A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3.
Smad proteins are essential components of the signalling cascade initiated by members of the Transforming Growth Factor-beta family. TGFbeta 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-beta, 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 TGFbeta/ restricted Smad2 and Smad3 are not functionally equivalent. As we have previously shown, Smad3 acts as a transcription factor by binding to a TGFbeta-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 TGFbeta pleiotropic effects.
Dennler
S
S
Laboratoire Glaxo Wellcome, LES ULIS, France.
Huet
S
S
Gauthier
J M
JM
D000595:Amino Acid Sequence; D001692:Biological Transport; D001704:Biopolymers; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000502:physiology
D001704:Biopolymers; D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D011993:Recombinant Fusion Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta