Rheb Binds and Regulates the mTOR Kinase.

@article{citeulike:176338, abstract = {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.}, address = {Diabetes Unit and Medical Services and Department of Molecular Biology, Massachusetts General Hospital andDepartment of Medicine, Harvard Medical School, Boston, Massachusetts 02114.}, author = {Long, X. and Lin, Y. and Ortiz-Vega, S. and Yonezawa, K. and Avruch, J. }, citeulike-article-id = {176338}, doi = {http://dx.doi.org/10.1016/j.cub.2005.02.053}, issn = {0960-9822}, journal = {Curr Biol}, keywords = {mtor, rheb}, month = {April}, number = {8}, pages = {702--713}, posted-at = {2005-05-02 14:16:22}, priority = {2}, title = {Rheb Binds and Regulates the mTOR Kinase.}, url = {http://dx.doi.org/10.1016/j.cub.2005.02.053}, volume = {15}, year = {2005} }

TY - JOUR ID - citeulike:176338 L3 - citeulike-article-id:176338 TI - Rheb Binds and Regulates the mTOR Kinase. JF - Curr Biol VL - 15 IS - 8 SP - 702 EP - 713 AD - Diabetes Unit and Medical Services and Department of Molecular Biology, Massachusetts General Hospital andDepartment of Medicine, Harvard Medical School, Boston, Massachusetts 02114. SN - 0960-9822 N2 - 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. KW - mtor KW - rheb AU - Long, X AU - Lin, Y AU - Ortiz-Vega, S AU - Yonezawa, K AU - Avruch, J PY - 2005/04/26/ UR - http://dx.doi.org/10.1016/j.cub.2005.02.053 ER -