Tks5-dependent, nox-mediated generation of reactive oxygen species is necessary for invadopodia formation.
Invadopodia are actin-rich membrane protrusions of cancer cells that facilitate pericellular proteolysis and invasive behavior. We show here that reactive oxygen species (ROS) generated by the NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox) system are necessary for invadopodia formation and function. Knockdown of the invadopodia protein Tks5 [tyrosine kinase substrate with five Src homology 3 (SH3) domains], which is structurally related to the Nox component p47(phox), reduces total ROS abundance in cancer cells. Furthermore, Tks5 and p22(phox) can associate with each other, suggesting that Tks5 is part of the Nox complex. Tyrosine phosphorylation of Tks5 and Tks4, but not other Src substrates, is reduced by Nox inhibition. We propose that Tks5 facilitates the production of ROS necessary for invadopodia formation, and that in turn ROS modulate Tks5 tyrosine phosphorylation in a positive feedback loop.
Diaz
Begoña
B
Tumor Microenvironment Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Shani
Gidon
G
Pass
Ian
I
Anderson
Diana
D
Quintavalle
Manuela
M
Courtneidge
Sara A
SA
D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D022081:Cell Surface Extensions; D003573:Cytochrome b Group / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D028044:Phosphate-Binding Proteins; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014162:Transfection
D033942:Adaptor Proteins, Vesicular Transport; D003573:Cytochrome b Group; C114235:Fish protein, mouse; D028044:Phosphate-Binding Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C478582:SH3PXD2A protein, human; D019255:NADPH Oxidases; C515614:Cyba protein, mouse