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

EMBO J. 1992 Sep;11(9):3469-79.

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 insulin-stimulated 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Enzyme Activation / drug effects
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins
  • Molecular Sequence Data
  • Oligopeptides / pharmacology
  • Phosphatidylinositol 3-Kinases
  • Phosphoproteins / metabolism*
  • Phosphotransferases / metabolism*
  • Phosphotyrosine
  • Protein-Tyrosine Kinases / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, Insulin / metabolism
  • Signal Transduction
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Insulin
  • Insulin Receptor Substrate Proteins
  • Oligopeptides
  • Phosphoproteins
  • Phosphotyrosine
  • Tyrosine
  • Phosphotransferases
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Receptor, Insulin