In response to signals by the TGF-β superfamily of ligands these proteins associate with receptor kinases and are phosphorylated at an SSXS motif at their extreme C-terminus. These proteins then typically bind to the common mediator Smad or co-SMAD SMAD4.
Smad complexes then accumulate in the cell nucleus where they regulate transcription of specific target genes:
- SMAD2 and SMAD3 are activated in response to TGF-β or Activin signals.
- SMAD1, SMAD5 and SMAD9 are activated in response to BMP or bone morphogenetic protein signals.