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

American Association for the Advancement of Science (AAAS) - Tập 307 Số 5712 - Trang 1098-1101 - 2005
Dos D. Sarbassov1, David A. Guertin1, Siraj M. Ali1, David M. Sabatini1
1Whitehead 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.

Tóm tắt

Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr 308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser 473 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 Ser 473 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 Ser 473 in vitro and facilitated Thr 308 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.

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Materials and methods are presented as supporting material on Science Online.

This work was supported by a grant from the NIH (R01 AI47389) and awards from the Pew Charitable Trust and the Rita Allen Foundation to D.M.S. as well as fellowships from the Anna Fuller Fund to D.D.S. Damon Runyon Cancer Research Foundation to D.A.G. and the Howard Hughes Medical Institute to S.M.A. We thank members of the Sabatini lab for suggestions on the manuscript and M. B. Yaffe for helpful discussions. Molecular interaction data have been deposited in the Biomolecular Interaction Network Database with accession codes 195918 to 195923.

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American Association for the Advancement of Science (AAAS)

Tập 307 Số 5712

1098-1101

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