Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B.
Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms.
Two novel phosphorylkation sites on FKHR
that are critical for its nuclear exclusion.
Accili, "Insulin stimulates phosphorylation of the forkhead transcription factor FKHR
on serine 253 through a wortmannin-sensitive pathway," The Journal of Biological Chemistry, vol.
Members of the forkhead box O (Foxo) family of transcription factors, including Foxo1 (previously described as FKHR
), Foxo3a (FKHRL1), Foxo4 (AFX), and Foxo6, are phosphorylated by insulin/IGF-1 through a PI3K/Akt-dependent pathway and excluded from nucleus to inhibit their transcriptional activity (Accili et al., 2004).
Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR
, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway.
Accili, "Insulin regulation of gene expression through the forkhead transcription factor foxol (Fkhr
) requires kinases distinct from Akt," Biochemistry, vol.
The loss of their phosphatase activity prevents the dephosphorylation of phosphatidylinositol-3,4,5-trisphosphate to phosphatidylinositol-4,5-bisphosphate, which then allows the transfer of phosphate molecule to PDK1 and AKT proteins, allowing the activation of MDM2, GSK3, P27, P21, CASP9, BAD, FKHR
, IKK, and MTOR genes (Figure 1).
(105) The 2 most common translocations involve FKHR
gene (FOXO1A) on 13q14, and either Pax3 (2q35) or Pax7 (1p36) genes.
Unterman, "Roles of the forkhead in rhabdomyosarcoma (FKHR
) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting," Biochemical Journal, vol.