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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Atsuhito Nakao & Mozhgan Afrakhte & Anita Morn & Takuya Nakayama & Jan L. Christian & Rainer Heuchel & Susumu Itoh & Masahiro Kawabata & Nils-Erik Heldin & Carl-Henrik Heldin & Peter ten Dijke, 1997. "Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling," Nature, Nature, vol. 389(6651), pages 631-635, October.
    • Handle: RePEc:nat:nature:v:389:y:1997:i:6651:d:10.1038_39369
    DOI: 10.1038/39369
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