Stimulus-dependent regulation of the phagocyte NADPH oxidase by a VAV1, Rac1, and PAK1 signaling axis.
J Biol Chem
; 283(12): 7983-93, 2008 Mar 21.
Article
em En
| MEDLINE
| ID: mdl-18160398
ABSTRACT
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 FcgammaR 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.
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Base de dados:
MEDLINE
Assunto principal:
Neuropeptídeos
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Glicoproteínas de Membrana
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Transdução de Sinais
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NADPH Oxidases
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Proteínas rac de Ligação ao GTP
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Proteínas rac1 de Ligação ao GTP
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Proteínas Proto-Oncogênicas c-vav
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Quinases Ativadas por p21
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article