Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 2004 Jun 1;380(Pt 2):297–309. doi: 10.1042/BJ20040167

The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation.

Lars P Van Der Heide 1, Marco F M Hoekman 1, Marten P Smidt 1
PMCID: PMC1224192  PMID: 15005655

Abstract

FoxO (forkhead box O; forkhead members of the O class) are transcription factors that function under the control of insulin/insulin-like signalling. FoxO factors have been associated with a multitude of biological processes, including cell-cycle, cell death, DNA repair, metabolism and protection from oxidative stress. Central to the regulation of FoxO factors is a shuttling system, which confines FoxO factors to either the nucleus or the cytosol. Shuttling of FoxO requires protein phosphorylation within several domains, and association with 14-3-3 proteins and the nuclear transport machinery. Description of the FoxO-shuttling mechanism contributes to the understanding of FoxO function in relation to signalling and gene regulation.

Full Text

The Full Text of this article is available as a PDF (983.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alessi D. R., Caudwell F. B., Andjelkovic M., Hemmings B. A., Cohen P. Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 1996 Dec 16;399(3):333–338. doi: 10.1016/s0014-5793(96)01370-1. [DOI] [PubMed] [Google Scholar]
  2. Alessi D. R. Discovery of PDK1, one of the missing links in insulin signal transduction. Colworth Medal Lecture. Biochem Soc Trans. 2001 May;29(Pt 2):1–14. doi: 10.1042/0300-5127:0290001. [DOI] [PubMed] [Google Scholar]
  3. Altomonte Jennifer, Richter Anja, Harbaran Sonal, Suriawinata Jenny, Nakae Jun, Thung Swan N., Meseck Marcia, Accili Domenico, Dong Hengjiang. Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab. 2003 Jun 3;285(4):E718–E728. doi: 10.1152/ajpendo.00156.2003. [DOI] [PubMed] [Google Scholar]
  4. Alvarez B., Martínez-A C., Burgering B. M., Carrera A. C. Forkhead transcription factors contribute to execution of the mitotic programme in mammals. Nature. 2001 Oct 18;413(6857):744–747. doi: 10.1038/35099574. [DOI] [PubMed] [Google Scholar]
  5. Ayala J. E., Streeper R. S., Desgrosellier J. S., Durham S. K., Suwanichkul A., Svitek C. A., Goldman J. K., Barr F. G., Powell D. R., O'Brien R. M. Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. Diabetes. 1999 Sep;48(9):1885–1889. doi: 10.2337/diabetes.48.9.1885. [DOI] [PubMed] [Google Scholar]
  6. Becker W., Weber Y., Wetzel K., Eirmbter K., Tejedor F. J., Joost H. G. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem. 1998 Oct 2;273(40):25893–25902. doi: 10.1074/jbc.273.40.25893. [DOI] [PubMed] [Google Scholar]
  7. Biggs W. H., 3rd, Cavenee W. K., Arden K. C. Identification and characterization of members of the FKHR (FOX O) subclass of winged-helix transcription factors in the mouse. Mamm Genome. 2001 Jun;12(6):416–425. doi: 10.1007/s003350020002. [DOI] [PubMed] [Google Scholar]
  8. Bos J. L. All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral. EMBO J. 1998 Dec 1;17(23):6776–6782. doi: 10.1093/emboj/17.23.6776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brownawell A. M., Kops G. J., Macara I. G., Burgering B. M. Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX. Mol Cell Biol. 2001 May;21(10):3534–3546. doi: 10.1128/MCB.21.10.3534-3546.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Brunet A., Bonni A., Zigmond M. J., Lin M. Z., Juo P., Hu L. S., Anderson M. J., Arden K. C., Blenis J., Greenberg M. E. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19;96(6):857–868. doi: 10.1016/s0092-8674(00)80595-4. [DOI] [PubMed] [Google Scholar]
  11. Brunet A., Datta S. R., Greenberg M. E. Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol. 2001 Jun;11(3):297–305. doi: 10.1016/s0959-4388(00)00211-7. [DOI] [PubMed] [Google Scholar]
