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Science 307 (5712): 1098-1101

Copyright © 2005 by the American Association for the Advancement of Science

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

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

Abstract: 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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A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1.
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Science 340, 1100-1106
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Mammalian Target of Rapamycin (mTor) Mediates Tau Protein Dyshomeostasis: IMPLICATION FOR ALZHEIMER DISEASE.
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Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer.
R. L. Bitting and A. J. Armstrong (2013)
Endocr. Relat. Cancer 20, R83-R99
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Protein Phosphatase 2A and DNA-dependent Protein Kinase Are Involved in Mediating Rapamycin-induced Akt Phosphorylation.
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Inactivation of mTORC1 in the Developing Brain Causes Microcephaly and Affects Gliogenesis.
D. Cloetta, V. Thomanetz, C. Baranek, R. M. Lustenberger, S. Lin, F. Oliveri, S. Atanasoski, and M. A. Ruegg (2013)
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mTOR and vascular remodeling in lung diseases: current challenges and therapeutic prospects.
E. A. Goncharova (2013)
FASEB J 27, 1796-1807
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CHD1 Is a 5q21 Tumor Suppressor Required for ERG Rearrangement in Prostate Cancer.
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Transition from Heterotypic to Homotypic PDK1 Homodimerization Is Essential for TCR-Mediated NF-{kappa}B Activation.
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Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence.
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