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Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1 - Nature

  • ️Massagu, Joan
  • ️Thu Oct 09 1997
  • Letter
  • Published: 09 October 1997

Nature volume 389, pages 618–622 (1997)Cite this article

Abstract

The growth factor TGF-β, bone morphogenetic proteins (BMPs) and related factors regulate cell proliferation, differentiation and apoptosis, controlling the development and maintenance of most tissues1,2. Their signals are transmitted through the phosphorylation of the tumour-suppressor SMAD proteins by receptor protein serine/threonine kinases (RS/TKs)3,4,5,6,7,8,9,10, leading to the nuclear accumulation5,9,11,12 and transcriptional activity of SMAD proteins6,12,13. Here we report that Smad1, which mediates BMP signals, is also a target of mitogenic growth-factor signalling through epidermal growth factor and hepatocyte growth factor receptor protein tyrosine kinases (RTKs). Phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of Smad1, and is catalysed by the Erk family of mitogen-activated protein kinases. In contrast to the BMP-stimulated phosphorylation of Smad1, which affects carboxy-terminal serines and induces nuclear accumulation of Smad16, Erk-mediated phosphorylation specifically inhibits the nuclear accumulation of Smad1. Thus, Smad1 receives opposing regulatory inputs through RTKs and RS/TKs, and it is this balance that determines the level of Smad1 activity in the nucleus, and so possibly the role of Smad1 in the control of cell fate.

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References

  1. Roberts,A. B., Sporn,M. B. in Peptide Growth Factors and their Receptors (eds Sporn, M. B. &Roberts, A. B.) 419–472 (Springer, Heidelberg, (1990)).

    Book  Google Scholar 

  2. Hogan,B. L. M. Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev. 10, 1580–1594 (1996).

    Article  CAS  Google Scholar 

  3. Eppert,K. et al. MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86, 543–552 (1996).

    Article  CAS  Google Scholar 

  4. Graff,J. M., Bansal,A. & Melton,D. A. Xenopus Mad proteins transduce distinct subsets of signals for the TGFβ superfamily. Cell 85, 479–487 (1996).

    Article  CAS  Google Scholar 

  5. Hoodless,P. A. et al. MADR1, a MAD-related protein that functions in BMP2 signalling pathways. Cell 85, 489–500 (1996).

    Article  CAS  Google Scholar 

  6. Kretzschmar,M., Liu,F., Hata,A., Doody,J. & Massagué,J. The TGFβ family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev. 11, 984–995 (1997).

    Article  CAS  Google Scholar 

  7. Lagna,G., Hata,A., Hemmati-Brivanlou,A. & Massagué,J. Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways. Nature 383, 832–836 (1996).

    Article  ADS  CAS  Google Scholar 

  8. Lechleider,R. J., de Caestecker,M. P., Dehejia,A., Polymeropoulos,M. H. & Roberts,A. B. Serine phosphorylation, chromosomal localization and TGFβ signal transduction by human bsp-1. J. Biol. Chem. 271, 17617–17620 (1996).

    Article  CAS  Google Scholar 

  9. Macias-Silva,M. et al. MADR2 is a substrate of the TGFβ receptor and phosphorylation is required for nuclear accumulation and signaling. Cell 87, 1215–1224 (1996).

    Article  CAS  Google Scholar 

  10. Yingling,J. M. et al. Mammalian Dwarfins are phosphorylated in response to TGF-β and are implicated in control of cell growth. Proc. Natl Acad. Sci. USA 93, 8940–8944 (1996).

    Article  ADS  CAS  Google Scholar 

  11. Baker,J. & Harland,R. M. Anovel mesoderm inducer, mMadr-2, functions in the activin signal transduction pathway. Genes Dev. 10, 1880–1889 (1996).

    Article  CAS  Google Scholar 

  12. Liu,F. et al. Ahuman Mad protein acting as a BMP-regulated transcriptional activator. Nature 381, 620–623 (1996).

    Article  ADS  CAS  Google Scholar 

  13. Chen,X., Rubock,M. J. & Whitman,M. Atranscriptional partner of MAD proteins in TGF-β signalling. Nature 383, 691–696 (1996).

    Article  ADS  CAS  Google Scholar 

  14. Niswander,L. & Martin,G. R. FGF-4 and BMP-2 have opposite effects on limb growth. Nature 361, 68–71 (1993).

    Article  ADS  CAS  Google Scholar 

  15. Ganan,Y., Macias,D., Duterque-Coquillaud,M., Ros,M. A. & Hurle,J. M. Role of TGFβs and BMPs as signals controlling the position of the digits and the areas of interdigital cell death in the developing chick limb autopod. Development 122, 2349–2357 (1996).