  12. Brunet A., Park J., Tran H., Hu L. S., Hemmings B. A., Greenberg M. E. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol. 2001 Feb;21(3):952–965. doi: 10.1128/MCB.21.3.952-965.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Brunet Anne, Kanai Fumihiko, Stehn Justine, Xu Jian, Sarbassova Dilara, Frangioni John V., Dalal Sorab N., DeCaprio James A., Greenberg Michael E., Yaffe Michael B. 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol. 2002 Feb 25;156(5):817–828. doi: 10.1083/jcb.200112059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Brunet Anne, Sweeney Lora B., Sturgill J. Fitzhugh, Chua Katrin F., Greer Paul L., Lin Yingxi, Tran Hien, Ross Sarah E., Mostoslavsky Raul, Cohen Haim Y. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004 Feb 19;303(5666):2011–2015. doi: 10.1126/science.1094637. [DOI] [PubMed] [Google Scholar]
  15. Budd D. C., McDonald J. E., Tobin A. B. Phosphorylation and regulation of a Gq/11-coupled receptor by casein kinase 1alpha. J Biol Chem. 2000 Jun 30;275(26):19667–19675. doi: 10.1074/jbc.M000492200. [DOI] [PubMed] [Google Scholar]
  16. Cahill C. M., Tzivion G., Nasrin N., Ogg S., Dore J., Ruvkun G., Alexander-Bridges M. Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and function via 14-3-3-dependent and 14-3-3-independent pathways. J Biol Chem. 2000 Dec 20;276(16):13402–13410. doi: 10.1074/jbc.M010042200. [DOI] [PubMed] [Google Scholar]
  17. Castrillon Diego H., Miao Lili, Kollipara Ramya, Horner James W., DePinho Ronald A. Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science. 2003 Jul 11;301(5630):215–218. doi: 10.1126/science.1086336. [DOI] [PubMed] [Google Scholar]
  18. Cegielska A., Gietzen K. F., Rivers A., Virshup D. M. Autoinhibition of casein kinase I epsilon (CKI epsilon) is relieved by protein phosphatases and limited proteolysis. J Biol Chem. 1998 Jan 16;273(3):1357–1364. doi: 10.1074/jbc.273.3.1357. [DOI] [PubMed] [Google Scholar]
  19. Chan H. M., La Thangue N. B. p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci. 2001 Jul;114(Pt 13):2363–2373. doi: 10.1242/jcs.114.13.2363. [DOI] [PubMed] [Google Scholar]
  20. Charvet Céline, Alberti Isabelle, Luciano Frederic, Jacquel Arnaud, Bernard Alain, Auberger Patrick, Deckert Marcel. Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases. Oncogene. 2003 Jul 17;22(29):4557–4568. doi: 10.1038/sj.onc.1206778. [DOI] [PubMed] [Google Scholar]
  21. Christian Mark, Zhang Xiaohui, Schneider-Merck Tanja, Unterman Terry G., Gellersen Birgit, White John O., Brosens Jan J. Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein beta in differentiating human endometrial stromal cells. J Biol Chem. 2002 Mar 13;277(23):20825–20832. doi: 10.1074/jbc.M201018200. [DOI] [PubMed] [Google Scholar]
  22. Ciechomska Iwona, Pyrzynska Beata, Kazmierczak Piotr, Kaminska Bozena. Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells. Oncogene. 2003 Oct 23;22(48):7617–7627. doi: 10.1038/sj.onc.1207137. [DOI] [PubMed] [Google Scholar]
  23. Cohen G. M. Caspases: the executioners of apoptosis. Biochem J. 1997 Aug 15;326(Pt 1):1–16. doi: 10.1042/bj3260001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Collins Barry J., Deak Maria, Arthur J. Simon C., Armit Laura J., Alessi Dario R. In vivo role of the PIF-binding docking site of PDK1 defined by knock-in mutation. EMBO J. 2003 Aug 15;22(16):4202–4211. doi: 10.1093/emboj/cdg407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Dasso Mary. The Ran GTPase: theme and variations. Curr Biol. 2002 Jul 23;12(14):R502–R508. doi: 10.1016/s0960-9822(02)00970-3. [DOI] [PubMed] [Google Scholar]
  26. Datta S. R., Brunet A., Greenberg M. E. Cellular survival: a play in three Akts. Genes Dev. 1999 Nov 15;13(22):2905–2927. doi: 10.1101/gad.13.22.2905. [DOI] [PubMed] [Google Scholar]
  27. Davis R. J., Bennicelli J. L., Macina R. A., Nycum L. M., Biegel J. A., Barr F. G. Structural characterization of the FKHR gene and its rearrangement in alveolar rhabdomyosarcoma. Hum Mol Genet. 1995 Dec;4(12):2355–2362. doi: 10.1093/hmg/4.12.2355. [DOI] [PubMed] [Google Scholar]
