The activity of FoxO transcription factors is largely controlled by posttranslational regulation. Activation of growth factor receptors activates phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway which results in phosphorylation of FoxO proteins at three serine/threonine residues – threonine 24, serine 256 and serine 316 for FoxO1, and threonine 32, serine 253 and serine 315 for FoxO3a (11-16). Phosphorylation of FoxOs results in redistribution from the nucleus to the cytosol and therefore prevents their binding to DNA (11, 15-18). Besides inhibition by Akt-induced phosphorylation, phosphorylation by other protein kinases, nuclear acetylation, and proteasomal degradation also contribute to the multiple levels of posttranslational regulation of FoxO transcriptional activity (19-23).
