Cell biology of Smad2/3 linker region phosphorylation in vascular smooth muscle

1. The transforming growth factor (TGF)-beta superfamily of ligands regulates a diverse set of cellular functions. Transforming growth factor-beta induces its biological effects through Type I and Type II transmembrane receptors that have serine/threonine kinase activities and weak tyrosine kinase activity. In vascular smooth muscle, TGF-beta binds to the TGF-beta Type II receptor (T beta RII) at the cell surface, recruiting the Type I receptor (T beta RI) to form a heterocomplex. Consequently, after phosphorylation and activation of T beta RI, the transcription factors receptor activated (R-) Smad2 and Smad3 are recruited and activated through phosphorylation of C terminal residues. Overall, Smad2/3 and co-Smad4 have similar structures consisting of three regions an N-terminal MH1 domain, a C-terminal MH2 domain and a central linker region. 2. Phosphorylation of the Smad linker region appears to have an important role in the regulation of Smad activity and function. The mitogen-activated protein kinase (MAPK) family, CDK2, CDK4 and calciumcalmodulin dependent kinase are the main kinases that phosphorylate sites in the linker region. The role of the linker region includes enabling the formation of Smad homo-oligomers and provision of phosphorylation sites for MAPK and other kinases. In some instances, linker region phosphorylation regulates the inhibition of the nuclear translocation of Smads. 3. In the present review, we describe TGF-beta signalling through Smad2/3 and the importance of the linker region in the regulation and expression of genes induced by TGF-beta superfamily ligands in the context of vascular smooth muscle.