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Smad6 inhibits signalling by the TGF-β superfamily

Nature volume 389, pages 622–626 (1997)Cite this article

Abstract

SMAD proteins1 have been identified as signalling mediators of the TGF-β superfamily, which is involved in a range of biological activities including cell growth, morphogenesis, development and immune responses2,3. Smad1, Smad2, Smad3 and Smad5 are ligand-specific: Smad1 and Smad5 transduce signals from bone morphogenetic proteins4,5,6,7, and Smad2 and Smad3 mediate signalling by TGF-β and activin8,9, whereas Smad4 acts as a common signalling component10. For example, Smad2 is phosphorylated by the TGF-β type I receptor upon ligand binding, forms a heteromer with Smad4, and then translocates into the nucleus where it activates transcription10,11. Here we report the isolation of Smad6 in the mouse. Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with type I receptors. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the bone morphogenetic protein type IB receptor. These data indicate that signals of the TGF-β superfamily are regulated both positively and negatively by members of the SMAD family.

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Figure 1: Protein sequence alignment and tissue distribution of mouse Smad6.
Figure 2: Binding of Smad6 to the type I receptors.
Figure 3: Effect of Smad6 on the phosphorylation of Smad2, Smad3 or Smad1 by the constitutively active type I receptors.
Figure 4: Effect of Smad6 on the heteromerization of Smad2, Smad3 and Smad4.
Figure 5: Effect of Smad6 on the transcriptional responses of TGF-β.

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Acknowledgements

We thank A. Nakao for the Smad1 and Smad2 cDNAs; S. Kern for the Smad4/DPC4 cDNA; J. Massagué for the p3TP-Lux reporter and R mutant cells; R. Derynck for Smad3 cDNA and the pCAL2 cyclin A reporter; Y. Eto for activin A; T. K. Sampath for OP-1/BMP-7; P. Horton for critical reading of the manuscript; and Y. Inada for technical assistance. This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan, and special coordiantion funds for promoting science and technology from the Science and Technology Agency. K.M. is supported by the Toray Scientific Foundation and Uehara Memorial Foundation.

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  1. Takeshi Imamura, Masao Takase, Ayako Nishihara, Eiichi Oeda, Jun-ichi Hanai, Masahiro Kawabata and Kohei Miyazono: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry, The Cancer Institute, Tokyo, Japanese Foundation for Cancer Research, and Research for the Future Program, Japan Society for the Promotion of Science, 1-37-1 Kami-Ikebukuro, Toshima-ku, 170, Tokyo, Japan

    Takeshi Imamura, Masao Takase, Ayako Nishihara, Eiichi Oeda, Jun-ichi Hanai, Masahiro Kawabata & Kohei Miyazono

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  1. Takeshi Imamura
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Correspondence to Masahiro Kawabata.

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Imamura, T., Takase, M., Nishihara, A. et al. Smad6 inhibits signalling by the TGF-β superfamily. Nature 389, 622–626 (1997). https://doi.org/10.1038/39355

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