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:

Receptor-associated Mad homologues synergize as effectors of the TGF-β response

Nature volume 383, pages 168–172 (1996)Cite this article

Abstract

TRANSFORMING growth factor-β TGF-β is the prototype for a family of extracellular proteins that affect cell proliferation and tissue differentiation1–3. TGF-β-related factors, including BMP-2/4, Dpp and activin, act through two types of serine/threonine kinase receptors which can form a heteromeric complex3,4. However, the mechanism of signal transduction by these receptors is largely unknown. In Drosophila, Mad is required for signalling by Dpp5. We have isolated complementary DNAs for four human Mad homologues, one of which, hMAD-4, is identical to DPC-4, a candidate tumour suppressor6. hMAD-3 and -4 synergized to induce strong ligand-independent TGF-β-like responses. When truncated at their carboxy termini, hMAD-3 and -4 act as dominant-negative inhibitors of the normal TGF-β response. The activity of hMAD-3 and -4 was regulated by the TGF-β receptors, and hMAD-3 but not hMAD-4 was phosphorylated and associated with the ligand-bound receptor complex. These results define hMAD-3 and -4 as effectors of the TGF-β response and demonstrate a function for DPC-4/hMAD-4 as a tumour suppressor.

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

Similar content being viewed by others

References

  1. Derynck, R. in The Cytokine Handbook (ed. Thomson, A. W.) 319–342 (Academic, San Diego, 1994).

    Google Scholar 

  2. Kingsley, D. M. Genes Dev. 8, 133–146 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Massagué, J., Attisano, L. & Wrana, J. L. Trends Cell Biol. 4, 172–177 (1994).

    Article  PubMed  Google Scholar 

  4. Derynck, R. Trends Biochem. Sci. 19, 548–553 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H. & Gelbart, W. M. Genetics 139, 1347–1358 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hahn, S. A. et al. Science 271, 350–353 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Hoodless, P. A. et al. Cell 85, 489–500 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Graff, J. M., Bansal, A. & Melton, D. A. Cell 85, 479–487 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Abe, M. et al. Anal. Biochem. 216, 276–284 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Goyette, M. C. et al. Mol. Cell. Biol. 12, 1387–1395 (1994).

    Article  Google Scholar 

  11. Wrana, J. L. et al. Cell 71, 1003–1014 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Weis-Garcia, F. & Massagué, J. EMBO J. 15, 276–289 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Feng, X.-H., Filvaroff, E. H. & Derynck, R. J. Biol. Chem. 270, 24237–24245 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Matzuk, M. M. & Bradley, A. Biochim. Biophys. Acta 1130, 105–108 (1992) (erratum, 243).

    Article  CAS  PubMed  Google Scholar 

  15. Ebner, R. et al. Science 260, 1344–1348 (1993).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Gyuris, J., Golemis, E., Chertkov, H. & Brent, R. Cell 75, 791–803 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Liu, F. et al. Nature 381, 620–623 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Ihle, J. Nature 377, 591–594 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Arora, K. et al. Cell 81, 781–790 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Grieder, N. C., Nellen, D., Burke, R., Basler, K. & Affolter, M. Cell 81, 791–800 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. de Celis, J. F., Barrio, R. & Kafatos, F. C. Nature 381, 421–424 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Markowitz, S. et al. Science 268, 1336–1338 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Laiho, M., DeCaprio, J. A., Ludlow, J. W. & Livingston, D. M. Cell 62, 175–185 (1990).

    Article  CAS  PubMed  Google Scholar 

  24. Lennon, G. G., Auffray, C., Polymeropoulos, M. & Soares, M. B. Genomics 33, 151–152 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, R.-H., Miettinen, P. J., Maruoka, E. M., Choy, L. & Derynck, R. Nature 377, 548–552 (1995).

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Lin, H. Y., Wang, X.-F., Ng-Eaton, E., Weinberg, R. A. & Lodish, H. F. Cell 68, 775–785 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Keeton, M. R., Curriden, S. A., van Zonneveld, A. & Loskutoff, D. J. J. Biol. Chem. 266, 23048–23052 (1991).

    CAS  PubMed  Google Scholar 

  28. Like, B. & Massagué, J. J. Biol. Chem. 261, 13426–13429 (1986).

    CAS  PubMed  Google Scholar 

  29. Smith, D. B. & Johnson, K. S. Gene 67, 31–40 (1990).

    Article  Google Scholar 

  30. Eppert, K. et al. Cell 86, 543–552 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Riggin, G. J. et al. Nature Genet. 13, 347–349 (1996).

    Article  Google Scholar 

  32. Baker, J. C. & Harland, R. M. Genes Dev. 10 1880–1889 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Growth and Development, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, California, 94143-0640, USA

    Ying Zhang, Xin-Hua Feng, Rui-Yun Wu & Rik Derynck

Authors
  1. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xin-Hua Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rui-Yun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rik Derynck
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Y., Feng, XH., Wu, RY. et al. Receptor-associated Mad homologues synergize as effectors of the TGF-β response. Nature 383, 168–172 (1996). https://doi.org/10.1038/383168a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/383168a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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