HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 12, 7983-7993, March 21, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/12/7983    most recent M708281200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roepstorff, K. Articles by Vilhardt, F. Search for Related Content PubMed PubMed Citation Articles by Roepstorff, K. Articles by Vilhardt, F. Social Bookmarking                      What's this?

Stimulus-dependent Regulation of the Phagocyte NADPH Oxidase by a VAV1, Rac1, and PAK1 Signaling Axis^*

Kirstine Roepstorff, Izabela Rasmussen, Makoto Sawada, Cristophe Cudre-Maroux^¶, Patrick Salmon^¶, Gary Bokoch^||, Bo van Deurs, and Frederik Vilhardt¹

From the Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200N Copenhagen, Denmark, the ^¶Department of Microbiology, Université de Genève, 1211 Genève, Switzerland, the ^||Departments of Immunology and Cell Biology, Scripps Research Institute, La Jolla, California 92037, and the Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan

The p21-activated kinase-1 (PAK1) is best known for its role in the regulation of cytoskeletal and transcriptional signaling pathways. We show here in the microglia cell line Ra2 that PAK1 regulates NADPH oxidase (NOX-2) activity in a stimulus-specific manner. Thus, conditional expression of PAK1 dominant-positive mutants enhanced, whereas dominant-negative mutants inhibited, NADPH oxidase-mediated superoxide generation following formyl-methionyl-leucylphenylalanine or phorbol 12-myristate 13-acetate stimulation. Both Rac1 and the GTP exchange factor VAV1 were required as upstream signaling proteins in the formyl-methionyl-leucyl-phenylalanine-induced activation of endogenous PAK1. In contrast, PAK1 mutants had no effect on superoxide generation downstream of FcR signaling during phagocytosis of IgG-immune complexes. We further present evidence that the effect of PAK1 on the respiratory burst is mediated through phosphorylation of p47^Phox, and we show that expression of a p47^Phox (S303D/S304D/S320D) mutant, which mimics phosphorylation by PAK1, induced basal superoxide generation in vivo. In contrast PAK1 substrates LIMK-1 or RhoGDI are not likely to contribute to the PAK1 effect on NADPH oxidase activation. Collectively, our findings define a VAV1-Rac1-PAK1 signaling axis in mononuclear phagocytes regulating superoxide production in a stimulus-dependent manner.

Received for publication, October 4, 2007 , and in revised form, December 17, 2007.

^* This work was supported by Danish Research Council Grant 22-04-0336, grants from Scleroseforeningen and the Lundbeck Foundation (to F. V.), and National Institutes of Health Grant HL48008 (to G. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-4.

¹ To whom correspondence should be addressed: Dept. of Cellular and Molecular Medicine, Bldg. 18.4, The Panum Institute, Copenhagen University, Blegdamsvej 3, 2200N Copenhagen, Denmark. Tel.: 45-35327120; Fax: 45-35327285; E-mail: f.vilhardt{at}mai.ku.dk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. S. Terada What Underlies Endothelial Shear Sensing? The Matrix, of Course Circ. Res., September 12, 2008; 103(6): 562 - 564. [Full Text] [PDF]