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Science 18 February 2005:
Vol. 307. no. 5712, pp. 1098 - 1101
DOI: 10.1126/science.1106148
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Reports

Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex

Dos D. Sarbassov, David A. Guertin,* Siraj M. Ali,* David M. Sabatini{dagger}

Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on Ser473 in vitro and facilitated Thr308 phosphorylation by PDK1. Rictor-mTOR may serve as a drug target in tumors that have lost the expression of PTEN, a tumor suppressor that opposes Akt/PKB activation.

Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA. Broad Institute, 320 Charles Street, Cambridge, MA 02141, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: sabatini{at}wi.mit.edu

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Rapamycin does not improve insulin sensitivity despite elevated mammalian target of rapamycin complex 1 activity in muscles of ob/ob mice.
A. M. Miller, J. R. Brestoff, C. B. Phelps, E. Z. Berk, and T. H. Reynolds IV (2008)
Am J Physiol Regulatory Integrative Comp Physiol 295, R1431-R1438
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Cyclic AMP Inhibits the Proliferation of Thyroid Carcinoma Cell Lines through Regulation of CDK4 Phosphorylation.
A. S. Rocha, S. Paternot, K. Coulonval, J. E. Dumont, P. Soares, and P. P. Roger (2008)
Mol. Biol. Cell 19, 4814-4825
   Abstract »    Full Text »    PDF »
In Vivo Analysis of Protein Kinase B (PKB)/Akt Regulation in DNA-PKcs-null Mice Reveals a Role for PKB/Akt in DNA Damage Response and Tumorigenesis.
B. Surucu, L. Bozulic, D. Hynx, A. Parcellier, and B. A. Hemmings (2008)
J. Biol. Chem. 283, 30025-30033
   Abstract »    Full Text »    PDF »
{beta}-Catenin Levels Influence Rapid Mechanical Responses in Osteoblasts.
N. Case, M. Ma, B. Sen, Z. Xie, T. S. Gross, and J. Rubin (2008)
J. Biol. Chem. 283, 29196-29205
   Abstract »    Full Text »    PDF »
Semaphorin 3B Inhibits the Phosphatidylinositol 3-Kinase/Akt Pathway through Neuropilin-1 in Lung and Breast Cancer Cells.
E. Castro-Rivera, S. Ran, R. A. Brekken, and J. D. Minna (2008)
Cancer Res. 68, 8295-8303
   Abstract »    Full Text »    PDF »
The protein phosphatase PP2A-B' subunit Widerborst is a negative regulator of cytoplasmic activated Akt and lipid metabolism in Drosophila.
N. Vereshchagina, M.-C. Ramel, E. Bitoun, and C. Wilson (2008)
J. Cell Sci. 121, 3383-3392
   Abstract »    Full Text »    PDF »
Use of Akt Inhibitor and a Drug-resistant Mutant Validates a Critical Role for Protein Kinase B/Akt in the Insulin-dependent Regulation of Glucose and System A Amino Acid Uptake.
C. J. Green, O. Goransson, G. S. Kular, N. R. Leslie, A. Gray, D. R. Alessi, K. Sakamoto, and H. S. Hundal (2008)
J. Biol. Chem. 283, 27653-27667
   Abstract »    Full Text »    PDF »
Protein Kinase B/Akt Phosphorylates and Inhibits the Cardiac Na+/H+ Exchanger NHE1.
A. K. Snabaitis, F. Cuello, and M. Avkiran (2008)
Circ. Res. 103, 881-890
   Abstract »    Full Text »    PDF »
NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations.
V. Serra, B. Markman, M. Scaltriti, P. J.A. Eichhorn, V. Valero, M. Guzman, M. L. Botero, E. Llonch, F. Atzori, S. Di Cosimo, et al. (2008)
Cancer Res. 68, 8022-8030
   Abstract »    Full Text »    PDF »
Integrin-linked kinase - essential roles in physiology and cancer biology.
P. C. McDonald, A. B. Fielding, and S. Dedhar (2008)
J. Cell Sci. 121, 3121-3132
   Abstract »    Full Text »    PDF »
A Gene Signature-Based Approach Identifies mTOR as a Regulator of p73.
J. M. Rosenbluth, D. J. Mays, M. F. Pino, L. J. Tang, and J. A. Pietenpol (2008)
Mol. Cell. Biol. 28, 5951-5964
   Abstract »    Full Text »    PDF »
Regulation of Akt signaling by O-GlcNAc in euglycemia.
Y. A. Soesanto, B. Luo, D. Jones, R. Taylor, J. S. Gabrielsen, G. Parker, and D. A. McClain (2008)
Am J Physiol Endocrinol Metab 295, E974-E980
   Abstract »    Full Text »    PDF »
Spatiotemporal Analysis of Differential Akt Regulation in Plasma Membrane Microdomains.
X. Gao and J. Zhang (2008)
Mol. Biol. Cell 19, 4366-4373
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Superoxide anions regulate TORC1 and its ability to bind Fpr1:rapamycin complex.
T. K. Neklesa and R. W. Davis (2008)
PNAS 105, 15166-15171
   Abstract »    Full Text »    PDF »
Enhancing Mammalian Target of Rapamycin (mTOR)-Targeted Cancer Therapy by Preventing mTOR/Raptor Inhibition-Initiated, mTOR/Rictor-Independent Akt Activation.
X. Wang, P. Yue, Y. A. Kim, H. Fu, F. R. Khuri, and S.-Y. Sun (2008)
Cancer Res. 68, 7409-7418
   Abstract »    Full Text »    PDF »
Defects in Skin {gamma}{delta} T Cell Function Contribute to Delayed Wound Repair in Rapamycin-Treated Mice.
R. E. Mills, K. R. Taylor, K. Podshivalova, D. B. McKay, and J. M. Jameson (2008)
J. Immunol. 181, 3974-3983
   Abstract »    Full Text »    PDF »
Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in Apc{Delta}716 mice.
T. Fujishita, K. Aoki, H. A. Lane, M. Aoki, and M. M. Taketo (2008)
PNAS 105, 13544-13549
   Abstract »    Full Text »    PDF »


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