Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt–β-catenin signalling through Dishevelled

Nature Cell Biology volume 8, pages 501–508 (2006)Cite this article

Abstract

Dishevelled (Dvl) transduces signals from the Wnt receptor, Frizzled, to downstream components, leading to the stabilization of β-catenin and subsequent activation of the transcription factor T cell factor (TCF) and/or lymphoid enchancer factor (LEF)1,2,3. However, the mechanism of Dvl action remains unclear. Here, we report that nucleoredoxin (NRX)4, a thioredoxin (TRX) family protein, interacts with Dvl. Overexpression of NRX selectively suppresses the Wnt–β-catenin pathway and ablation of NRX by RNA-interference (RNAi) results in activation of TCF, accelerated cell proliferation and enhancement of oncogenicity through cooperation with mitogen-activated extracellular signal regulated kinase kinase (MEK) or Ras. We find that cells respond to H2O2 stimulation by activating TCF. Redox-dependent activation of the Wnt–β-catenin pathway occurs independently of extracellular Wnts and is impaired by RNAi of NRX . In addition, association between Dvl and NRX is inhibited by H2O2 treatment. These data suggest a relationship between the Wnt–β-catenin pathway and redox signalling through redox-sensitive association of NRX with Dvl.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Redox-dependent association between Dvl and NRX.
Figure 2: NRX suppresses Wnt–β-catenin signalling.
Figure 3: NRX RNAi shows TCF activation and increased cell proliferation.
Figure 4: NRX inhibits Wnt–β-catenin signalling in Xenopus.
Figure 5: Activation of the Wnt–β-catenin pathway by H2O2.

Similar content being viewed by others

References

  1. Nelson, W. J. & Nusse, R. Convergence of Wnt, β-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).

    Article  CAS  Google Scholar 

  2. Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).

    Article  CAS  Google Scholar 

  3. Moon, R. T., Kohn, A. D., De Ferrari, G. V. & Kaykas, A. WNT and β-catenin signalling: diseases and therapies. Nature Rev. Genet. 5, 691–701 (2004).

    Article  CAS  Google Scholar 

  4. Kurooka, H. et al. Cloning and characterization of the nucleoredoxin gene that encodes a novel nuclear protein related to thioredoxin. Genomics 39, 331–339 (1997).

    Article  CAS  Google Scholar 

  5. Laurent, T. C., Moore, E. C. & Reichard, P. Enzymatic synthesis of deoxyribonucleotides. IV. Isolation and characterization of thioredoxin, the hydrogen donor from Escherichia coli B. J. Biol. Chem. 239, 3436–3444 (1964).

    CAS  PubMed  Google Scholar 

  6. Chae, H. Z. et al. Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes. Proc. Nat. Acad. Sci. USA 91, 7017–7021 (1994).

    Article  CAS  Google Scholar 

  7. Saitoh, M. et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17, 2596–2606 (1998).

    Article  CAS  Google Scholar 

  8. Yanagawa, S., van Leeuwen, F., Wodarz, A., Klingensmith, J. & Nusse, R. The dishevelled protein is modified by wingless signaling in Drosophila. Genes Dev. 9, 1087–1097 (1995).

    Article  CAS  Google Scholar 

  9. Barth, A. I., Pollack, A. L., Altschuler, Y., Mostov, K.E. & Nelson, W. J. NH2-terminal deletion of β-catenin results in stable colocalization of mutant β-catenin with adenomatous polyposis coli protein and altered MDCK cell adhesion. J. Cell Biol. 136, 693–706 (1997).

    Article  CAS  Google Scholar 

  10. Li, L. et al. Dishevelled proteins lead to two signaling pathways. Regulation of LEF-1 and c-Jun N-terminal kinase in mammalian cells. J. Biol. Chem. 274, 129–134 (1999).

    Article  CAS  Google Scholar 

  11. Moriguchi, T. et al. Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase–stress-activated protein kinase activation and the axis formation in vertebrates. J. Biol. Chem. 274, 30957–30962 (1999).

    Article  CAS  Google Scholar 

  12. Yost, C. et al. GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 93, 1031–1041 (1998).

    Article  CAS  Google Scholar 

  13. Li, L. et al. Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1. EMBO J. 18, 4233–4240 (1999).

    Article  CAS  Google Scholar 

  14. Hino, S., Michiue, T., Asashima, M. & Kikuchi, A. Casein kinase Iɛ enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of β-catenin. J. Biol. Chem. 278, 14066–14073 (2003).

    Article  CAS  Google Scholar 

  15. He, T. C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998).

    Article  CAS  Google Scholar 

  16. Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).

