Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C (original) (raw)

. 1996 Sep 2;15(17):4526–4536.

Abstract

The Drosophila gene product Wingless (Wg) is a secreted glycoprotein and a member of the Wnt gene family. Genetic analysis of Drosophila epidermal development has defined a putative paracrine Wg signalling pathway involving the zeste-white 3/shaggy (zw3/sgg) gene product. Although putative components of Wg- (and by inference Wnt-) mediated signalling pathways have been identified by genetic analysis, the biochemical significance of most factors remains unproven. Here we show that in mouse 10T1/2 fibroblasts the activity of glycogen synthase kinase-3 (GSK-3), the murine homologue of Zw3/Sgg, is inactivated by Wg. This occurs through a signalling pathway that is distinct from insulin-mediated regulation of GSK-3 in that Wg signalling to GSK-3 is insensitive to wortmannin. Additionally, Wg-induced inactivation of GSK-3 is sensitive to both the protein kinase C (PKC) inhibitor Ro31-8220 and prolonged pre-treatment of 10T1/2 fibroblasts with phorbol ester. These findings provide the first biochemical evidence in support of the genetically defined pathway from Wg to Zw3/Sgg, and suggest a previously uncharacterized role for a PKC upstream of GSK-3/Zw3 during Wnt/Wg signal transduction.

