Science · 2005 · 6.2K citations · 28 references
Life SciencesCell BiologyMolecular BiologyCell SignalingMolecular Cell BiologySignal TransductionCancer Cell SignalingCell Signaling NetworksMtor Inhibitor TherapyOncogenic Signaling PathwaysProtein Kinase CascadesTumor Suppressor GenesActivation Loop RegulationMammalian Target Of Rapamycin SignalingMtor SignalingPi3 Kinase-akt SignalingPi3k-akt Signaling PathwayPi3k-akt-mtor SignalingTumor Suppressor LossTumor Suppressor Pathways
Akt/PKB deregulation contributes to cancer and diabetes, requiring phosphorylation at Thr308 by PDK1 and at Ser473 by an unknown kinase, and the rictor‑mTOR complex may be a therapeutic target in PTEN‑deficient tumors. In Drosophila and human cells, the rictor‑mTOR complex is required for Ser473 phosphorylation of Akt/PKB, directly phosphorylates Ser473 in vitro, promotes Thr308 phosphorylation by PDK1, and its depletion impairs Akt/PKB signaling.
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.
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Mechanism of activation of protein kinase B by insulin and IGF‐1.
Dario R. Alessi, Mirjana Andjelković, B. Caudwell et al. · The EMBO Journal · 1996 · 3K citations · Full text