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Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway

J Li1, K DeFea, R A Roth

  • 1Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, California 94305, USA.

The Journal of Biological Chemistry
|March 27, 1999
PubMed

Insights

Platelet-derived growth factor (PDGF) negatively regulates insulin signaling through specific serine residues on IRS-1, distinct from protein kinase C pathways. This regulation involves the Akt kinase cascade and is sensitive to mTOR inhibitors.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Endocrinology

Background:

  • Serine/threonine phosphorylation of insulin receptor substrate 1 (IRS-1) is a known negative regulator of insulin signaling.
  • Protein kinase C (PKC) mediated regulation involves mitogen-activated protein kinase (MAPK) and IRS-1 serine 612 phosphorylation.

Purpose of the Study:

  • To compare the negative regulation of insulin signaling by platelet-derived growth factor (PDGF) with that induced by endothelin-1 (ET-1), a PKC activator.
  • To elucidate the specific molecular mechanisms and signaling pathways involved in PDGF-mediated negative regulation of insulin signaling.

Main Methods:

  • Comparative analysis of insulin signaling inhibition by PDGF and ET-1.
  • Investigation of the role of MAPK and specific IRS-1 serine phosphorylation sites (S612, S632, S662, S731).
  • Assessment of Akt kinase activity and its role in PDGF-induced inhibition.
  • Evaluation of the effects of rapamycin, an mTOR inhibitor, on PDGF and Akt mediated signaling.

Main Results:

  • PDGF-induced inhibition of insulin signaling did not involve MAPK or IRS-1 S612 phosphorylation, unlike ET-1.
  • PDGF-mediated negative regulation required phosphorylation of IRS-1 serines 632, 662, and 731.
  • The serine/threonine kinase Akt, activated by PDGF, was identified as an inhibitor of insulin signaling.
  • Inhibition by both PDGF and Akt required the same IRS-1 serine residues and was sensitive to rapamycin, indicating involvement of the mTOR pathway.

Conclusions:

  • The phosphatidylinositol 3-kinase (PI3K)/Akt kinase cascade represents an alternative negative regulatory pathway for insulin signaling, distinct from PKC/MAPK.
  • Specific serine residues (632, 662, 731) in IRS-1 are critical for negative regulation mediated by PDGF and Akt.
  • The PI3K/Akt/mTOR pathway plays a significant role in modulating insulin receptor substrate 1 function and insulin signal transduction.

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