    Article  CAS  Google Scholar 

  17. Rimerman, R. A., Gellert-Randleman, A. & Diehl, J. A. Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. J. Biol. Chem. 275, 14736–14742 (2000).

    Article  CAS  Google Scholar 

  18. Sokol, S. Y., Klingensmith, J., Perrimon, N. & Itoh, K. Dorsalizing and neuralizing properties of Xdsh, a maternally expressed Xenopus homolog of dishevelled. Development 121, 1637–1647 (1995).

    CAS  PubMed  Google Scholar 

  19. Kim, C. H. et al. Repressor activity of Headless–Tcf3 is essential for vertebrate head formation. Nature 407, 913–916 (2000).

    Article  CAS  Google Scholar 

  20. Kiecker, C. & Niehrs, C. A morphogen gradient of Wnt–β-catenin signalling regulates anteroposterior neural patterning in Xenopus. Development 128, 4189–4201 (2001).

    CAS  PubMed  Google Scholar 

  21. Michiue, T. et al. XIdax, an inhibitor of the canonical Wnt pathway, is required for anterior neural structure formation in Xenopus. Dev. Dyn. 230, 79–90 (2004).

    Article  CAS  Google Scholar 

  22. Leyns, L., Bouwmeester, T., Kim, S. H., Piccolo, S. & De Robertis, E. M. Frzb-1 is a secreted antagonist of Wnt signaling expressed in the Spemann organizer. Cell 88, 747–756 (1997).

    Article  CAS  Google Scholar 

  23. Wang, S., Krinks, M., Lin, K., Luyten, F. P. & Moos, M., Jr. Frzb, a secreted protein expressed in the Spemann organizer, binds and inhibits Wnt-8. Cell 88, 757–766 (1997).

    Article  CAS  Google Scholar 

  24. Burdon, R. H. & Rice-Evans, C. Free radicals and the regulation of mammalian cell proliferation. Free Radic. Res. Commun. 6, 345–358 (1989).

    Article  CAS  Google Scholar 

  25. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    Article  CAS  Google Scholar 

  26. Finkel, T. Oxidant signals and oxidative stress. Curr. Opin. Cell Biol. 15, 247–254 (2003).

    Article  CAS  Google Scholar 

  27. Rhee, S. G. et al. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr. Opin. Cell Biol. 17, 183–189 (2005).

    Article  CAS  Google Scholar 

  28. Miki, H., Fukuda, M., Nishida, E. & Takenawa, T. Phosphorylation of WAVE downstream of mitogen-activated protein kinase signaling. J. Biol. Chem. 274, 27605–27609 (1999).

    Article  CAS  Google Scholar 

  29. Molenaar, M., et al. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell 86, 391–399 (1996).

    Article  CAS  Google Scholar 

  30. Fujita, M. et al. Up-regulation of the ectodermal-neural cortex 1 (ENC1) gene, a downstream target of the β-catenin–T-cell factor complex, in colorectal carcinomas. Cancer Res. 61, 7722–7726 (2001).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Ohmi and H. Fukuda for mass spectrometry analysis. We are grateful to R. J. Davis for JNK1, S. Yokoyama for RasG12V, E. Nishida for HA–MEK LA SDSE, Y. Furukawa and Y. Nakamura for wild-type TCF-4 and dominant negative TCF-4, and Y. Gotoh for β-catenin and c-Jun. We also appreciate helpful advice and support from T. Takenawa, K. Takenaka, H. Yamaguchi, T. Terabayashi, A. Yukita, K. Haraguchi, S. Aizawa and T. Chano. This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture of Japan.

Author information

Authors and Affiliations

  1. Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yosuke Funato & Hiroaki Miki

  2. Division of Biochemistry, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yosuke Funato

  3. Department of Life Sciences (Biology), Graduate School of Arts and Sciences, University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo, 153-8902, Japan

    Tatsuo Michiue & Makoto Asashima

  4. ICORP, Japan Science and Technology Agency (JST), 3-8-1, Komaba, Meguro-ku, Tokyo, 153-8902, Japan

    Makoto Asashima

  5. PRESTO, JST, 4-1-8 Honcho, Kawaguchi-shi, Saitama, 332-0012, Japan

    Hiroaki Miki

Authors
  1. Yosuke Funato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatsuo Michiue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Makoto Asashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Miki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroaki Miki.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3 and Supplementary Table 1 (PDF 709 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Funato, Y., Michiue, T., Asashima, M. et al. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt–β-catenin signalling through Dishevelled. Nat Cell Biol 8, 501–508 (2006). https://doi.org/10.1038/ncb1405

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1405

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing