Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.
Journal:
Science 2005 FebAuthors:
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM
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
...[more] 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.[less]
Mesh Headings:
Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Line, Cell Line, Tumor, Drosophila Proteins, Drosophila melanogaster, Enzyme Activation, Humans, Hydrophobic and Hydrophilic Interactions, Immunoprecipitation, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, RNA Interference, Serine, TOR Serine-Threonine Kinases