Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins

Nat Cell Biol. 2003 Jun;5(6):578-81. doi: 10.1038/ncb999.

Abstract

Mutations in the TSC1 or TSC2 genes cause tuberous sclerosis, a benign tumour syndrome in humans. Tsc2 possesses a domain that shares homology with the GTPase-activating protein (GAP) domain of Rap1-GAP, suggesting that a GTPase might be the physiological target of Tsc2. Here we show that the small GTPase Rheb (Ras homologue enriched in brain) is a direct target of Tsc2 GAP activity both in vivo and in vitro. Point mutations in the GAP domain of Tsc2 disrupted its ability to regulate Rheb without affecting the ability of Tsc2 to form a complex with Tsc1. Our studies identify Rheb as a molecular target of the TSC tumour suppressors.

Publication types

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

MeSH terms

  • Animals
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster
  • GTP-Binding Proteins / metabolism
  • GTPase-Activating Proteins / physiology
  • Gene Expression Regulation, Fungal
  • Genes, Suppressor
  • Glutathione Transferase / metabolism
  • In Vitro Techniques
  • Monomeric GTP-Binding Proteins / genetics*
  • Monomeric GTP-Binding Proteins / metabolism
  • Neuropeptides / genetics*
  • Neuropeptides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Point Mutation
  • Protein Kinases
  • Proteins / metabolism
  • Ras Homolog Enriched in Brain Protein
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis / genetics*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins

Substances

  • Drosophila Proteins
  • GTPase-Activating Proteins
  • Neuropeptides
  • Proteins
  • Ras Homolog Enriched in Brain Protein
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Rheb protein, Drosophila
  • TSC1 protein, human
  • TSC2 protein, human
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Glutathione Transferase
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • target of rapamycin protein, Drosophila
  • TOR Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • GTP-Binding Proteins
  • Monomeric GTP-Binding Proteins