Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling

Atsuhito Nakao, Mozhgan Afrakhte, Anita Morn, Takuya Nakayama, Jan L. Christian, Rainer Heuchel, Susumu Itoh, Masahiro Kawabata, Nils-Erik Heldin, Carl-Henrik Heldin and Peter ten Dijke ()
Additional contact information
Atsuhito Nakao: Ludwig Institute for Cancer Research, Box 595, Biomedical Center
Mozhgan Afrakhte: University Hospital
Anita Morn: Ludwig Institute for Cancer Research, Box 595, Biomedical Center
Takuya Nakayama: L215, Oregon Health Sciences University, School of Medicine
Jan L. Christian: L215, Oregon Health Sciences University, School of Medicine
Rainer Heuchel: Ludwig Institute for Cancer Research, Box 595, Biomedical Center
Susumu Itoh: Ludwig Institute for Cancer Research, Box 595, Biomedical Center
Masahiro Kawabata: The Cancer Institute, Tokyo, The Japanese Foundation for Cancer Research, and Research for the Future Program, Japan Society for the Promotion of Science
Nils-Erik Heldin: University Hospital
Carl-Henrik Heldin: Ludwig Institute for Cancer Research, Box 595, Biomedical Center
Peter ten Dijke: Ludwig Institute for Cancer Research, Box 595, Biomedical Center

Nature, 1997, vol. 389, issue 6651, 631-635

Abstract: Abstract TGF-β signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins1. The activated TGF-β receptor induces phosphorylation of two such proteins, Smad2 and Smad3 (refs 2, 3, 5, 6), which form hetero-oligomeric complex(es) with Smad4/DPC4 (refs 5, 6, 7, 8, 9, 10) that translocate to the nucleus2,4,5,7, where they then regulate transcriptional responses11,12. However, the mechanisms by which the intracellular signals of TGF-β are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6 (ref. 13). Transfection of Smad7 blocks responses mediated by TGF-β in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-β signalling. Smad7 associates stably with the TGF-β receptor complex, but is not phosphorylated upon TGF-β stimulation. TGFβ-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-β rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-β responses.

Date: 1997
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DOI: 10.1038/39369

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