: IC, immune complex; ROS, reactive oxygen species; PLC, phospholipase C; GEF, guanine exchange factor; WT, wild type; EGFP, enhanced GFP; LA, latrunculin A; PAK, p21-activated kinase; Wrt, wortmannin; BM, bone marrow; IgGSRBC, IgG opsonized sheep RBCs; BMDM, BM-derived macrophage; NBT, nitroblue tetrazolium; CD, cytochalasin D; GPCR, G protein-coupled receptor; p-p40, phospho-p40(phox); p, phospho; RLU, relative luminometer unit.
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