  28. De Ruiter N. D., Burgering B. M., Bos J. L. Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451. Mol Cell Biol. 2001 Dec;21(23):8225–8235. doi: 10.1128/MCB.21.23.8225-8235.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Dijkers P. F., Medema R. H., Lammers J. W., Koenderman L., Coffer P. J. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol. 2000 Oct 5;10(19):1201–1204. doi: 10.1016/s0960-9822(00)00728-4. [DOI] [PubMed] [Google Scholar]
  30. Dijkers P. F., Medema R. H., Pals C., Banerji L., Thomas N. S., Lam E. W., Burgering B. M., Raaijmakers J. A., Lammers J. W., Koenderman L. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol Cell Biol. 2000 Dec;20(24):9138–9148. doi: 10.1128/mcb.20.24.9138-9148.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Dowell Paul, Otto Tamara C., Adi Saleh, Lane M. Daniel. Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem. 2003 Sep 9;278(46):45485–45491. doi: 10.1074/jbc.M309069200. [DOI] [PubMed] [Google Scholar]
  32. Durham S. K., Suwanichkul A., Scheimann A. O., Yee D., Jackson J. G., Barr F. G., Powell D. R. FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. Endocrinology. 1999 Jul;140(7):3140–3146. doi: 10.1210/endo.140.7.6856. [DOI] [PubMed] [Google Scholar]
  33. Flotow H., Graves P. R., Wang A. Q., Fiol C. J., Roeske R. W., Roach P. J. Phosphate groups as substrate determinants for casein kinase I action. J Biol Chem. 1990 Aug 25;265(24):14264–14269. [PubMed] [Google Scholar]
  34. Foster Fiona M., Traer Colin J., Abraham Siemon M., Fry Michael J. The phosphoinositide (PI) 3-kinase family. J Cell Sci. 2003 Aug 1;116(Pt 15):3037–3040. doi: 10.1242/jcs.00609. [DOI] [PubMed] [Google Scholar]
  35. Fotaki Vassiliki, Dierssen Mara, Alcántara Soledad, Martínez Salvador, Martí Eulàlia, Casas Caty, Visa Joana, Soriano Eduardo, Estivill Xavier, Arbonés Maria L. Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol Cell Biol. 2002 Sep;22(18):6636–6647. doi: 10.1128/MCB.22.18.6636-6647.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Fredericks W. J., Galili N., Mukhopadhyay S., Rovera G., Bennicelli J., Barr F. G., Rauscher F. J., 3rd The PAX3-FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3. Mol Cell Biol. 1995 Mar;15(3):1522–1535. doi: 10.1128/mcb.15.3.1522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Fukuoka Masahiro, Daitoku Hiroaki, Hatta Mitsutoki, Matsuzaki Hitomi, Umemura Satoshi, Fukamizu Akiyoshi. Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Int J Mol Med. 2003 Oct;12(4):503–508. [PubMed] [Google Scholar]
  38. Furuyama Tatsuo, Kitayama Kazuko, Yamashita Hitoshi, Mori Nozomu. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J. 2003 Oct 15;375(Pt 2):365–371. doi: 10.1042/BJ20030022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ghaffari Saghi, Jagani Zainab, Kitidis Claire, Lodish Harvey F., Khosravi-Far Roya. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A. 2003 May 15;100(11):6523–6528. doi: 10.1073/pnas.0731871100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Gilley Jonathan, Coffer Paul J., Ham Jonathan. FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol. 2003 Aug 11;162(4):613–622. doi: 10.1083/jcb.200303026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Graves P. R., Roach P. J. Role of COOH-terminal phosphorylation in the regulation of casein kinase I delta. J Biol Chem. 1995 Sep 15;270(37):21689–21694. doi: 10.1074/jbc.270.37.21689. [DOI] [PubMed] [Google Scholar]
  42. Gross S. D., Anderson R. A. Casein kinase I: spatial organization and positioning of a multifunctional protein kinase family. Cell Signal. 1998 Nov;10(10):699–711. doi: 10.1016/s0898-6568(98)00042-4. [DOI] [PubMed] [Google Scholar]
  43. Guo S., Rena G., Cichy S., He X., Cohen P., Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem. 1999 Jun 11;274(24):17184–17192. doi: 10.1074/jbc.274.24.17184. [DOI] [PubMed] [Google Scholar]
  44. Henderson S. T., Johnson T. E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol. 2001 Dec 11;11(24):1975–1980. doi: 10.1016/s0960-9822(01)00594-2. [DOI] [PubMed] [Google Scholar]
  45. Himpel S., Panzer P., Eirmbter K., Czajkowska H., Sayed M., Packman L. C., Blundell T., Kentrup H., Grötzinger J., Joost H. G. Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. Biochem J. 2001 Nov 1;359(Pt 3):497–505. doi: 10.1042/0264-6021:3590497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Hirota Keiko, Daitoku Hiroaki, Matsuzaki Hitomi, Araya Natsumi, Yamagata Kazuyuki, Asada Sachie, Sugaya Takeshi, Fukamizu Akiyoshi. Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor. J Biol Chem. 2003 Jan 7;278(15):13056–13060. doi: 10.1074/jbc.C200553200. [DOI] [PubMed] [Google Scholar]
  47. Hosaka Taisuke, Biggs William H., 3rd, Tieu David, Boyer Antonia D., Varki Nissi M., Cavenee Webster K., Arden Karen C. Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci U S A. 2004 Feb 20;101(9):2975–2980. doi: 10.1073/pnas.0400093101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Huang Haojie, Muddiman David C., Tindall Donald J. Androgens negatively regulate forkhead transcription factor FKHR (FOXO1) through a proteolytic mechanism in prostate cancer cells. J Biol Chem. 2004 Jan 15;279(14):13866–13877. doi: 10.1074/jbc.M314143200. [DOI] [PubMed] [Google Scholar]
  49. Imae M., Fu Z., Yoshida A., Noguchi T., Kato H. Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. J Mol Endocrinol. 2003 Apr;30(2):253–262. doi: 10.1677/jme.0.0300253. [DOI] [PubMed] [Google Scholar]
  50. Jacobs Frank M. J., van der Heide Lars P., Wijchers Patrick J. E. C., Burbach J. Peter H., Hoekman Marco F. M., Smidt Marten P. FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem. 2003 Jul 11;278(38):35959–35967. doi: 10.1074/jbc.M302804200. [DOI] [PubMed] [Google Scholar]
  51. Jünger Martin A., Rintelen Felix, Stocker Hugo, Wasserman Jonathan D., Végh Mátyás, Radimerski Thomas, Greenberg Michael E., Hafen Ernst. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol. 2003 Aug 7;2(3):20–20. doi: 10.1186/1475-4924-2-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Kamei Yasutomi, Mizukami Junko, Miura Shinji, Suzuki Miki, Takahashi Nobuyuki, Kawada Teruo, Taniguchi Tomoyasu, Ezaki Osamu. A forkhead transcription factor FKHR up-regulates lipoprotein lipase expression in skeletal muscle. FEBS Lett. 2003 Feb 11;536(1-3):232–236. doi: 10.1016/s0014-5793(03)00062-0. [DOI] [PubMed] [Google Scholar]
  53. Kavurma M. M., Khachigian L. M. Signaling and transcriptional control of Fas ligand gene expression. Cell Death Differ. 2003 Jan;10(1):36–44. doi: 10.1038/sj.cdd.4401179. [DOI] [PubMed] [Google Scholar]
  54. Kentrup H., Becker W., Heukelbach J., Wilmes A., Schürmann A., Huppertz C., Kainulainen H., Joost H. G. Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII. J Biol Chem. 1996 Feb 16;271(7):3488–3495. doi: 10.1074/jbc.271.7.3488. [DOI] [PubMed] [Google Scholar]
  55. Kim J. Julie, Taylor Hugh S., Akbas G. Eda, Foucher Isabelle, Trembleau Alain, Jaffe Randal C., Fazleabas Asgerally T., Unterman Terry G. Regulation of insulin-like growth factor binding protein-1 promoter activity by FKHR and HOXA10 in primate endometrial cells. Biol Reprod. 2003 Jan;68(1):24–30. doi: 10.1095/biolreprod.102.009316. [DOI] [PubMed] [Google Scholar]
  56. Kitamura Tadahiro, Nakae Jun, Kitamura Yukari, Kido Yoshiaki, Biggs William H., 3rd, Wright Christopher V. E., White Morris F., Arden Karen C., Accili Domenico. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest. 2002 Dec;110(12):1839–1847. doi: 10.1172/JCI200216857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Komeili A., O'Shea E. K. New perspectives on nuclear transport. Annu Rev Genet. 2001;35:341–364. doi: 10.1146/annurev.genet.35.102401.090720. [DOI] [PubMed] [Google Scholar]
  58. Kops G. J., Burgering B. M. Forkhead transcription factors: new insights into protein kinase B (c-akt) signaling. J Mol Med (Berl) 1999 Sep;77(9):656–665. doi: 10.1007/s001099900050. [DOI] [PubMed] [Google Scholar]
  59. Kops G. J., de Ruiter N. D., De Vries-Smits A. M., Powell D. R., Bos J. L., Burgering B. M. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature. 1999 Apr 15;398(6728):630–634. doi: 10.1038/19328. [DOI] [PubMed] [Google Scholar]
  60. Kops Geert J. P. L., Dansen Tobias B., Polderman Paulien E., Saarloos Ingrid, Wirtz Karel W. A., Coffer Paul J., Huang Ting-T, Bos Johannes L., Medema René H., Burgering Boudewijn M. T. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002 Sep 19;419(6904):316–321. doi: 10.1038/nature01036. [DOI] [PubMed] [Google Scholar]
  61. Kortylewski Marcin, Feld Florian, Krüger Klaus-Dieter, Bahrenberg Gregor, Roth Richard A., Joost Hans-Georg, Heinrich Peter C., Behrmann Iris, Barthel Andreas. Akt modulates STAT3-mediated gene expression through a FKHR (FOXO1a)-dependent mechanism. J Biol Chem. 2002 Nov 26;278(7):5242–5249. doi: 10.1074/jbc.M205403200. [DOI] [PubMed] [Google Scholar]
  62. Kramer Jamie M., Davidge Jason T., Lockyer Joseph M., Staveley Brian E. Expression of Drosophila FOXO regulates growth and can phenocopy starvation. BMC Dev Biol. 2003 Jul 5;3:5–5. doi: 10.1186/1471-213X-3-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Kuersten S., Ohno M., Mattaj I. W. Nucleocytoplasmic transport: Ran, beta and beyond. Trends Cell Biol. 2001 Dec;11(12):497–503. doi: 10.1016/s0962-8924(01)02144-4. [DOI] [PubMed] [Google Scholar]
  64. Lawlor M. A., Alessi D. R. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci. 2001 Aug;114(Pt 16):2903–2910. doi: 10.1242/jcs.114.16.2903. [DOI] [PubMed] [Google Scholar]
  65. Lee R. Y., Hench J., Ruvkun G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol. 2001 Dec 11;11(24):1950–1957. doi: 10.1016/s0960-9822(01)00595-4. [DOI] [PubMed] [Google Scholar]
  66. Leo C., Li H., Chen J. D. Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3. J Biol Chem. 2000 Feb 25;275(8):5976–5982. doi: 10.1074/jbc.275.8.5976. [DOI] [PubMed] [Google Scholar]
  67. Leong Meredith L. L., Maiyar Anita C., Kim Brian, O'Keeffe Bridget A., Firestone Gary L. Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells. J Biol Chem. 2002 Dec 16;278(8):5871–5882. doi: 10.1074/jbc.M211649200. [DOI] [PubMed] [Google Scholar]
  68. Li Pengfei, Lee Heehyoung, Guo Shaodong, Unterman Terry G., Jenster Guido, Bai Wenlong. AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR. Mol Cell Biol. 2003 Jan;23(1):104–118. doi: 10.1128/MCB.23.1.104-118.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Lin Jiandie, Tarr Paul T., Yang Ruojing, Rhee James, Puigserver Pere, Newgard Christopher B., Spiegelman Bruce M. PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem. 2003 Jun 13;278(33):30843–30848. doi: 10.1074/jbc.M303643200. [DOI] [PubMed] [Google Scholar]
  70. Linseman Daniel A., Phelps Reid A., Bouchard Ron J., Le Shoshona S., Laessig Tracey A., McClure Maria L., Heidenreich Kim A. Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons. J Neurosci. 2002 Nov 1;22(21):9287–9297. doi: 10.1523/JNEUROSCI.22-21-09287.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Liu F., Ma X. H., Ule J., Bibb J. A., Nishi A., DeMaggio A. J., Yan Z., Nairn A. C., Greengard P. Regulation of cyclin-dependent kinase 5 and casein kinase 1 by metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11062–11068. doi: 10.1073/pnas.191353898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Luo Jianyuan, Li Muyang, Tang Yi, Laszkowska Monika, Roeder Robert G., Gu Wei. Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2259–2264. doi: 10.1073/pnas.0308762101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Lussier G., Larose L. A casein kinase I activity is constitutively associated with Nck. J Biol Chem. 1997 Jan 31;272(5):2688–2694. doi: 10.1074/jbc.272.5.2688. [DOI] [PubMed] [Google Scholar]
