Regulation of localization of FOXO transcription factors

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Homo sapiens
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Localization of FOXO transcription factors FOXO1, FOXO3 and FOXO4 is regulated by AKT-mediated phosphorylation. In the absence of PI3K/AKT signaling, FOXO1, FOXO3 and FOXO4 localize to the nucleus. AKT-mediated phosphorylation induces a conformational change that exposes a nuclear export signal (NES) and promotes translocation of FOXO1, FOXO3 and FOXO4 to the cytosol (Rena et al. 1999, Brunet et al. 1999, Kops et al. 1999). AKT-phosphorylated FOXO1, FOXO3 and FOXO4 bind to 14-3-3 proteins, which contributes to their retention in the cytosol (Rena et al. 2001, Brunet et al. 1999, Arimoto Ishida et al. 2004, Obsilova et al. 2005, Boura et al. 2007, Silhan et al. 2009). FOXO6 lacks the NES sequence and is exclusively nuclear, but phosphorylation in response to PI3K/AKT signaling affects the transcriptional activity of FOXO6 (Jacobs et al. 2003, van der Heide et al. 2005).

Literature References
PubMed ID Title Journal Year
19416966 14-3-3 protein masks the DNA binding interface of forkhead transcription factor FOXO4

Sulc, M, Silhan, J, Obsil, T, Obsilova, V, Vecer, J, Strnadova, P, Teisinger, J, Herman, P, Vacha, P

J. Biol. Chem. 2009
10217147 Direct control of the Forkhead transcription factor AFX by protein kinase B

Powell, DR, Burgering, BM, De Vries-Smits, AM, de Ruiter, ND, Bos, JL, Kops, GJ

Nature 1999
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
17244620 Both the N-terminal loop and wing W2 of the forkhead domain of transcription factor Foxo4 are important for DNA binding

Sulc, M, Silhan, J, Boura, E, Obsil, T, Obsilova, V, Vecer, J, Teisinger, J, Herman, P

J. Biol. Chem. 2007
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
16114898 14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4

Sulc, M, Boura, E, Obsil, T, Obsilova, V, Pabianova, A, Vecer, J, Teisinger, J, Herman, P

Biochemistry 2005
11237865 Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting

Cohen, P, Guo, S, Prescott, AR, Rena, G, Unterman, TG

Biochem. J. 2001
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
14701673 Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin

Takahashi, T, Ohshima, C, Arimoto-Ishida, E, Nishio, Y, Sakata, M, Ohmichi, M, Hayakawa, J, Tasaka, K, Kurachi, H, Murata, Y, Takahashi, K, Mabuchi, S, Kimura, A

Endocrinology 2004
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