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

A Nakao, M Afrakhte, A Morn, T Nakayama… - Nature, 1997 - nature.com
A Nakao, M Afrakhte, A Morn, T Nakayama, JL Christian, R Heuchel, S Itoh, M Kawabata…
Nature, 1997nature.com
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 (,,,), which form hetero-
oligomeric complex (es) with Smad4/DPC4 (,,,,,) 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 …
Abstract
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 (, , , ), which form hetero-oligomeric complex(es) with Smad4/DPC4 (, , , , , ) 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 . 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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