    CAS  PubMed  Google Scholar 

  16. Bernier,S. M. & Goltzman,D. Effect of protein and steroidal osteotropic agents on differentiation and epidermal growth factor-mediated growth of the CFK1 osseous cell line. J. Cell Physiol. 152, 317–327 (1992).

    Article  CAS  Google Scholar 

  17. Neubüser,A., Peters,H., Balling,R. & Martin,G. R. Antagonistic interactions between FGF and BMP signaling pathways: a mechanism for positioning the sites of tooth formation. Cell 90, 247–255 (1997).

    Article  Google Scholar 

  18. Hata,A., Lo,R. S., Wotton,D., Lagna,G. & Massagué,J. Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Nature 388, 82–87 (1997).

    Article  ADS  CAS  Google Scholar 

  19. Kim,J., Johnson,K., Chen,H. J., Carroll,S. & Laughon,A. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Decapentaplegic. Nature 388, 304–308 (1997).

    Article  ADS  CAS  Google Scholar 

  20. Zhang,Y., Feng,X.-, Wu,R.-Y. & Derynck,R. Receptor-associated Mad homologues synergize as effectors of the TGF-β response. Nature 383, 168–172 (1996).

    Article  ADS  CAS  Google Scholar 

  21. Wu,R.-Y., Zhang,Y., Feng,X.-H. & Derynck,R. Heteromeric and homomeric interactions correlate with signalling activity and functional cooperativity of Smad3 and Smad4/DPC4. Mol. Cell. Biol. 17, 2521–2528 (1997).

    Article  CAS  Google Scholar 

  22. Hahn,S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996).

    Article  ADS  CAS  Google Scholar 

  23. Shi,Y., Hata,A., Lo,R. S., Massagué,J. & Pavletich,N. P. Astructural basis for mutational inactivation of the tumour suppressor Smad4. Nature 388, 87–93 (1997).

    Article  ADS  CAS  Google Scholar 

  24. Zhang,Y., Musci,T. & Derynck,R. The tumor suppressor Smad4/DPC4 as a central mediator of Smad function. Curr. Biol. 7, 270–276 (1997).

    Article  Google Scholar 

  25. Hill,C. S. & Treisman,R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 80, 199–211 (1995).

    Article  CAS  Google Scholar 

  26. Vandenabeele,P., Declercg,W., Beyaert,R. & Fiers,W. Two tumour necrosis factor receptors: structure and function. Trends Cell Biol. 5, 392–399 (1995).

    Article  CAS  Google Scholar 

  27. Marshall,C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    Article  CAS  Google Scholar 

  28. Franke,T. F., Kaplan,D. R. & Cantley,L. C. PI3K: downstream AKTion blocks apoptosis. Cell 88, 435–437 (1997).

    Article  CAS  Google Scholar 

  29. Besser,D. et al. Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2. Oncogene 14, 705–711 (1997).

    Article  CAS  Google Scholar 

  30. Blenis,J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc. Natl Acad. Sci. USA 90, 5889–5892 (1993).

    Article  ADS  CAS  Google Scholar 

  31. ten Dijke,P. et al. Identification of type I receptors for Osteogenic Protein-1 and Bone Morphogenetic Protein-4. J. Biol. Chem. 269, 16985–16988 (1994).

    CAS  PubMed  Google Scholar 

  32. Schagger,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. 166, 368–379 (1987).

    Article  CAS  Google Scholar 

  33. Gu,W., Shi,X.-L. & Roeder,R. G. Synergistic activation of transcription by CBP and p53. Nature 387, 819–823 (1997).

    Article  ADS  CAS  Google Scholar 

  34. Massagué,J., Hata,A. & Liu,F. TGF-β signalling through the Smad pathway. Trends Cell Biol. 7, 187–192 (1997).

    Article  Google Scholar 

Download references

Acknowledgements

We thank the Genetics Institute for providing BMP; Memorial Sloan-Kettering Cancer Center for use of the Molecular Cytology Core Facility; and I. Timokhina for discussions. This work was supported by NIH grants to J.M. and to Memorial Sloan-Kettering Cancer Center. M.K. is a recipient of a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft. J.M. is an investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Cell Biology and Genetics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Marcus Kretzschmar, Jacqueline Doody & Joan Massagu

Authors

  1. Marcus Kretzschmar

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  2. Jacqueline Doody

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  3. Joan Massagu

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Correspondence to Joan Massagu.

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Kretzschmar, M., Doody, J. & Massagu, J. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389, 618–622 (1997). https://doi.org/10.1038/39348

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  • Received: 02 June 1997

  • Accepted: 18 August 1997

  • Issue Date: 09 October 1997

  • DOI: https://doi.org/10.1038/39348