SMADs are transcription factors that transduce extracellular TGF-β superfamily ligand signaling from cell membrane bound TGF-β receptors into the nucleus where they activate transcription TGF-β target genes.
R-SMADS are directly phosphorylated on their c-terminus by type 1 TGF-β receptors through their intracellular kinase domain, leading to R-SMAD activation.
[1] 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: SMAD6 and SMAD7 may be referred to as I-SMADs (inhibitory SMADS), which form trimers with R-SMADS and block their ability to induce gene transcription by competing with R-SMADs for receptor binding and by marking TGF-β receptors for degradation.