Novel p47(phox)-related organizers regulate localized NADPH oxidase 1 (Nox1) activity.
The mechanisms that determine localized formation of reactive oxygen species (ROS) through NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) family members in nonphagocytic cells are unknown. We show that the c-Src substrate proteins Tks4 (tyrosine kinase substrate with four SH3 domains) and Tks5 are functional members of a p47(phox)-related organizer superfamily. Tks proteins selectively support Nox1 and Nox3 (and not Nox2 and Nox4) activity in reconstituted cellular systems and interact with the NoxA1 activator protein through an Src homology 3 domain-mediated interaction. Endogenous Tks4 is required for Rac guanosine triphosphatase- and Nox1-dependent ROS production by DLD1 colon cancer cells. Our results are consistent with the Tks-mediated recruitment of Nox1 to invadopodia that form in DLD1 cells in a Tks- and Nox-dependent fashion. We propose that Tks organizers represent previously unrecognized members of an organizer superfamily that link Nox to localized ROS formation.
Gianni
Davide
D
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Diaz
Begoña
B
Taulet
Nicolas
N
Fowler
Bruce
B
Courtneidge
Sara A
SA
Bokoch
Gary M
GM
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C478582:SH3PXD2A protein, human; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C431570:Nox3 protein, human; C060505:neutrophil cytosolic factor 1