  74. Mahmud Dolores L., G-Amlak Maaza, Deb Dilip K., Platanias Leonidas C., Uddin Shahab, Wickrema Amittha. Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene. 2002 Feb 28;21(10):1556–1562. doi: 10.1038/sj.onc.1205230. [DOI] [PubMed] [Google Scholar]
  75. Martínez-Gac Lorena, Marqués Miriam, García Zaira, Campanero Miguel R., Carrera Ana C. Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead. Mol Cell Biol. 2004 Mar;24(5):2181–2189. doi: 10.1128/MCB.24.5.2181-2189.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Matsuzaki Hitomi, Daitoku Hiroaki, Hatta Mitsutoki, Tanaka Keiji, Fukamizu Akiyoshi. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci U S A. 2003 Sep 17;100(20):11285–11290. doi: 10.1073/pnas.1934283100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Medema R. H., Kops G. J., Bos J. L., Burgering B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature. 2000 Apr 13;404(6779):782–787. doi: 10.1038/35008115. [DOI] [PubMed] [Google Scholar]
  78. Modur Vijayanand, Nagarajan Rakesh, Evers B. Mark, Milbrandt Jeffrey. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem. 2002 Sep 25;277(49):47928–47937. doi: 10.1074/jbc.M207509200. [DOI] [PubMed] [Google Scholar]
  79. Motta Maria Carla, Divecha Nullin, Lemieux Madeleine, Kamel Christopher, Chen Delin, Gu Wei, Bultsma Yvette, McBurney Michael, Guarente Leonard. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004 Feb 20;116(4):551–563. doi: 10.1016/s0092-8674(04)00126-6. [DOI] [PubMed] [Google Scholar]
  80. Nakae J., Barr V., Accili D. Differential regulation of gene expression by insulin and IGF-1 receptors correlates with phosphorylation of a single amino acid residue in the forkhead transcription factor FKHR. EMBO J. 2000 Mar 1;19(5):989–996. doi: 10.1093/emboj/19.5.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Nakae Jun, Biggs William H., 3rd, Kitamura Tadahiro, Cavenee Webster K., Wright Christopher V. E., Arden Karen C., Accili Domenico. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet. 2002 Sep 3;32(2):245–253. doi: 10.1038/ng890. [DOI] [PubMed] [Google Scholar]
  82. Nakae Jun, Kitamura Tadahiro, Kitamura Yukari, Biggs William H., 3rd, Arden Karen C., Accili Domenico. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell. 2003 Jan;4(1):119–129. doi: 10.1016/s1534-5807(02)00401-x. [DOI] [PubMed] [Google Scholar]
  83. Nasrin N., Ogg S., Cahill C. M., Biggs W., Nui S., Dore J., Calvo D., Shi Y., Ruvkun G., Alexander-Bridges M. C. DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10412–10417. doi: 10.1073/pnas.190326997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Obsil Tomas, Ghirlando Rodolfo, Anderson D. Eric, Hickman Alison Burgess, Dyda Fred. Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding. Biochemistry. 2003 Dec 30;42(51):15264–15272. doi: 10.1021/bi0352724. [DOI] [PubMed] [Google Scholar]
  85. Ogg S., Paradis S., Gottlieb S., Patterson G. I., Lee L., Tissenbaum H. A., Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997 Oct 30;389(6654):994–999. doi: 10.1038/40194. [DOI] [PubMed] [Google Scholar]
  86. Pearce D. The role of SGK1 in hormone-regulated sodium transport. Trends Endocrinol Metab. 2001 Oct;12(8):341–347. doi: 10.1016/s1043-2760(01)00439-8. [DOI] [PubMed] [Google Scholar]
  87. Perrot Valerie, Rechler Matthew M. Characterization of insulin inhibition of transactivation by a C-terminal fragment of the forkhead transcription factor Foxo1 in rat hepatoma cells. J Biol Chem. 2003 Apr 29;278(28):26111–26119. doi: 10.1074/jbc.M212750200. [DOI] [PubMed] [Google Scholar]
  88. Plas David R., Thompson Craig B. Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem. 2003 Jan 6;278(14):12361–12366. doi: 10.1074/jbc.M213069200. [DOI] [PubMed] [Google Scholar]
