Proceedings of the National Academy of Sciences · 2018 · 105 citations · 49 references
Life SciencesBiochemistryMolecular BiologyCell SignalingMolecular OncologySignal TransductionConformational ChangeConformational SamplingEnzyme FunctionLipid-protein InteractionsMembrane DynamicsProtein PhosphorylationActivationPh DomainsPhosphatasesPhosphatidylinositol 3-Kinase-akt PathwayPi3k SignalingProtein Conformational ChangesProtein Conformational SamplingSignal Transduction Conformational Change
Significance Akt is a paradigmatic lipid-activated kinase, which is frequently hyperactivated in human cancer. In the absence of PI(3,4,5)P 3 or PI(3,4)P 2 , Akt is maintained in an inactive conformation by an inhibitory interaction between its membrane-binding PH domain and its kinase domain. Here, we describe the conformational changes associated with its binding to PI(3,4,5)P 3 , leading to disruption of the inhibitory PH−kinase interface, and its consequent activation by protein kinases. Intriguingly, we find that reversal of those conformational changes promotes its inactivation by protein phosphatases. The activation of Akt is thereby restricted to discrete membrane locations, and it is rapidly inactivated upon dissociation. We propose a model in which activation, substrate phosphorylation, and inactivation of Akt are tightly coupled to the membrane.
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Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex
Dos D. Sarbassov, David A. Guertin, Siraj M. Ali et al. · Science · 2005 · 6.2K citations