4526

Images in this article

Selected References

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

  1. Adams J. C., Gullick W. J. Differences in phorbol-ester-induced down-regulation of protein kinase C between cell lines. Biochem J. 1989 Feb 1;257(3):905–911. doi: 10.1042/bj2570905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arcaro A., Wymann M. P. Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem J. 1993 Dec 1;296(Pt 2):297–301. doi: 10.1042/bj2960297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bradbury J. M., Niemeyer C. C., Dale T. C., Edwards P. A. Alterations of the growth characteristics of the fibroblast cell line C3H 10T1/2 by members of the Wnt gene family. Oncogene. 1994 Sep;9(9):2597–2603. [PubMed] [Google Scholar]
  4. Cross D. A., Alessi D. R., Cohen P., Andjelkovich M., Hemmings B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995 Dec 21;378(6559):785–789. doi: 10.1038/378785a0. [DOI] [PubMed] [Google Scholar]
  5. Cross D. A., Alessi D. R., Vandenheede J. R., McDowell H. E., Hundal H. S., Cohen P. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem J. 1994 Oct 1;303(Pt 1):21–26. doi: 10.1042/bj3030021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cumberledge S., Krasnow M. A. Intercellular signalling in Drosophila segment formation reconstructed in vitro. Nature. 1993 Jun 10;363(6429):549–552. doi: 10.1038/363549a0. [DOI] [PubMed] [Google Scholar]
  7. Davis P. D., Hill C. H., Keech E., Lawton G., Nixon J. S., Sedgwick A. D., Wadsworth J., Westmacott D., Wilkinson S. E. Potent selective inhibitors of protein kinase C. FEBS Lett. 1989 Dec 18;259(1):61–63. doi: 10.1016/0014-5793(89)81494-2. [DOI] [PubMed] [Google Scholar]
  8. Dominguez I., Itoh K., Sokol S. Y. Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8498–8502. doi: 10.1073/pnas.92.18.8498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dudley D. T., Pang L., Decker S. J., Bridges A. J., Saltiel A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686–7689. doi: 10.1073/pnas.92.17.7686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eldar-Finkelman H., Seger R., Vandenheede J. R., Krebs E. G. Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J Biol Chem. 1995 Jan 20;270(3):987–990. doi: 10.1074/jbc.270.3.987. [DOI] [PubMed] [Google Scholar]
  11. Goode N., Hughes K., Woodgett J. R., Parker P. J. Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes. J Biol Chem. 1992 Aug 25;267(24):16878–16882. [PubMed] [Google Scholar]
  12. Harwood A. J., Plyte S. E., Woodgett J., Strutt H., Kay R. R. Glycogen synthase kinase 3 regulates cell fate in Dictyostelium. Cell. 1995 Jan 13;80(1):139–148. doi: 10.1016/0092-8674(95)90458-1. [DOI] [PubMed] [Google Scholar]
  13. He X., Saint-Jeannet J. P., Woodgett J. R., Varmus H. E., Dawid I. B. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature. 1995 Apr 13;374(6523):617–622. doi: 10.1038/374617a0. [DOI] [PubMed] [Google Scholar]
  14. Hooper J. E. Distinct pathways for autocrine and paracrine Wingless signalling in Drosophila embryos. Nature. 1994 Dec 1;372(6505):461–464. doi: 10.1038/372461a0. [DOI] [PubMed] [Google Scholar]
  15. Hughes K., Nikolakaki E., Plyte S. E., Totty N. F., Woodgett J. R. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 1993 Feb;12(2):803–808. doi: 10.1002/j.1460-2075.1993.tb05715.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Itoh K., Tang T. L., Neel B. G., Sokol S. Y. Specific modulation of ectodermal cell fates in Xenopus embryos by glycogen synthase kinase. Development. 1995 Dec;121(12):3979–3988. doi: 10.1242/dev.121.12.3979. [DOI] [PubMed] [Google Scholar]
  17. Noordermeer J., Klingensmith J., Perrimon N., Nusse R. dishevelled and armadillo act in the wingless signalling pathway in Drosophila. Nature. 1994 Jan 6;367(6458):80–83. doi: 10.1038/367080a0. [DOI] [PubMed] [Google Scholar]
  18. Nusse R., Varmus H. E. Wnt genes. Cell. 1992 Jun 26;69(7):1073–1087. doi: 10.1016/0092-8674(92)90630-u. [DOI] [PubMed] [Google Scholar]
  19. Olivier A. R., Parker P. J. Identification of multiple PKC isoforms in Swiss 3T3 cells: differential down-regulation by phorbol ester. J Cell Physiol. 1992 Aug;152(2):240–244. doi: 10.1002/jcp.1041520204. [DOI] [PubMed] [Google Scholar]
  20. Pierce S. B., Kimelman D. Regulation of Spemann organizer formation by the intracellular kinase Xgsk-3. Development. 1995 Mar;121(3):755–765. doi: 10.1242/dev.121.3.755. [DOI] [PubMed] [Google Scholar]
  21. Price D. J., Grove J. R., Calvo V., Avruch J., Bierer B. E. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992 Aug 14;257(5072):973–977. doi: 10.1126/science.1380182. [DOI] [PubMed] [Google Scholar]
  22. Ramakrishna N. R., Brown A. M. Wingless, the Drosophila homolog of the proto-oncogene Wnt-1, can transform mouse mammary epithelial cells. Dev Suppl. 1993:95–103. [PubMed] [Google Scholar]
  23. Reznikoff C. A., Brankow D. W., Heidelberger C. Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division. Cancer Res. 1973 Dec;33(12):3231–3238. [PubMed] [Google Scholar]
  24. Saito Y., Vandenheede J. R., Cohen P. The mechanism by which epidermal growth factor inhibits glycogen synthase kinase 3 in A431 cells. Biochem J. 1994 Oct 1;303(Pt 1):27–31. doi: 10.1042/bj3030027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Schägger H., von Jagow G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 1987 Nov 1;166(2):368–379. doi: 10.1016/0003-2697(87)90587-2. [DOI] [PubMed] [Google Scholar]
  26. Siegfried E., Chou T. B., Perrimon N. wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate. Cell. 1992 Dec 24;71(7):1167–1179. doi: 10.1016/s0092-8674(05)80065-0. [DOI] [PubMed] [Google Scholar]
  27. Siegfried E., Wilder E. L., Perrimon N. Components of wingless signalling in Drosophila. Nature. 1994 Jan 6;367(6458):76–80. doi: 10.1038/367076a0. [DOI] [PubMed] [Google Scholar]
  28. Stambolic V., Woodgett J. R. Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. Biochem J. 1994 Nov 1;303(Pt 3):701–704. doi: 10.1042/bj3030701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sturgill T. W., Ray L. B., Erikson E., Maller J. L. Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature. 1988 Aug 25;334(6184):715–718. doi: 10.1038/334715a0. [DOI] [PubMed] [Google Scholar]
  30. Sussman D. J., Klingensmith J., Salinas P., Adams P. S., Nusse R., Perrimon N. Isolation and characterization of a mouse homolog of the Drosophila segment polarity gene dishevelled. Dev Biol. 1994 Nov;166(1):73–86. doi: 10.1006/dbio.1994.1297. [DOI] [PubMed] [Google Scholar]
  31. Sutherland C., Cohen P. The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett. 1994 Jan 24;338(1):37–42. doi: 10.1016/0014-5793(94)80112-6. [DOI] [PubMed] [Google Scholar]
  32. Sutherland C., Leighton I. A., Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J. 1993 Nov 15;296(Pt 1):15–19. doi: 10.1042/bj2960015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Welsh G. I., Foulstone E. J., Young S. W., Tavaré J. M., Proud C. G. Wortmannin inhibits the effects of insulin and serum on the activities of glycogen synthase kinase-3 and mitogen-activated protein kinase. Biochem J. 1994 Oct 1;303(Pt 1):15–20. doi: 10.1042/bj3030015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Welsh G. I., Proud C. G. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294(Pt 3):625–629. doi: 10.1042/bj2940625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Weng Q. P., Andrabi K., Kozlowski M. T., Grove J. R., Avruch J. Multiple independent inputs are required for activation of the p70 S6 kinase. Mol Cell Biol. 1995 May;15(5):2333–2340. doi: 10.1128/mcb.15.5.2333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wilkinson S. E., Parker P. J., Nixon J. S. Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C. Biochem J. 1993 Sep 1;294(Pt 2):335–337. doi: 10.1042/bj2940335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Woodgett J. R. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 1990 Aug;9(8):2431–2438. doi: 10.1002/j.1460-2075.1990.tb07419.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yang S. D., Yu J. S., Wen Z. D. Tumor promoter phorbol ester reversibly modulates tyrosine dephosphorylation/inactivation of protein kinase FA/GSK-3 alpha in A431 cells. J Cell Biochem. 1994 Dec;56(4):550–558. doi: 10.1002/jcb.240560416. [DOI] [PubMed] [Google Scholar]
  39. van Leeuwen F., Samos C. H., Nusse R. Biological activity of soluble wingless protein in cultured Drosophila imaginal disc cells. Nature. 1994 Mar 24;368(6469):342–344. doi: 10.1038/368342a0. [DOI] [PubMed] [Google Scholar]
  40. van den Heuvel M., Nusse R., Johnston P., Lawrence P. A. Distribution of the wingless gene product in Drosophila embryos: a protein involved in cell-cell communication. Cell. 1989 Nov 17;59(4):739–749. doi: 10.1016/0092-8674(89)90020-2. [DOI] [PubMed] [Google Scholar]