Vav proteins in neutrophils are required for FcγR-mediated signaling to Rac GTPases and nicotinamide adenine dinucleotide phosphate oxidase component p40(phox)

Ahmad Utomo, Xavier Cullere, Michael Glogauer, Wojciech Swat, Tanya N. Mayadas

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Phagocytes generate reactive oxygen species, the regulation of which is important in eliminating ingested microbes while limiting tissue damage. Clustering of FcγRs 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 FcαR clustering. However, studies in cytokine-primed cells revealed a strict requirement for Vav1 and Vav3 and Rac1 and Rac2 in the FcγR-mediated oxidative burst. In comparison, Vav was not essential for PMA or G protein-coupled receptor-mediated superoxide generation. The FcγR-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 FcγR-mediated activation of the oxidative burst, but not in phagocytosis. Thus, Vav proteins specifically couple FcγR 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.

Original languageEnglish
Pages (from-to)6388-6397
Number of pages10
JournalJournal of Immunology
Volume177
Issue number9
DOIs
StatePublished - Nov 1 2006

Fingerprint

Dive into the research topics of 'Vav proteins in neutrophils are required for FcγR-mediated signaling to Rac GTPases and nicotinamide adenine dinucleotide phosphate oxidase component p40(phox)'. Together they form a unique fingerprint.

Cite this