Rheb binds and regulates the mTOR kinase

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


研究成果: 雜誌貢獻期刊論文同行評審

801 引文 斯高帕斯(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.

頁(從 - 到)702-713
期刊Current Biology
出版狀態已發佈 - 2005 4月 26

ASJC Scopus subject areas

  • 一般神經科學
  • 一般生物化學,遺傳學和分子生物學
  • 一般農業與生物科學


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