A REDOX-TRIGGERED RAS-EFFECTOR INTERACTION - RECRUITMENT OF PHOSPHATIDYLINOSITOL 5'-KINASE TO RAS BY REDOX STRESS

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 Ra s. We examined two physiologically relevant models of redox signaling: 1) nitric oxide in human T cells, and 2) advanced glycation end produ ct in rat pheochromocytoma cells. Reactive free radical species genera ted by nitric oxide donors and the interaction of advanced glycation e nd product with its receptor led to the recruitment of p85/p110 phosph atidylinositol 3'-kinase (PI3K) to the plasma membrane, where it assoc iated directly with the effector domain of Ras and became activated. O nly the p110 beta and p110 delta (but not p110 alpha) catalytic subuni ts were recruited by redox-activated Ras. Activation of downstream tar gets of PI3K such as protein kinase B/Akt and mitogen-activated protei n kinase was found to be PI3K dependent. Our study demonstrates that n itrosative and oxidative stressors trigger Ras-dependent and PI3K-regu lated events in cells and define a biochemical pathway that is trigger ed by redox signaling.