![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
1 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA; 2 Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA; 3 Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109, USA
Target of rapamycin (TOR) is an evolutionally conserved protein kinase in eukaryotes and a central cell growth controller. TOR exists in two distinct complexes, termed TORC1 and TORC2. Mammalian TORC2 has recently been shown to possess kinase activity toward the C-terminal hydrophobic site of Akt/PKB. Here, we report that Sin1 is an essential component of TORC2 but not of TORC1, and functions similarly to Rictor, the defining member of TORC2, in complex formation and kinase activity. Knockdown of Sin1decreases Akt phosphorylation in both Drosophila and mammalian cells and diminishes Akt function in vivo. It also disrupts the interaction between Rictor and mTOR. Furthermore, Sin1 is required for TORC2 kinase activity in vitro. Disruption of the Rictor gene in mice results in embryonic lethality and ablates Akt phosphorylation. These data demonstrate that Sin1 together with Rictor are key components of mTORC2 and play an essential role in Akt phosphorylation and signaling.
[Keywords: Sin1; TORC; TSC; Rictor; Akt; mTOR]
Received June 20, 2006; revised version accepted October 5, 2006.
E-MAIL kunliang{at}umich.edu; FAX (734) 647-9702.
Supplemental material is available at http://www.genesdev.org
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1461206.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Rosner and M. Hengstschlager Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1 Hum. Mol. Genet., October 1, 2008; 17(19): 2934 - 2948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ghosh, G. P. Srivastava, D. Xu, L. C. Schulz, and R. M. Roberts A link between SIN1 (MAPKAP1) and poly(rC) binding protein 2 (PCBP2) in counteracting environmental stress PNAS, August 19, 2008; 105(33): 11673 - 11678. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Ho, H.-Y. Lee, H.-C. Liao, and M.-Y. Chen Involvement of Saccharomyces cerevisiae Avo3p/Tsc11p in Maintaining TOR Complex 2 Integrity and Coupling to Downstream Signaling Eukaryot. Cell, August 1, 2008; 7(8): 1328 - 1343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. N. Hagan, Y. Lin, M. A. Magnuson, J. Avruch, and M. P. Czech A Rictor-Myo1c Complex Participates in Dynamic Cortical Actin Events in 3T3-L1 Adipocytes Mol. Cell. Biol., July 1, 2008; 28(13): 4215 - 4226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-M. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell, C. Fritsch, S. Brachmann, P. Chene, A. De Pover, K. Schoemaker, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity Mol. Cancer Ther., July 1, 2008; 7(7): 1851 - 1863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Huang, C. C. Dibble, M. Matsuzaki, and B. D. Manning The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2 Mol. Cell. Biol., June 15, 2008; 28(12): 4104 - 4115. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Dan, M. J. Cooper, P. C. Cogswell, J. A. Duncan, J. P.-Y. Ting, and A. S. Baldwin Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK Genes & Dev., June 1, 2008; 22(11): 1490 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Garcia and D. Danielpour Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies Mol. Cancer Ther., June 1, 2008; 7(6): 1347 - 1354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-H. Shen, Z. Chen, S. Shi, H. Chen, W. Zhu, A. Penner, G. Bu, W. Li, D. W. Boyle, M. Rubart, et al. Cardiac Restricted Overexpression of Kinase-dead Mammalian Target of Rapamycin (mTOR) Mutant Impairs the mTOR-mediated Signaling and Cardiac Function J. Biol. Chem., May 16, 2008; 283(20): 13842 - 13849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Johansson, Y. Y. Mahller, M. H. Collins, M.-O. Kim, T. Nobukuni, J. Perentesis, T. P. Cripe, H. A. Lane, S. C. Kozma, G. Thomas, et al. Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors Mol. Cancer Ther., May 1, 2008; 7(5): 1237 - 1245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. T. Jindra, A. Hsueh, L. Hong, D. Gjertson, X.-D. Shen, F. Gao, J. Dang, P. S. Mischel, W. M. Baldwin III, M. C. Fishbein, et al. Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts J. Immunol., February 15, 2008; 180(4): 2214 - 2224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. T. Jindra, Y.-P. Jin, E. Rozengurt, and E. F. Reed HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway J. Immunol., February 15, 2008; 180(4): 2357 - 2366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Diaz-Troya, F. J. Florencio, and J. L. Crespo Target of Rapamycin and LST8 Proteins Associate with Membranes from the Endoplasmic Reticulum in the Unicellular Green Alga Chlamydomonas reinhardtii Eukaryot. Cell, February 1, 2008; 7(2): 212 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. P. Krymskaya Smooth Muscle like Cells in Pulmonary Lymphangioleiomyomatosis Proceedings of the ATS, January 1, 2008; 5(1): 119 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Masri, A. Bernath, J. Martin, O. D. Jo, R. Vartanian, A. Funk, and J. Gera mTORC2 Activity Is Elevated in Gliomas and Promotes Growth and Cell Motility via Overexpression of Rictor Cancer Res., December 15, 2007; 67(24): 11712 - 11720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, Y. Wang, E. Kim, P. Beemiller, C.-Y. Wang, J. Swanson, M. You, and K.-L. Guan Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb J. Biol. Chem., December 7, 2007; 282(49): 35803 - 35813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Andrabi, O. V. Gjoerup, J. A. Kean, T. M. Roberts, and B. Schaffhausen Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner PNAS, November 27, 2007; 104(48): 19011 - 19016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. He, J. C. Marecki, G. Serrero, F. A. Simmen, M. J. J. Ronis, and T. M. Badger Dose-Dependent Effects of Alcohol on Insulin Signaling: Partial Explanation for Biphasic Alcohol Impact on Human Health Mol. Endocrinol., October 1, 2007; 21(10): 2541 - 2550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-Y. Woo, D.-H. Kim, C.-B. Jun, Y.-M. Kim, E. V. Haar, S.-i. Lee, J. W. Hegg, S. Bandhakavi, T. J. Griffin, and D.-H. Kim PRR5, a Novel Component of mTOR Complex 2, Regulates Platelet-derived Growth Factor Receptor beta Expression and Signaling J. Biol. Chem., August 31, 2007; 282(35): 25604 - 25612. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Vary and C. J. Lynch Nutrient Signaling Components Controlling Protein Synthesis in Striated Muscle J. Nutr., August 1, 2007; 137(8): 1835 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Frost and C. H. Lang Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass J Appl Physiol, July 1, 2007; 103(1): 378 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Qiao, J. D. Iglehart, and A. B. Pardee Metastatic Potential of 21T Human Breast Cancer Cells Depends on Akt/Protein Kinase B Activation Cancer Res., June 1, 2007; 67(11): 5293 - 5299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Naimi, N. Gautier, C. Chaussade, A. M. Valverde, D. Accili, and E. Van Obberghen Nuclear Forkhead Box O1 Controls and Integrates Key Signaling Pathways in Hepatocytes Endocrinology, May 1, 2007; 148(5): 2424 - 2434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Hietakangas and S. M. Cohen Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth Genes & Dev., March 15, 2007; 21(6): 632 - 637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu and X. F. S. Zheng Endoplasmic Reticulum and Golgi Localization Sequences for Mammalian Target of Rapamycin Mol. Biol. Cell, March 1, 2007; 18(3): 1073 - 1082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Urano, T. Sato, T. Matsuo, Y. Otsubo, M. Yamamoto, and F. Tamanoi Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells PNAS, February 27, 2007; 104(9): 3514 - 3519. [Abstract] [Full Text] [PDF]
|
|