  89. Puig Oscar, Marr Michael T., Ruhf M. Laure, Tjian Robert. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev. 2003 Jul 31;17(16):2006–2020. doi: 10.1101/gad.1098703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Puigserver Pere, Rhee James, Donovan Jerry, Walkey Christopher J., Yoon J. Cliff, Oriente Francesco, Kitamura Yukari, Altomonte Jennifer, Dong Hengjiang, Accili Domenico. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003 May 18;423(6939):550–555. doi: 10.1038/nature01667. [DOI] [PubMed] [Google Scholar]
  91. Ramaswamy Shivapriya, Nakamura Noriaki, Sansal Isabelle, Bergeron Louise, Sellers William R. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell. 2002 Jul;2(1):81–91. doi: 10.1016/s1535-6108(02)00086-7. [DOI] [PubMed] [Google Scholar]
  92. Rena G., Prescott A. R., Guo S., Cohen P., Unterman T. G. Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Biochem J. 2001 Mar 15;354(Pt 3):605–612. doi: 10.1042/0264-6021:3540605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Rena Graham, Bain Jenny, Elliott Matthew, Cohen Philip. D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep. 2004 Jan;5(1):60–65. doi: 10.1038/sj.embor.7400048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Rena Graham, Woods Yvonne L., Prescott Alan R., Peggie Mark, Unterman Terry G., Williams Michayla R., Cohen Philip. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J. 2002 May 1;21(9):2263–2271. doi: 10.1093/emboj/21.9.2263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Rochette-Egly Cécile. Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell Signal. 2003 Apr;15(4):355–366. doi: 10.1016/s0898-6568(02)00115-8. [DOI] [PubMed] [Google Scholar]
  96. Rong Rong, Ahn Jee-Yin, Huang Honglian, Nagata Eiichiro, Kalman Daniel, Kapp Judith A., Tu Jiancheng, Worley Paul F., Snyder Solomon H., Ye Keqiang. PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nat Neurosci. 2003 Oct 5;6(11):1153–1161. doi: 10.1038/nn1134. [DOI] [PubMed] [Google Scholar]
  97. Samatar Ahmed A., Wang Luquan, Mirza Asra, Koseoglu Sandra, Liu Suxing, Kumar Chandra C. Transforming growth factor-beta 2 is a transcriptional target for Akt/protein kinase B via forkhead transcription factor. J Biol Chem. 2002 May 14;277(31):28118–28126. doi: 10.1074/jbc.M203686200. [DOI] [PubMed] [Google Scholar]
  98. Santos J. A., Logarinho E., Tapia C., Allende C. C., Allende J. E., Sunkel C. E. The casein kinase 1 alpha gene of Drosophila melanogaster is developmentally regulated and the kinase activity of the protein induced by DNA damage. J Cell Sci. 1996 Jul;109(Pt 7):1847–1856. doi: 10.1242/jcs.109.7.1847. [DOI] [PubMed] [Google Scholar]
  99. Scheid Michael P., Woodgett James R. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 2003 Jul 3;546(1):108–112. doi: 10.1016/s0014-5793(03)00562-3. [DOI] [PubMed] [Google Scholar]
  100. Schuur E. R., Loktev A. V., Sharma M., Sun Z., Roth R. A., Weigel R. J. Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family. J Biol Chem. 2001 Jul 2;276(36):33554–33560. doi: 10.1074/jbc.M105555200. [DOI] [PubMed] [Google Scholar]
  101. Seol Ki-Cheon, Kim Sung-Jin. Nuclear matrix association of insulin receptor and IRS-1 by insulin in osteoblast-like UMR-106 cells. Biochem Biophys Res Commun. 2003 Jul 11;306(4):898–904. doi: 10.1016/s0006-291x(03)01046-5. [DOI] [PubMed] [Google Scholar]
  102. Stahl Marie, Dijkers Pascale F., Kops Geert J. P. L., Lens Susanne M. A., Coffer Paul J., Burgering Boudewijn M. T., Medema René H. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol. 2002 May 15;168(10):5024–5031. doi: 10.4049/jimmunol.168.10.5024. [DOI] [PubMed] [Google Scholar]
  103. Sunters Andrew, Fernández de Mattos Silvia, Stahl Marie, Brosens Jan J., Zoumpoulidou Georgia, Saunders Catherine A., Coffer Paul J., Medema René H., Coombes R. Charles, Lam Eric W-F. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem. 2003 Oct 3;278(50):49795–49805. doi: 10.1074/jbc.M309523200. [DOI] [PubMed] [Google Scholar]
  104. Tejedor F., Zhu X. R., Kaltenbach E., Ackermann A., Baumann A., Canal I., Heisenberg M., Fischbach K. F., Pongs O. minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron. 1995 Feb;14(2):287–301. doi: 10.1016/0896-6273(95)90286-4. [DOI] [PubMed] [Google Scholar]
