Fig. 3

AKT-mediated GSK3 phosphorylation and regulation. A AKT-mediated GSK3 regulation in normal cells. AKT-mediated GSK3 regulation is exerted by AKT phosphorylation on GSK3 amino-terminus, thereby creating an intramolecular pseudo-substrate that occludes the phosphate-binding pocket, and inhibits substrate accessibility to GSK3. When in active (on) form, GSK3 can only recognise and phosphorylate substrates previously phosphorylated by a priming kinase. Conversely, when in inactive (off) form, GSK3 results blocked due to AKT phosphorylation, and thus, its access to primed substrates is denied. Some GSK3 substrates, with their corresponding cellular function are shown. B AKT-mediated GSK3 regulation in cancer cells. Mutations in AKT can enhance phosphorylation, and thus, inactivation of GSK3. Consequently, inactivation or limited amount of active GSK3 can lead to dysregulation of several signal transduction, resulting in cancer onset and/or progression. Reduction or absence of phosphorylation, and thence decreased proteasomal degradation of molecules (e.g. β-catenin) can arise from excessive inhibition of GSK3 by AKT phosphorylation, which can lead to increased survival, enhanced proliferation, and boosted metabolism. Red lightning symbol shows mutation for a particular gene in the PAM pathway. TFs: transcription factors. Phosphorylation is shown with arrowhead lines, whereas inhibition is indicated with blocked lines. Red crosses emphasise signaling blockage. P: phosphoryl group