Abstract
The cellular pathways involved in the impairment of insulin signaling by cellular stress, triggered by the inflammatory cytokine tumor necrosis factor-alpha (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 NDFbeta1, 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.
Highlights
Insulin mediates a wide spectrum of biological responses upon binding to its cell surface receptor [1]
2—We have previously reported that tumor necrosis factor-␣ (TNF) and SMase impair insulin signaling in rat hepatoma Fao cells [14, 16, 17]
Such treatment reduced the extent of insulin-induced tyrosine phosphorylation of insulin receptor substrates (IRS)-1 and IRS-2 (Fig. 1, A and B), reduced the association of IRS proteins with the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) (Fig. 1, A and B) and reduced PI3K activity
Summary
Insulin mediates a wide spectrum of biological responses upon binding to its cell surface receptor [1]. To determine whether this pathway contributes to the serine phosphorylation of IRS proteins, induced by inflammatory cytokines or translational inhibitors, Fao cells were treated with the different stress inducers, with or without the addition of PD98059, a specific inhibitor of MEK, prior to incubation with insulin.
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