  105. Tissenbaum H. A., Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001 Mar 8;410(6825):227–230. doi: 10.1038/35065638. [DOI] [PubMed] [Google Scholar]
  106. Tobin A. B., Totty N. F., Sterlin A. E., Nahorski S. R. Stimulus-dependent phosphorylation of G-protein-coupled receptors by casein kinase 1alpha. J Biol Chem. 1997 Aug 15;272(33):20844–20849. doi: 10.1074/jbc.272.33.20844. [DOI] [PubMed] [Google Scholar]
  107. Tran Hien, Brunet Anne, Grenier Jill M., Datta Sandeep R., Fornace Albert J., Jr, DiStefano Peter S., Chiang Lillian W., Greenberg Michael E. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science. 2002 Apr 19;296(5567):530–534. doi: 10.1126/science.1068712. [DOI] [PubMed] [Google Scholar]
  108. Tsai Wen-Chi, Bhattacharyya Nisan, Han Li-Ying, Hanover John A., Rechler Matthew M. Insulin inhibition of transcription stimulated by the forkhead protein Foxo1 is not solely due to nuclear exclusion. Endocrinology. 2003 Sep 18;144(12):5615–5622. doi: 10.1210/en.2003-0481. [DOI] [PubMed] [Google Scholar]
  109. Tzivion G., Luo Z., Avruch J. A dimeric 14-3-3 protein is an essential cofactor for Raf kinase activity. Nature. 1998 Jul 2;394(6688):88–92. doi: 10.1038/27938. [DOI] [PubMed] [Google Scholar]
  110. Vanhaesebroeck B., Alessi D. R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000 Mar 15;346(Pt 3):561–576. [PMC free article] [PubMed] [Google Scholar]
  111. Vanhaesebroeck B., Waterfield M. D. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999 Nov 25;253(1):239–254. doi: 10.1006/excr.1999.4701. [DOI] [PubMed] [Google Scholar]
  112. Woods Y. L., Rena G., Morrice N., Barthel A., Becker W., Guo S., Unterman T. G., Cohen P. The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J. 2001 May 1;355(Pt 3):597–607. doi: 10.1042/bj3550597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Yaffe Michael B. How do 14-3-3 proteins work?-- Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett. 2002 Feb 20;513(1):53–57. doi: 10.1016/s0014-5793(01)03288-4. [DOI] [PubMed] [Google Scholar]
  114. Yoneda Y., Hieda M., Nagoshi E., Miyamoto Y. Nucleocytoplasmic protein transport and recycling of Ran. Cell Struct Funct. 1999 Dec;24(6):425–433. doi: 10.1247/csf.24.425. [DOI] [PubMed] [Google Scholar]
  115. Zhang Xiaohui, Gan Lixia, Pan Haiyun, Guo Shaodong, He Xiaowei, Olson Steven T., Mesecar Andrew, Adam Stephen, Unterman Terry G. Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding. J Biol Chem. 2002 Sep 12;277(47):45276–45284. doi: 10.1074/jbc.M208063200. [DOI] [PubMed] [Google Scholar]
  116. Zhao H. H., Herrera R. E., Coronado-Heinsohn E., Yang M. C., Ludes-Meyers J. H., Seybold-Tilson K. J., Nawaz Z., Yee D., Barr F. G., Diab S. G. Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions. J Biol Chem. 2001 May 15;276(30):27907–27912. doi: 10.1074/jbc.M104278200. [DOI] [PubMed] [Google Scholar]
  117. Zhao Xiangshan, Gan Lixia, Pan Haiyun, Kan Donghui, Majeski Michael, Adam Stephen A., Unterman Terry G. Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14-3-3-dependent and -independent mechanisms. Biochem J. 2004 Mar 15;378(Pt 3):839–849. doi: 10.1042/BJ20031450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. de Vries-Smits A. M., Burgering B. M., Leevers S. J., Marshall C. J., Bos J. L. Involvement of p21ras in activation of extracellular signal-regulated kinase 2. Nature. 1992 Jun 18;357(6379):602–604. doi: 10.1038/357602a0. [DOI] [PubMed] [Google Scholar]
  119. von Groote-Bidlingmaier Florian, Schmoll Dieter, Orth Hans Martin, Joost Hans Georg, Becker Walter, Barthel Andreas. DYRK1 is a co-activator of FKHR (FOXO1a)-dependent glucose-6-phosphatase gene expression. Biochem Biophys Res Commun. 2003 Jan 17;300(3):764–769. doi: 10.1016/s0006-291x(02)02914-5. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES