Figure 1. AKT is a central mediator of PI3K signaling.

Cartoon showing details of the regulation of AKT: AKT is co-translationally phosphorylated on the turn motif (orange circle, Thr450 in AKT1) by ribosome and ER-localized mTORC2 (orange oval). This phosphorylation stabilizes AKT and protects it from proteosome-mediated degradation. Signals that generate PIP₃ engage AKT’s PH domain and thus recruit it to the plasma membrane (middle panel; membrane-engaged species). Membrane-binding unmasks the activation loop, resulting in phosphorylation by PDK-1 (pink circle, Thr308 in AKT1) and a subsequent tightly-coupled phosphorylation on the hydrophobic motif (green circle, Ser473 in AKT1). Although mTORC2 has been proposed to phosphorylate this site too, mechanisms that displace the PH domain (e.g. tethering AKT to the membrane via myristoylation) bypass the requirement for mTORC2. This latter phosphorylation depends on the intrinsic catalytic activity of AKT, suggesting that, similar to PKC, this site is autophosphorylated following structuring of the active site by the PDK-1 phosphorylation of Thr308. The fully-phosphorylated species of AKT is locked in an active conformation and diffuses throughout the cell to mediate down stream signaling (bottom right species). Signaling is suppressed by dephosphorylation of PIP₃ by the tumor suppressor PTEN and acutely terminated by direct dephosphorylation of AKT to regenerate the mono-phosphorylated (phospho-Thr 450), auto-inhibited species. Dephosphorylation is catalyzed in part by the recently discovered PHLPP phosphatases, which directly dephosphorylate the hydrophobic motif, and by okadaic acid-sensitive phosphatases, such as PP2A, which dephosphorylate the activation loop.