title: A redox-triggered ras-effector interaction. Recruitment of phosphatidylinositol 3'-kinase to Ras by redox stress.
abstract: Reactive free radical species are known to trigger biochemical events culminating in transcription factor activation and modulation of gene expression. The cytosolic signaling events triggered by free radicals that result in nuclear responses are largely unknown. Here we identify a signaling cascade triggered immediately upon redox activation of Ras. We examined two physiologically relevant models of redox signaling: 1) nitric oxide in human T cells, and 2) advanced glycation end product in rat pheochromocytoma cells. Reactive free radical species generated by nitric oxide donors and the interaction of advanced glycation end product with its receptor led to the recruitment of p85/p110 phosphatidylinositol 3'-kinase (PI3K) to the plasma membrane, where it associated directly with the effector domain of Ras and became activated. Only the p110beta and p110delta (but not p110alpha) catalytic subunits were recruited by redox-activated Ras. Activation of downstream targets of PI3K such as protein kinase B/Akt and mitogen-activated protein kinase was found to be PI3K dependent. Our study demonstrates that nitrosative and oxidative stressors trigger Ras-dependent and PI3K-regulated events in cells and define a biochemical pathway that is triggered by redox signaling.
authors.affiliation: Department of Biochemistry, Cornell University Medical College, New York, New York 10021, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Deora
authors.forename: T
authors.initials: T
authors.lastname: Win
authors.forename: B
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: H M
authors.initials: HM
authors.lastname: Lander
mesh_terms: D000818:Animals; D006801:Humans; D019169:Jurkat Cells; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011233:Precipitin Tests; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins