Fig. 1.

The evolution of Smad signalling. a Canonical TGF-β receptor (TGFBR1) signalling results in the direct phosphorylation of Smad in the carboxyl-terminal region. Phosphorylated Smad forms a complex with Smad4 and enters the nucleus to regulate transcription. b Phosphorylation of the Smad2 linker region inhibits nuclear translocation and TGF-β signalling [8]. c Activation of the TGFBR1 leads to the phosphorylation of the Smad2 linker region via activation of serine/threonine kinases, and phosphorylated Smad2 in vascular smooth muscle cells stimulates the expression of genes associated with atherosclerosis [10]. d G protein-coupled receptor agonist phosphorylated the Smad2 in the linker region in the absence of Smad carboxyl phosphorylation to regulate gene expression and migration [6]