MECHANISMS OF SIGNAL TRANSDUCTION
Transactivation of ErbB2 and ErbB3 by Tumor Necrosis Factor-α and Anisomycin Leads to Impaired Insulin Signaling through Serine/Threonine Phosphorylation of IRS Proteins*

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The cellular pathways involved in the impairment of insulin signaling by cellular stress, triggered by the inflammatory cytokine tumor necrosis factor-α (TNF) or by translational inhibitors like cycloheximide and anisomycin were studied. Similar to TNF, cycloheximide and anisomycin stimulated serine phosphorylation of IRS-1 and IRS-2, reduced their ability to interact with the insulin receptor, inhibited the insulin-induced tyrosine phosphorylation of IRS proteins, and diminished their association with phosphatidylinositol 3-kinase (PI3K). These defects were partially reversed by wortmannin and LY294002, indicating that a PI3K-regulated step is critical for the impairment of insulin signaling by cellular stress. Induction of cellular stress resulted in complex formation between PI3K and ErbB2/ErbB3 and enhanced PI3K activity, implicating ErbB proteins as downstream effectors of stress-induced insulin resistance. Indeed, stimulation of ErbB2/ErbB3 by NDFβ1, the ErbB3 ligand, inhibited IRS protein tyrosine phosphorylation and recruitment of downstream effectors. Specific inhibitors of the ErbB2 tyrosine kinase abrogated the activation of ErbB2/ErbB3 and in parallel prevented the reduction in IRS protein functions. Taken together, our results suggest a novel mechanism by which cellular stress induces cross-talk between two different signaling pathways. Stress-dependent transactivation of ErbB2/ErbB3 receptors triggers a PI3K cascade that induces serine phosphorylation of IRS proteins culminating in insulin resistance.

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Published, JBC Papers in Press, January 4, 2002, DOI 10.1074/jbc.M109391200

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This work was supported in part by Research Grant 99-1310 from the Chief Scientist's Office of the Ministry of Health, the General Administrator, Ministry of Justice, and the Chudoeski fund (to H. K. and Y. Z.).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.

This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Rina Hemi, Sackler Faculty of Medicine, Tel-Aviv University, Israel.