IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85

M. G. Myers, J. M. Backer, Jian Sun Xiao Jian Sun, S. Shoelson, P. Hu, J. Schlessinger, M. Yoakim, B. Schaffhausen, M. F. White

Research output: Contribution to journalArticle

366 Scopus citations

Abstract

IRS-1 is an insulin receptor substrate that undergoes tyrosine phosphorylation and associates with the phosphatidylinositol (PtdIns) 3'- kinase immediately after insulin stimulation. Recombinant IRS-1 protein was tyrosine phosphorylated by the insulin receptor in vitro and associated with the PtdIns 3'-kinase from lysates of quiescent 3T3 fibroblasts. Bacterial fusion proteins containing the src homology 2 domains (SH2 domains) of the 85-kDa subunit (p85) of the PtdIns 3'-kinase bound quantitatively to tyrosine phosphorylated, but not unphosphorylated, IRS-1, and this association was blocked by phosphotyrosine-containing synthetic peptides. Moreover, the phosphorylated peptides and the SH2 domains each inhibited binding of PtdIns 3'-kinase to IRS-1. Phosphorylated IRS-1 activated PtdIns 3'-kinase in anti- p85 immunoprecipitates in vitro, and this activation was blocked by SH2 domain fusion proteins. These data suggest that the interaction between PtdIns 3'-kinase and IRS-1 is mediated by tyrosine phosphorylated motifs on IRS-1 and the SH2 domains of p85, and IRS-1 activates PtdIns 3'-kinase by binding to the SH2 domains of p85. Thus, IRS-1 likely serves to transmit the insulin signal by binding and regulating intracellular enzymes containing SH2 domains.

Original languageEnglish (US)
Pages (from-to)10350-10354
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number21
DOIs
StatePublished - 1992

ASJC Scopus subject areas

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    Myers, M. G., Backer, J. M., Xiao Jian Sun, J. S., Shoelson, S., Hu, P., Schlessinger, J., Yoakim, M., Schaffhausen, B., & White, M. F. (1992). IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. Proceedings of the National Academy of Sciences of the United States of America, 89(21), 10350-10354. https://doi.org/10.1073/pnas.89.21.10350