Figure 3. The insulin, Akt and FoxO pathway.
a | In the absence of insulin binding, FoxO is a transcriptional activator of multiple insulin-responsive (IR) genes.
b | Engagement of the phosphatidylinositol 3-kinase (PI3K) pathway in response to insulin or other factors leads to the activation of Akt and to the phosphorylation (P) of FoxO proteins on crucial serine and threonine residues (Thr24, Ser256 and Ser319 in FOXO1)45–47. Phosphorylation seems to be sequential and Ser256 is phosphorylated first. Ser256 phosphorylation is sufficient for reduced DNA- binding affinity, presumably because this residue is located in the basic region of the DNA-binding domain, but nuclear exclusion also requires phosphorylation of the other two residues, Thr24 and Ser319 (REF. 54). Therefore, an elegant mechanism for insulin-dependent gene inhibition exists: insulin binding to its receptor on the cell surface initiates PI3K and Akt activation, followed by FoxO phosphorylation, nuclear exclusion and loss of transcriptional activation.