Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner

Ariel F. Castro, John F. Rebhun, Geoffrey J. Clark, Lawrence Quilliam

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264 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)32493-32496
Number of pages4
JournalJournal of Biological Chemistry
Volume278
Issue number35
DOIs
StatePublished - Aug 29 2003

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Ribosomal Protein S6 Kinases
Prenylation
Tuberous Sclerosis
Sirolimus
Guanosine Triphosphate
Chemical activation
GTPase-Activating Proteins
Phosphorylation
GTP Phosphohydrolases
Transferases
S 6
Tumors
Monomeric GTP-Binding Proteins
Genes
Tumor Suppressor Genes
Pharmaceutical Preparations
Proteins
Tuberous Sclerosis 2

ASJC Scopus subject areas

  • Biochemistry

Cite this

Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. / Castro, Ariel F.; Rebhun, John F.; Clark, Geoffrey J.; Quilliam, Lawrence.

In: Journal of Biological Chemistry, Vol. 278, No. 35, 29.08.2003, p. 32493-32496.

Research output: Contribution to journalArticle

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