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Review
. 2020 Jun;72(6):1115-1125.
doi: 10.1002/iub.2264. Epub 2020 Mar 3.

Control of Akt activity and substrate phosphorylation in cells

Ivan Yudushkin  1
Affiliations
Review

Control of Akt activity and substrate phosphorylation in cells

Ivan Yudushkin. IUBMB Life. 2020 Jun.

Abstract

Protein kinase B/Akt is a serine/threonine kinase that links receptors coupled to the PI3K lipid kinase to cellular anabolic pathways. Its activity in cells is controlled by reversible phosphorylation and an intramolecular lipid-controlled allosteric switch. In this review, I outline the current progress in understanding Akt regulatory mechanisms, define three models of Akt activation in cells, and highlight how intramolecular allosterism cooperates with cell-autonomous mechanisms to control Akt localization and activity and direct it toward specific sets of substrates in cells.

Keywords: protein kinase Akt; signaling.

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Figures

Figure 1
Figure 1
Akt structure and activation. (a) In the autoinhibited conformation, stabilized by the allosteric inhibitor VIII (PDB: 3o96), the lipid‐binding pleckstrin homology (PH) domain (orange) forms an extensive allosteric interface with the C‐lobe of the kinase domain (KD, gray). In the rotated view, the PH domain is hidden for clarity. Location of the C‐ and R‐spines connecting the N‐ and C‐lobes of the kinase domain is shown by dotted rectangle. (b) Akt phosphorylation on T308/S473 and allosteric mechanism cooperate to activate the kinase by aligning residues in the conserved hydrophobic spines. In the autoinhibited conformation (PDB: 3o96), W80 and F293 occupy the corresponding positions of L202 and nucleotide in the C‐ and R‐spines of the active form (PDB: 1o6k). Residues comprising the C‐ and R‐spines are highlighted; numbering corresponds to human Akt1 isozyme
Figure 2
Figure 2
Models of intracellular Akt activation cycle. For all models, Akt activation requires binding to cellular membranes, containing PI(3,4,5)P3 and/or PI(3,4)P2 phosphoinositide lipids, accompanied by Akt phosphorylation on T308 and S473 (open and red‐filled circles) by membrane‐bound PDK1 and mTORC2 (not shown). PH domain is shown in orange, kinase domain in gray; red halo refers to catalytically active Akt. According to the diffusive model (a), phosphorylated, active Akt may dissociate from the membrane and diffuse in the cytosol phosphorylating the substrates (not shown) through multiple rounds of catalysis. An extension of the diffusive model, ATP on/off switch (b), links Akt dephosphorylation with the exchange of ATP for ADP during a single round of phosphate transfer onto the substrate. The allosteric lipid switch model (c) proposes that only membrane‐bound Akt is both phosphorylated and active, phosphorylating the substrates (not shown) in multiple rounds of catalysis. Dissociation from the membrane results in formation of the autoinhibited conformation and promotes rapid Akt dephosphorylation in the cytosol
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