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Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis.

The TSC1-TSC2/Rheb/Raptor-mTOR/S6K1 cell growth cassette has recently been shown to regulate cell autonomous insulin and insulin-like growth factor I (IGF-I) sensitivity by transducing a negative feedback signal that targets insulin receptor substrates 1 and 2 (IRS1 and -2). Using two cell culture models of the familial hamartoma syndrome, tuberous sclerosis, we show here that Raptor-mTOR and S6K1 are required for phosphorylation of IRS1 at a subset of serine residues frequently associated with insulin resistance, including S307, S312, S527, S616, and S636 (of human IRS1). Using loss- and gain-of-function S6K1 constructs, we demonstrate a requirement for the catalytic activity of S6K1 in both direct and indirect regulation of IRS1 serine phosphorylation. S6K1 phosphorylates IRS1 in vitro on multiple residues showing strong preference for RXRXXS/T over S/T,P sites. IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb. These studies suggest that, through serine phosphorylation, Raptor-mTOR and S6K1 cell autonomously promote the depletion of IRS1 from specific intracellular pools in pathological states of insulin and IGF-I resistance and thus potentially in lesions associated with tuberous sclerosis.

Pubmed ID: 16914728


  • Shah OJ
  • Hunter T


Molecular and cellular biology

Publication Data

September 17, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: CA14195
  • Agency: NCI NIH HHS, Id: CA82683
  • Agency: NIGMS NIH HHS, Id: GM67407
  • Agency: NCI NIH HHS, Id: T32-CA09523

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Culture Techniques
  • Cells, Cultured
  • Humans
  • Insulin Receptor Substrate Proteins
  • Mice
  • Monomeric GTP-Binding Proteins
  • Neuropeptides
  • Phosphoproteins
  • Phosphoserine
  • Protein Kinases
  • Proteins
  • Ribosomal Protein S6 Kinases
  • Subcellular Fractions
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis
  • Tumor Suppressor Proteins