Journal of Biological Chemistry
Volume 270, Issue 42, 20 October 1995, Pages 24670-24673
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Cell Biology and Metabolism
4PS/Insulin Receptor Substrate (IRS)-2 Is the Alternative Substrate of the Insulin Receptor in IRS-1-deficient Mice (∗)

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Insulin receptor substrate-1 (IRS-1) is the major cytoplasmic substrate of the insulin and insulin-like growth factor (IGF)-1 receptors. Transgenic mice lacking IRS-1 are resistant to insulin and IGF-1, but exhibit significant residual insulin action which corresponds to the presence of an alternative high molecular weight substrate in liver and muscle. Recently, Sun et al. (Sun, X.-J, Wang, L.-M., Zhang, Y., Yenush, L. P., Myers, M. G., Jr., Glasheen, E., Lane, W. S., Pierce, J. H., and White, M. F. (1995) Nature 377, 173-177) purified and cloned 4PS, the major substrate of the IL-4 receptor-associated tyrosine kinase in myeloid cells, which has significant structural similarity to IRS-1. To determine if 4PS is the alternative substrate of the insulin receptor in IRS-1-deficient mice, we performed immunoprecipitation, immunoblotting, and phosphatidylinositol (PI) 3-kinase assays using specific antibodies to 4PS. Following insulin stimulation, 4PS is rapidly phosphorylated in liver and muscle, binds to the p85 subunit of PI 3-kinase, and activates the enzyme. Insulin stimulation also results in the association of 4PS with Grb 2 in both liver and muscle. In IRS-1-deficient mice, both the phosphorylation of 4PS and associated PI 3-kinase activity are enhanced, without an increase in protein expression. Immunodepletion of 4PS from liver and muscle homogenates removes most of the phosphotyrosine-associated PI 3-kinase activity in IRS-1-deficient mice. Thus, 4PS is the primary alternative substrate, i.e. IRS-2, which plays a major role in physiologic insulin signal transduction via both PI 3-kinase activation and Grb 2/Sos association. In IRS-1-deficient mice, 4PS/IRS-2 provides signal transduction to these two major pathways of insulin signaling.

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This work was supported by Grants DK33201 (to C. R. K.) and DK43808 (to M. F. W.) from the National Institutes of Health and a Juvenile Diabetes Foundation grant (to X. J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

Mary K. Iacocca Fellow.

Supported by a postdoctoral fellowship of the Deutsche Forschungsgemeinschaft.

∗∗

Current address: Dept. of Metabolic Medicine, Kumamoto University Medical School, Kumamoto 860, Japan.

§§

Supported by the Harcourt General Charitable Foundation, The Greenwall Foundation, and a Career Development Award from the American Diabetes Association.