Aa. Deora et al., A REDOX-TRIGGERED RAS-EFFECTOR INTERACTION - RECRUITMENT OF PHOSPHATIDYLINOSITOL 5'-KINASE TO RAS BY REDOX STRESS, The Journal of biological chemistry, 273(45), 1998, pp. 29923-29928
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.