A Redox-triggered Ras-Effector Interaction

Abstract

Reactive free radical species are known to trigger biochemical events culminating in transcription factor activation and modulation of gene expression. The cyto- solic 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 physio- logically 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 phosphati- dylinositol 3-kinase (PI3K) to the plasma membrane, where it associated directly with the effector domain of Ras and became activated. Only the p110 and p110 (but not p110 ) catalytic subunits were recruited by redox-activated Ras. Activation of downstream targets of PI3K such as protein kinase B/Akt and mitogen-acti- vated 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