Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation

Jonathan M. Backer, Martin G. Myers, Steven E. Shoelson, Debra J. Chin, Xiao Jian Sun, Montserrat Miralpeix, Patrick Hu, Benjamin Margolis, Edward Y. Skolnik, Joseph Schlessinger, Morris F. White

Research output: Contribution to journalArticle

786 Citations (Scopus)

Abstract

IRS-1 undergoes rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (Ptdins) 3′-kinase, but p85 is not tyrosyl phosphorylated. IRS-1 contains nine tyrosine phosphorylation sites in YXXM (Tyr-Xxx-Xxx-Met) motifs. Formation of the IRS-1-PtdIns 3′-kinase complex in vitro is inhibited by synthetic peptides containing phosphorylated YXXM motifs, suggesting that the binding of PtdIns 3′-kinase to IRS-1 is mediated through the SH2 (src homology-2) domains of p85. Furthermore, overexpression of IRS-1 potentiates the activation of PtdIns 3-kinase in insulinstimulated cells, and tyrosyl phosphorylated IRS-1 or peptides containing phosphorylated YXXM motifs activate PtdIns 3′-kinase in vitro. We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3′-kinase during insulin stimulation.

Original languageEnglish (US)
Pages (from-to)3469-3479
Number of pages11
JournalEMBO Journal
Volume11
Issue number9
StatePublished - Sep 1992
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinases
Association reactions
Insulin
Phosphorylation
src Homology Domains
Tyrosine
Peptides
Chemical activation

Keywords

  • Insulin
  • IRS-1
  • Phosphatidylinositol 3′-kinase
  • Signal transduction
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Backer, J. M., Myers, M. G., Shoelson, S. E., Chin, D. J., Sun, X. J., Miralpeix, M., ... White, M. F. (1992). Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO Journal, 11(9), 3469-3479.

Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. / Backer, Jonathan M.; Myers, Martin G.; Shoelson, Steven E.; Chin, Debra J.; Sun, Xiao Jian; Miralpeix, Montserrat; Hu, Patrick; Margolis, Benjamin; Skolnik, Edward Y.; Schlessinger, Joseph; White, Morris F.

In: EMBO Journal, Vol. 11, No. 9, 09.1992, p. 3469-3479.

Research output: Contribution to journalArticle

Backer, JM, Myers, MG, Shoelson, SE, Chin, DJ, Sun, XJ, Miralpeix, M, Hu, P, Margolis, B, Skolnik, EY, Schlessinger, J & White, MF 1992, 'Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation', EMBO Journal, vol. 11, no. 9, pp. 3469-3479.
Backer JM, Myers MG, Shoelson SE, Chin DJ, Sun XJ, Miralpeix M et al. Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. EMBO Journal. 1992 Sep;11(9):3469-3479.
Backer, Jonathan M. ; Myers, Martin G. ; Shoelson, Steven E. ; Chin, Debra J. ; Sun, Xiao Jian ; Miralpeix, Montserrat ; Hu, Patrick ; Margolis, Benjamin ; Skolnik, Edward Y. ; Schlessinger, Joseph ; White, Morris F. / Phosphatidylinositol 3′-kinase is activated by association with IRS-1 during insulin stimulation. In: EMBO Journal. 1992 ; Vol. 11, No. 9. pp. 3469-3479.
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AU - Miralpeix, Montserrat

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AB - IRS-1 undergoes rapid tyrosine phosphorylation during insulin stimulation and forms a stable complex containing the 85 kDa subunit (p85) of the phosphatidylinositol (Ptdins) 3′-kinase, but p85 is not tyrosyl phosphorylated. IRS-1 contains nine tyrosine phosphorylation sites in YXXM (Tyr-Xxx-Xxx-Met) motifs. Formation of the IRS-1-PtdIns 3′-kinase complex in vitro is inhibited by synthetic peptides containing phosphorylated YXXM motifs, suggesting that the binding of PtdIns 3′-kinase to IRS-1 is mediated through the SH2 (src homology-2) domains of p85. Furthermore, overexpression of IRS-1 potentiates the activation of PtdIns 3-kinase in insulinstimulated cells, and tyrosyl phosphorylated IRS-1 or peptides containing phosphorylated YXXM motifs activate PtdIns 3′-kinase in vitro. We conclude that the binding of tyrosyl phosphorylated IRS-1 to the SH2 domains of p85 is the critical step that activates PtdIns 3′-kinase during insulin stimulation.

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