Reactome | AKT phosphorylates FOXO transcription factors

AKT phosphorylates FOXO transcription factors

Stable Identifier

R-HSA-199299

Type

Reaction [transition]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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AKT phosphorylates FOXO transcription factors

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AKT-mediated phosphorylation of Forkhead box (FOX) transcription factors of the FOXO family, FOXO1 (FKHR), FOXO3 (FoxO3a, also known as FKHRL1) and FOXO4 (AFX) contributes to PI3K/AKT signaling-stimulated cell survival and growth. Activated AKT1 phosphorylates FOXO1 on threonine residue T24 and serine residues S256 and S319 (Rena et al. 1999), FOXO3 on threonine residue T32 and serine residues S253 and S315 (Brunet et al. 1999), and FOXO4 on threonine residue T32 and serine residues S197 and S262 (Kops et al. 1999).
Based on studies with recombinant mouse Foxo6 expressed in the human embryonic kidney cell line HEK293, FOXO6 has two conserved AKT phosphorylation sites: T26 and S184. Mouse Foxo6 has a third predicted Akt phosphorylation site at the C-terminus, T338, which is not present in other Foxo family members and is not conserved in human FOXO6. T26 and S184 are phosphorylated in response to growth factors known to activate PI3K/AKT signaling, but AKT has not been explicitly identified as the responsible kinase. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of phosphorylated FOXO6 may shuttle to the cytosol. Phosphorylation of FOXO6 on putative AKT sites, however, may inhibit binding of FOXO6 to target DNA sites (Jacobs et al. 2003, van der Heide et al. 2005).
Protein phosphatase DUSP6 (MKP3) may act to dephosphorylate FOXO1 after AKT-mediated phosphorylation (Rodrigues et al. 2017).

Literature References

PubMed ID	Title	Journal	Year
10102273	Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor Hu, LS, Bonni, A, Brunet, A, Blenis, J, Zigmond, MJ, Anderson, MJ, Lin, MZ, Greenberg, ME, Juo, P, Arden, KC	Cell	1999
10358075	Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B Unterman, TG, Guo, S, Cichy, SC, Rena, G, Cohen, P	J Biol Chem	1999
15987244	FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling van der Heide, LP, Hoekman, MF, Smidt, MP, Jacobs, FM, Burbach, JP	Biochem. J.	2005
12857750	FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics van der Heide, LP, Hoekman, MF, Smidt, MP, Wijchers, PJ, Jacobs, FM, Burbach, JP	J. Biol. Chem.	2003