Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action

Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9660-4. doi: 10.1073/pnas.94.18.9660.

Abstract

The phosphorylation of insulin receptor substrate 1 (IRS-1) on tyrosine residues by the insulin receptor (IR) tyrosine kinase is involved in most of the biological responses of insulin. IRS-1 mediates insulin signaling by recruiting SH2 proteins through its multiple tyrosine phosphorylation sites. The phosphorylation of IRS-1 on serine/threonine residues also occurs in cells; however, the particular protein kinase(s) promoting this type of phosphorylation are unknown. Here we report that glycogen synthase kinase 3 (GSK-3) is capable of phosphorylating IRS-1 and that this modification converts IRS-1 into an inhibitor of IR tyrosine kinase activity in vitro. Expression of wild-type GSK-3 or an "unregulated" mutant of the kinase (S9A) in CHO cells overexpressing IRS-1 and IR, resulted in increased serine phosphorylation levels of IRS-1, suggesting that IRS-1 is a cellular target of GSK-3. Furthermore, insulin-induced tyrosine phosphorylation of IRS-1 and IR was markedly suppressed in cells expressing wild-type or the S9A mutant, indicating that expression of GSK-3 impairs IR tyrosine kinase activity. Taken together, our studies suggest a new role for GSK-3 in attenuating insulin signaling via its phosphorylation of IRS-1 and may provide new insight into mechanisms important in insulin resistance.

Publication types

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

MeSH terms

  • Animals
  • CHO Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cricetinae
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Recombinant Proteins / metabolism
  • Substrate Specificity

Substances

  • Insulin
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Recombinant Proteins
  • Glycogen Synthase Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3