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

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.

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Figure 1: Amino-acid sequence of Smad7 and expression of Smad7 mRNA.
Figure 2: Effects of mouse Smad7 transfection on responses induced by TGF-β family members, and effects of RNA injection in embryos.
Figure 3: Association of Smad7 with the TGF-β receptor complex.
Figure 4: Smad7 is not phosphorylated upon TβR activation, but inhibits TGFβ-mediated Smad2 and Smad3 phosphorylation.
Figure 5: Northern blot analyses.

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Acknowledgements

We thank K. Miyazono, T. Imamura and K. Cho for discussion; I. Nakao for encouragement; and H. Ohashi, R. Derynck, X.-F. Wang and J. Massagué for agents. This work was supported in part by grants from the NIH (J.L.C.), the American Heart Association, Oregon Affiliate (T.N.) and the Swedish Medical Research Council (N.-E.H.)

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Correspondence to Peter ten Dijke.

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Nakao, A., Afrakhte, M., Morn, A. et al. Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature 389, 631–635 (1997). https://doi.org/10.1038/39369

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