Bimodal regulation of FoxO3 by AKT and 14-3-3

► AKT binding to FoxO3 is independent of the RxRxxS/T AKT phosphorylation recognition motif. ► AKT activation is required for FoxO3 binding. ► AKT expression increases FoxO3 steady-state protein levels. ► 14‐3‐3 binding stabilizes phosphorylated FoxO3. ► FoxO3 P34A mutation impairs 14‐3‐3 binding, resulting in a constitutively active form.