Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner.
Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in ... this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug.
Mesh Terms:
Antineoplastic Agents, Cell Line, Enzyme Activation, Gene Expression Regulation, Enzymologic, Humans, Immunoblotting, Monomeric GTP-Binding Proteins, Neuropeptides, Phosphorylation, Plasmids, Protein Binding, Protein Kinases, Protein Prenylation, Repressor Proteins, Ribosomal Protein S6 Kinases, Sirolimus, Tumor Suppressor Proteins
Antineoplastic Agents, Cell Line, Enzyme Activation, Gene Expression Regulation, Enzymologic, Humans, Immunoblotting, Monomeric GTP-Binding Proteins, Neuropeptides, Phosphorylation, Plasmids, Protein Binding, Protein Kinases, Protein Prenylation, Repressor Proteins, Ribosomal Protein S6 Kinases, Sirolimus, Tumor Suppressor Proteins
J. Biol. Chem.
Date: Aug. 29, 2003
PubMed ID: 12842888
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