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. 2000 Nov;197(Pt 4):571–574. doi: 10.1046/j.1469-7580.2000.19740571.x

Forkhead transcription factors are targets of signalling by the proto-oncogene PKB (C-AKT)

G J P L KOPS 1, B M T BURGERING 1,
PMCID: PMC1468172  PMID: 11197530

Abstract

Following the discovery that the proto-oncogene protein kinase B (PKB) functions as a downstream element in signalling from phosphoinositide 3′-kinase (PI3-kinase) (Burgering & Coffer, 1995), PKB has been shown to mediate a diverse array of PI3-kinase dependent cellular responses. Most recently PKB-dependent phosphorylation of 3 members of the family of Forkhead transcription factors has been demonstrated to play a role in PI3-kinase dependent effects on transcription. This review focuses on this newly discovered function of PKB in conveying the diversity of PI3-kinase dependent cellular responses.

Keywords: Protein kinase B, c-akt

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Selected References

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  1. Borkhardt A., Repp R., Haas O. A., Leis T., Harbott J., Kreuder J., Hammermann J., Henn T., Lampert F. Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene. 1997 Jan 16;14(2):195–202. doi: 10.1038/sj.onc.1200814. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Burgering B. M., Coffer P. J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995 Aug 17;376(6541):599–602. doi: 10.1038/376599a0. [DOI] [PubMed] [Google Scholar]
  4. Cardone M. H., Roy N., Stennicke H. R., Salvesen G. S., Franke T. F., Stanbridge E., Frisch S., Reed J. C. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998 Nov 13;282(5392):1318–1321. doi: 10.1126/science.282.5392.1318. [DOI] [PubMed] [Google Scholar]
  5. Cichy S. B., Uddin S., Danilkovich A., Guo S., Klippel A., Unterman T. G. Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence. J Biol Chem. 1998 Mar 13;273(11):6482–6487. doi: 10.1074/jbc.273.11.6482. [DOI] [PubMed] [Google Scholar]
  6. Coffer P. J., Jin J., Woodgett J. R. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998 Oct 1;335(Pt 1):1–13. doi: 10.1042/bj3350001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Deprez J., Vertommen D., Alessi D. R., Hue L., Rider M. H. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem. 1997 Jul 11;272(28):17269–17275. doi: 10.1074/jbc.272.28.17269. [DOI] [PubMed] [Google Scholar]
  8. Dimmeler S., Fleming I., Fisslthaler B., Hermann C., Busse R., Zeiher A. M. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999 Jun 10;399(6736):601–605. doi: 10.1038/21224. [DOI] [PubMed] [Google Scholar]
  9. Dudek H., Datta S. R., Franke T. F., Birnbaum M. J., Yao R., Cooper G. M., Segal R. A., Kaplan D. R., Greenberg M. E. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science. 1997 Jan 31;275(5300):661–665. doi: 10.1126/science.275.5300.661. [DOI] [PubMed] [Google Scholar]
  10. Epstein J. A., Song B., Lakkis M., Wang C. Tumor-specific PAX3-FKHR transcription factor, but not PAX3, activates the platelet-derived growth factor alpha receptor. Mol Cell Biol. 1998 Jul;18(7):4118–4130. doi: 10.1128/mcb.18.7.4118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fulton D., Gratton J. P., McCabe T. J., Fontana J., Fujio Y., Walsh K., Franke T. F., Papapetropoulos A., Sessa W. C. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999 Jun 10;399(6736):597–601. doi: 10.1038/21218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gingras A. C., Kennedy S. G., O'Leary M. A., Sonenberg N., Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 1998 Feb 15;12(4):502–513. doi: 10.1101/gad.12.4.502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ginsberg J. P., Davis R. J., Bennicelli J. L., Nauta L. E., Barr F. G. Up-regulation of MET but not neural cell adhesion molecule expression by the PAX3-FKHR fusion protein in alveolar rhabdomyosarcoma. Cancer Res. 1998 Aug 15;58(16):3542–3546. [PubMed] [Google Scholar]
  14. 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]
  15. Kohn A. D., Summers S. A., Birnbaum M. J., Roth R. A. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem. 1996 Dec 6;271(49):31372–31378. doi: 10.1074/jbc.271.49.31372. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Liao J., Barthel A., Nakatani K., Roth R. A. Activation of protein kinase B/Akt is sufficient to repress the glucocorticoid and cAMP induction of phosphoenolpyruvate carboxykinase gene. J Biol Chem. 1998 Oct 16;273(42):27320–27324. doi: 10.1074/jbc.273.42.27320. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Rena G., Guo S., Cichy S. C., Unterman T. G., Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999 Jun 11;274(24):17179–17183. doi: 10.1074/jbc.274.24.17179. [DOI] [PubMed] [Google Scholar]
  20. Sublett J. E., Jeon I. S., Shapiro D. N. The alveolar rhabdomyosarcoma PAX3/FKHR fusion protein is a transcriptional activator. Oncogene. 1995 Aug 3;11(3):545–552. [PubMed] [Google Scholar]
  21. Tang E. D., Nuñez G., Barr F. G., Guan K. L. Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem. 1999 Jun 11;274(24):16741–16746. doi: 10.1074/jbc.274.24.16741. [DOI] [PubMed] [Google Scholar]
  22. Wang D., Sul H. S. Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-kinase pathway. Involvement of protein kinase B/Akt. J Biol Chem. 1998 Sep 25;273(39):25420–25426. doi: 10.1074/jbc.273.39.25420. [DOI] [PubMed] [Google Scholar]
  23. van Weeren P. C., de Bruyn K. M., de Vries-Smits A. M., van Lint J., Burgering B. M. Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB. J Biol Chem. 1998 May 22;273(21):13150–13156. doi: 10.1074/jbc.273.21.13150. [DOI] [PubMed] [Google Scholar]

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