Abstract
Smad proteins are essential components of the signalling cascade initiated by members of the Transforming Growth Factor-β family. TGFβ binding to heteromeric complexes of transmembrane Ser/Thr kinases induces Smad2 and Smad3 phosphorylation on their C terminus residues. This phosphorylation leads to oligomerization with Smad4, a common mediator of TGF-β, activin and BMP signalling. The Smad complexes then translocate to the nucleus where they play transcription regulator roles. Even if they share 92% identity, the two TGFβ restricted Smad2 and Smad3 are not functionally equivalent. As we have previously shown, Smad3 acts as a transcription factor by binding to a TGFβ-responsive sequence termed CAGA box whereas Smad2 does not. Smad2 differs from Smad3 mainly in the N-terminal MH1 domain where it contains two additional stretches of amino acids that are lacking in Smad3. Here, we show that one of these domains corresponding to exon 3 is responsible for the absence of Smad2 transcriptional activity in CAGA box-containing promoters. Furthermore, in vitro studies indicate that this domain prevents Smad2 from binding to this DNA sequence. This suggests that Smad2 and Smad3 may have different subsets of target genes participating thus in distinct responses among TGFβ pleiotropic effects.
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Abbreviations
- TGFβ:
-
Transforming Growth Factor β
- EMSA:
-
Electrophoretic Mobility Shift Assay
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Acknowledgements
We are grateful to Drs ten Dijke, Massagué and Derynck for gift of vectors. We wish to thank Peter ten Dijke, Didier Grillot, Mike Saunders, Hervé Coste and Philippe Dessen for discussions or technical help.
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Dennler, S., Huet, S. & Gauthier, JM. A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3. Oncogene 18, 1643–1648 (1999). https://doi.org/10.1038/sj.onc.1202729
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DOI: https://doi.org/10.1038/sj.onc.1202729
