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.
Pubmed ID: 12771962 RIS Download
Mesh terms: Animals | Drosophila Proteins | Drosophila melanogaster | GTP-Binding Proteins | GTPase-Activating Proteins | Gene Expression Regulation, Fungal | Genes, Suppressor | Glutathione Transferase | In Vitro Techniques | Monomeric GTP-Binding Proteins | Neuropeptides | Phosphatidylinositol 3-Kinases | Point Mutation | Protein Kinases | Proteins | Recombinant Fusion Proteins | Repressor Proteins | Ribosomal Protein S6 Kinases | TOR Serine-Threonine Kinases | Tuberous Sclerosis | Tumor Suppressor Proteins
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