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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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Molecular Mechanisms of Tamoxifen Therapy for Cholangiocarcinoma: Role of Calmodulin.
P. Pawar, L. Ma, C. H. Byon, H. Liu, E.-Y. Ahn, N. Jhala, J. P. Arnoletti, J. M. McDonald, and Y. Chen (2009)
Clin. Cancer Res. 15, 1288-1296
   Abstract »    Full Text »    PDF »
Insulin Resistance in Striated Muscle-specific Integrin Receptor {beta}1-deficient Mice.
H. Zong, C. C. Bastie, J. Xu, R. Fassler, K. P. Campbell, I. J. Kurland, and J. E. Pessin (2009)
J. Biol. Chem. 284, 4679-4688
   Abstract »    Full Text »    PDF »
Protein Kinase C-{delta} and Phosphatidylinositol 3-Kinase/Akt Activate Mammalian Target of Rapamycin to Modulate NF-{kappa}B Activation and Intercellular Adhesion Molecule-1 (ICAM-1) Expression in Endothelial Cells.
M. Minhajuddin, K. M. Bijli, F. Fazal, A. Sassano, K. I. Nakayama, N. Hay, L. C. Platanias, and A. Rahman (2009)
J. Biol. Chem. 284, 4052-4061
   Abstract »    Full Text »    PDF »
Pharmacological Inhibition of mTORC1 Suppresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-Specific Pten Knock-Out Mice.
J. Zhou, J. Blundell, S. Ogawa, C.-H. Kwon, W. Zhang, C. Sinton, C. M. Powell, and L. F. Parada (2009)
J. Neurosci. 29, 1773-1783
   Abstract »    Full Text »    PDF »
The TSC-mTOR Pathway Mediates Translational Activation of TOP mRNAs by Insulin Largely in a Raptor- or Rictor-Independent Manner.
I. Patursky-Polischuk, M. Stolovich-Rain, M. Hausner-Hanochi, J. Kasir, N. Cybulski, J. Avruch, M. A. Ruegg, M. N. Hall, and O. Meyuhas (2009)
Mol. Cell. Biol. 29, 640-649
   Abstract »    Full Text »    PDF »
Development of LanthaScreenTM Cellular Assays for Key Components within the PI3K/AKT/mTOR Pathway.
C. B. Carlson, M. B. Robers, K. W. Vogel, and T. Machleidt (2009)
J Biomol Screen 14, 121-132
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Inhibition of Class I Phosphoinositide 3-Kinase Activity Impairs Proliferation and Triggers Apoptosis in Acute Promyelocytic Leukemia without Affecting Atra-Induced Differentiation.
C. Billottet, L. Banerjee, B. Vanhaesebroeck, and A. Khwaja (2009)
Cancer Res. 69, 1027-1036
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Curcumin Disrupts the Mammalian Target of Rapamycin-Raptor Complex.
C. S. Beevers, L. Chen, L. Liu, Y. Luo, N. J.G. Webster, and S. Huang (2009)
Cancer Res. 69, 1000-1008
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mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes.
B. Vollenbroker, B. George, M. Wolfgart, M. A. Saleem, H. Pavenstadt, and T. Weide (2009)
Am J Physiol Renal Physiol 296, F418-F426
   Abstract »    Full Text »    PDF »
The Rheb-mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord.
S. Codeluppi, C. I. Svensson, M. P. Hefferan, F. Valencia, M. D. Silldorff, M. Oshiro, M. Marsala, and E. B. Pasquale (2009)
J. Neurosci. 29, 1093-1104
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Differential Requirement of mTOR in Postmitotic Tissues and Tumorigenesis.
C. Nardella, A. Carracedo, A. Alimonti, R. M. Hobbs, J. G. Clohessy, Z. Chen, A. Egia, A. Fornari, M. Fiorentino, M. Loda, et al. (2009)
Science Signaling 2, ra2
   Abstract »    Full Text »    PDF »
Distinct Roles for Mammalian Target of Rapamycin Complexes in the Fibroblast Response to Transforming Growth Factor-{beta}.
R. A. Rahimi, M. Andrianifahanana, M. C. Wilkes, M. Edens, T. J. Kottom, J. Blenis, and E. B. Leof (2009)
Cancer Res. 69, 84-93
   Abstract »    Full Text »    PDF »
Mutations in the Phosphatidylinositol-3-Kinase Pathway Predict for Antitumor Activity of the Inhibitor PX-866 whereas Oncogenic Ras Is a Dominant Predictor for Resistance.
N. T. Ihle, R. Lemos Jr., P. Wipf, A. Yacoub, C. Mitchell, D. Siwak, G. B. Mills, P. Dent, D. L. Kirkpatrick, and G. Powis (2009)
Cancer Res. 69, 143-150
   Abstract »    Full Text »    PDF »


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