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Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a genetic disorder that occurs through the loss of heterozygosity of either TSC1 or TSC2, which encode Hamartin or Tuberin, respectively. Tuberin and Hamartin form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR) nutrient signaling input, but how this occurs is unclear. RESULTS: We show that the small G protein Rheb (Ras homolog enriched in brain) is a molecular target of TSC1/TSC2 that regulates mTOR signaling. Overexpression of Rheb activates 40S ribosomal protein S6 kinase 1 (S6K1) but not p90 ribosomal S6 kinase 1 (RSK1) or Akt. Furthermore, Rheb induces phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and causes 4E-BP1 to dissociate from eIF4E. This dissociation is completely sensitive to rapamycin (an mTOR inhibitor) but not wortmannin (a phosphoinositide 3-kinase [PI3K] inhibitor). Rheb also activates S6K1 during amino acid insufficiency via a rapamycin-sensitive mechanism, suggesting that Rheb participates in nutrient signaling through mTOR. Moreover, Rheb does not activate a S6K1 mutant that is unresponsive to mTOR-mediated signals, confirming that Rheb functions upstream of mTOR. Overexpression of the Tuberin-Hamartin heterodimer inhibits Rheb-mediated S6K1 activation, suggesting that Tuberin functions as a Rheb GTPase activating protein (GAP). Supporting this notion, TSC patient-derived Tuberin GAP domain mutants were unable to inactivate Rheb in vivo. Moreover, in vitro studies reveal that Tuberin, when associated with Hamartin, acts as a Rheb GTPase-activating protein. Finally, we show that membrane localization of Rheb is important for its biological activity because a farnesylation-defective mutant of Rheb stimulated S6K1 activation less efficiently. CONCLUSIONS: We show that Rheb acts as a novel mediator of the nutrient signaling input to mTOR and is the molecular target of TSC1 and TSC2 within mammalian cells.

Pubmed ID: 12906785

Authors

  • Tee AR
  • Manning BD
  • Roux PP
  • Cantley LC
  • Blenis J

Journal

Current biology : CB

Publication Data

August 5, 2003

Associated Grants

  • Agency: NCI NIH HHS, Id: CA46595
  • Agency: NIGMS NIH HHS, Id: GM41890
  • Agency: NIGMS NIH HHS, Id: GM51405
  • Agency: NIGMS NIH HHS, Id: GM56203
  • Agency: NIGMS NIH HHS, Id: R01 GM056203

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Biological Assay
  • Blotting, Western
  • Carrier Proteins
  • DNA-Binding Proteins
  • Electrophoresis, Polyacrylamide Gel
  • GTPase-Activating Proteins
  • Humans
  • Monomeric GTP-Binding Proteins
  • Mutagenesis, Site-Directed
  • Neuropeptides
  • Phosphoproteins
  • Plasmids
  • Precipitin Tests
  • Protein Kinases
  • Proteins
  • Repressor Proteins
  • Ribosomal Protein S6 Kinases
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transcription Factors
  • Transfection
  • Tuberous Sclerosis
  • Tumor Suppressor Proteins