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

Martin G. Myers, Jonathan M. Backer, Xiao Jian Sun, Steven Shoelson, Patrick Hu, Joseph Schlessinger, Monique Yoakim, Brian Schaffhausen, Morris F. White

Research output: Contribution to journalArticle

359 Citations (Scopus)

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
StatePublished - 1992
Externally publishedYes

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Phosphatidylinositol 3-Kinase
src Homology Domains
Tyrosine
Insulin
Insulin Receptor Substrate Proteins
Peptides
Phosphotyrosine
Bacterial Proteins
Insulin Receptor
Proteins
Fibroblasts
Phosphorylation
Enzymes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

IRS-1 activates phosphatidylinositol 3′-kinase by associating with src homology 2 domains of p85. / Myers, Martin G.; Backer, Jonathan M.; Sun, Xiao Jian; Shoelson, Steven; Hu, Patrick; Schlessinger, Joseph; Yoakim, Monique; Schaffhausen, Brian; White, Morris F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 21, 1992, p. 10350-10354.

Research output: Contribution to journalArticle

Myers, MG, Backer, JM, Sun, XJ, Shoelson, S, Hu, P, Schlessinger, J, Yoakim, M, Schaffhausen, B & White, MF 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, vol. 89, no. 21, pp. 10350-10354.
Myers, Martin G. ; Backer, Jonathan M. ; Sun, Xiao Jian ; Shoelson, Steven ; Hu, Patrick ; Schlessinger, Joseph ; Yoakim, Monique ; Schaffhausen, Brian ; White, Morris F. / IRS-1 activates phosphatidylinositol 3′-kinase by associating with src homology 2 domains of p85. In: Proceedings of the National Academy of Sciences of the United States of America. 1992 ; Vol. 89, No. 21. pp. 10350-10354.
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AU - Sun, Xiao Jian

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AU - Hu, Patrick

AU - Schlessinger, Joseph

AU - Yoakim, Monique

AU - Schaffhausen, Brian

AU - White, Morris F.

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AB - 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.

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