Insulin signal transduction and the IRS proteins

Annu Rev Pharmacol Toxicol. 1996:36:615-58. doi: 10.1146/


Insulin controls organismal and cellular physiology by initiating numerous intracellular signals. Insulin first binds the extracellular domain of the insulin receptor, which activates the receptor's intracellular tyrosine kinase. Receptor-mediated phosphorylation of the IRS proteins is required for the propagation of signals for mitogenesis, glucose transport, and numerous other biological and biochemical events during insulin signaling. IRS proteins also mediate signaling by a subset of other growth factor and cytokine receptors; recognition and phosphorylation by specific receptors appears to be mediated by the PH and PTB domains of the IRS proteins. The best understood mechanism of IRS-protein-mediated signaling is the binding of SH2 domain-containing signaling molecules (such as PI 3'-kinase) by tyrosine phosphorylation sites on IRS proteins. Other paradigms of IRS-protein signaling are beginning to emerge, however, and these exciting molecules promise to teach us much in the next few years.

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
  • Diabetes Mellitus / drug therapy
  • Diabetes Mellitus / enzymology
  • Diabetes Mellitus / physiopathology
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Insulin / therapeutic use
  • Molecular Sequence Data
  • Phosphorylation
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / metabolism
  • Receptor, Insulin / chemistry
  • Receptor, Insulin / drug effects
  • Receptor, Insulin / metabolism*
  • Receptors, Cytokine / drug effects
  • Receptors, Cytokine / metabolism
  • Sequence Alignment
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Substrate Specificity


  • Insulin
  • Receptors, Cytokine
  • Protein-Tyrosine Kinases
  • Receptor, Insulin
  • Glucose