IRS-3 inhibits IRS-2-mediated signaling in pancreatic beta-cells

Mol Cell Endocrinol. 2003 Jun 30;204(1-2):85-99. doi: 10.1016/s0303-7207(03)00124-2.


IRS-2 plays an important role in the control of pancreatic beta-cell growth, however it is unclear if other IRS family members are also involved. Using recombinant adenoviruses, IRS-1, -2 and -3 expression was varied in the beta-cell line, INS-1. Increased IRS-1 expression had no appreciable effect on beta-cell growth. However, increased IRS-2 expression augmented glucose/IGF-1 induced beta-cell growth mitogenesis and decreased apoptosis due to glucose-deprivation. In contrast, increased IRS-3 expression significantly inhibited mitogenesis and increased apoptosis. IRS-3 was intransiently located to the beta-cell plasma membrane, and appeared to be inert in terms of IGF-1 induced signaling. However, increased IRS-3 expression blocked glucose/IGF-1 induced IRS-2 translocation from the cytosol to the plasma membrane, dampening IRS-2/IGF-1R interaction and subsequent activation of the PI3K/PKB/GSK3 signaling pathway. In contrast, glucose/IGF-1 induced Erk-1/-2 and p70S6K activation were unaffected by IRS-3. These data emphasize the importance of IRS-2/PI3K/PKB signal transduction for beta-cell growth and survival.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Cell Division
  • Glucose / pharmacology
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Male
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction*
  • Transfection


  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, rat
  • Irs2 protein, rat
  • Irs3 protein, rat
  • Phosphoproteins
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Glucose