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Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex
Dos D. Sarbassov,
David A. Guertin,*
Siraj M. Ali,*
David M. Sabatini
Abstract:
Deregulation of Akt/protein kinase B (PKB) is implicated inthe pathogenesis of cancer and diabetes. Akt/PKB activationrequires the phosphorylation of Thr308 in the activation loopby the phosphoinositide-dependent kinase 1 (PDK1) and Ser473within the carboxyl-terminal hydrophobic motif by an unknownkinase. We show that in Drosophila and human cells the targetof rapamycin (TOR) kinase and its associated protein rictorare necessary for Ser473 phosphorylation and that a reductionin rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKBeffector. The rictor-mTOR complex directly phosphorylated Akt/PKBon Ser473 in vitro and facilitated Thr308 phosphorylation byPDK1. Rictor-mTOR may serve as a drug target in tumors thathave lost the expression of PTEN, a tumor suppressor that opposesAkt/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.
To whom correspondence should be addressed. E-mail: sabatini{at}wi.mit.edu
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Comment on "A Dynamic Network Model of mTOR Signaling Reveals TSC-Independent mTORC2 Regulation": Building a Model of the mTOR Signaling Network with a Potentially Faulty Tool.
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