Rheb binds and regulates the mTOR kinase

Xiaomeng Long, Yenshou Lin, Sara Ortiz-Vega, Kazuyoshi Yonezawa, Joseph Avruch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

793 Citations (Scopus)


Background: The target of rapamycin (TOR), in complex with the proteins raptor and LST8 (TOR complex 1), phosphorylates the p70S6K and 4E-BP1 to promote mRNA translation. Genetic evidence establishes that TOR complex activity in vivo requires the small GTPase Rheb, and overexpression of Rheb can rescue TOR from inactivation in vivo by amino-acid withdrawal. The Tuberous Sclerosis heterodimer (TSC1/TSC2) functions as a Rheb GTPase activator and inhibits TOR signaling in vivo. Results: Here, we show that Rheb binds to the TOR complex specifically, independently of its ability to bind TSC2, through separate interactions with the mTOR catalytic domain and with LST8. Rheb binding to the TOR complex in vivo and in vitro does not require Rheb guanyl nucleotide charging but is modulated by GTP and impaired by certain mutations (Ile39Lys) in the switch 1 loop. Nucleotide-deficient Rheb mutants, although capable of binding mTOR in vivo and in vitro, are inhibitory in vivo, and the mTOR polypeptides that associate with nucleotide-deficient Rheb in vivo lack kinase activity in vitro. Reciprocally, mTOR polypeptides bound to Rheb(Gln64Leu), a mutant that is nearly 90% GTP charged, exhibit substantially higher protein kinase specific activity than mTOR bound to wild-type Rheb. Conclusions: The TOR complex 1 is a direct target of Rheb-GTP, whose binding enables activation of the TOR kinase.

Original languageEnglish
Pages (from-to)702-713
Number of pages12
JournalCurrent Biology
Issue number8
Publication statusPublished - 2005 Apr 26
Externally publishedYes

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


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