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

TGF-β signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins. 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 nucleus,,, where they then regulate transcriptional responses,. 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.