Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation

Mol Cell Biol. 2006 Jan;26(1):63-76. doi: 10.1128/MCB.26.1.63-76.2006.

Abstract

Nutritional excess and/or obesity represent well-known predisposition factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, molecular links between obesity and NIDDM are only beginning to emerge. Here, we demonstrate that nutrients suppress phosphatidylinositol 3 (PI3)-kinase/Akt signaling via Raptor-dependent mTOR (mammalian target of rapamycin)-mediated phosphorylation of insulin receptor substrate 1 (IRS-1). Raptor directly binds to and serves as a scaffold for mTOR-mediated phosphorylation of IRS-1 on Ser636/639. These serines lie close to the Y(632)MPM motif that is implicated in the binding of p85alpha/p110alpha PI3-kinase to IRS-1 upon insulin stimulation. Phosphomimicking mutations of these serines block insulin-stimulated activation of IRS-1-associated PI3-kinase. Knockdown of Raptor as well as activators of the LKB1/AMPK pathway, such as the widely used antidiabetic compound metformin, suppress IRS-1 Ser636/639 phosphorylation and reverse mTOR-mediated inhibition on PI3-kinase/Akt signaling. Thus, diabetes-related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1-dependent PI3-kinase/Akt signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / metabolism*
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Leucine / metabolism
  • Leucine / pharmacology
  • Mice
  • Monomeric GTP-Binding Proteins / metabolism
  • Mutation
  • Neuropeptides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / analysis
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism*
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Ras Homolog Enriched in Brain Protein
  • Rats
  • Regulatory-Associated Protein of mTOR
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases

Substances

  • Adaptor Proteins, Signal Transducing
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Irs1 protein, rat
  • Neuropeptides
  • Phosphoproteins
  • Proteins
  • RHEB protein, human
  • RPTOR protein, human
  • Ras Homolog Enriched in Brain Protein
  • Regulatory-Associated Protein of mTOR
  • Serine
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • mTOR protein, rat
  • Proto-Oncogene Proteins c-akt
  • Monomeric GTP-Binding Proteins
  • Leucine
  • Glucose
  • Sirolimus