Fig. 4

AKT-induced FOXO phosphorylation and regulation. A AKT-induced FOXO phosphorylation and regulation in normal cells. In normal condition, AKT exerts an ordinary moderate FOXO phosphorylation, which allows FOXO to transcribe its target genes. B AKT-induced FOXO phosphorylation and regulation in cancer cells. Mutations upstream AKT and/or AKT, with its consequent overexpression, can increase FOXO phosphorylation by AKT, resulting in binding of 14–3-3 adapter protein to FOXO, and leading to 14–3-3/FOXO complex being shuttled from nucleus to cytoplasm, thereby inhibiting the expression of FOXO gene targets. Therefore, excessive inhibition of FOXO by AKT phosphorylation can ultimately increase survival, enhance proliferation, increase growth, and suppress cell metabolism. Activation (phosphorylation or non-phosphorylation), interactions, and nucleus/cytoplasm shuttling are shown with arrowhead lines, moderate or possible phosphorylation is indicated with dotted-arrowhead lines, and inhibition is displayed with blocked lines. Red lightning symbol shows mutation for a particular gene in the PAM pathway. Red crosses emphasise signaling blockage. P: phosphoryl group. Survival: Cell survival; Proliferation: Cell proliferation; Growth: Cell growth; Metabolism: tissue-specific metabolic changes