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

Abstract

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.