The new elements of insulin signaling. Insulin receptor substrate-1 and proteins with SH2 domains

Diabetes. 1993 May;42(5):643-50. doi: 10.2337/diab.42.5.643.


Since the discovery of insulin and its receptor, the downstream elements responsible for the pleiotropic insulin signal have been difficult to define. The recently discovered insulin receptor substrate, IRS-1, provides an innovative and simple way to think about this problem: IRS-1 may mediate the control of various cellular processes by insulin. Overexpression of IRS-1 enhances insulin-stimulated DNA synthesis in Chinese hamster ovary cells, and microinjection of IRS-1 protein potentiates the maturation of Xenopus oocytes. We suspect that insulin signals are enabled when the activated insulin receptor kinase phosphorylates specific tyrosine residues in IRS-1. These phosphorylated sites associate with high affinity to cellular proteins that contain SH2 (src homology-2) domains. This association is specific and depends on the amino acid sequence surrounding the phosphotyrosine residue and the isoform of the SH2 domain. A growing number of SH2 domain-containing proteins have been identified, and we suspect that IRS-1 has the potential to simultaneously regulate many of them. We have only begun to identify the specific proteins that associate with phosphorylated IRS-1. One of them, the phosphatidylinositol 3'-kinase, is activated when the SH2 domains in its 85,000-M(r) regulatory subunit bind to phosphorylated IRS-1. IRS-1 also interacts with other proteins such as SHPTP2, a novel SH2 domain-containing Tyr phosphatase, and GRB-2/sem-5, a protein that is implicated in p21ras signaling. The interaction between phosphorylated IRS-1 and multiple SH2 domain-containing proteins may ultimately explain the pleiotropic effects of insulin.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CHO Cells
  • Cricetinae
  • DNA Replication
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins
  • Models, Biological
  • Molecular Sequence Data
  • Oocytes / physiology
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, Insulin / physiology*
  • Signal Transduction*
  • Xenopus
  • Xenopus Proteins


  • Insulin
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Xenopus Proteins
  • irs1 protein, Xenopus
  • Protein-Tyrosine Kinases
  • Receptor, Insulin