A Redox-triggered Ras-Effector Interaction
RECRUITMENT OF PHOSPHATIDYLINOSITOL 3′-KINASE TO Ras BY REDOX STRESS*
- From the ‡Department of Biochemistry, Cornell University Medical College, New York, New York 10021 and§Ludwig Institute for Cancer Research, London W1P 8BT, United Kingdom
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 p110β and p110δ (but not p110α) 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.
Footnotes
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↵* This work was supported in part by National Institutes of Health Grants GM55509 and AI37637 (to H. M. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ Supported in part by the Flanders Fund for Scientific Research, Belgium.
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↵‖ To whom correspondence should be addressed: Dept. of Biochemistry, Cornell University Medical College, New York, NY 10021. Tel.: 212-746-6462; Fax: 212-746-8789; E-mail: hmlander{at}mail.med.cornell.edu.
- Abbreviations:
- AGE
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advanced glycation end product
- NO
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nitric oxide
- PI3K
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phosphotidylinositol 3′-kinase
- SNP
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sodium nitroprusside
- SNAP
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S-nitroso-N-acetylpenicillamine
- ERK
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extracellular signal-regulated kinase.
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- Received May 5, 1998.
- Revision received August 11, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
