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

• Published in: Science (American Association for the Advancement of Science) Vol. 307; no. 5712; pp. 1098 - 1101
• Main Authors: Sarbassov, Dos D, Guertin, David A, Ali, Siraj M, Sabatini, David M
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 18.02.2005; The American Association for the Advancement of Science
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Adaptor Proteins, Signal Transducing; Animals; B lymphocytes; Biochemistry; Biological and medical sciences; Birds of prey; Cancer; Cancer genetics; Carrier Proteins - metabolism; Cell Line; Cell Line, Tumor; Cell lines; Cellular biology; Double stranded RNA; Drosophila; Drosophila melanogaster; Drosophila Proteins - metabolism; Enzyme Activation; Enzymes; Gene expression regulation; General aspects; Genetic aspects; HeLa cells; HT29 cells; Humans; Hydrophobic and Hydrophilic Interactions; Immunoprecipitation; Inhibition; Literary Devices; Medical sciences; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Protein kinases; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rapamycin; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; RNA Interference; Serine - metabolism; TOR Serine-Threonine Kinases; Tumors; United States; Phosphorylation; Regulation(control); Protein kinase B
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1106148

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.