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

The Transforming Growth Factor ß (TGF-ß) superfamily of ligands regulate a diverse set of cellular functions. TGF-ß induces its biological effects through type I and type II transmembrane receptors which have serine/threonine kinase activities and weak tyrosine kinase activity. In vascular smooth muscle TGF-ß binds to the TGF-ß type II receptor (TßRII) at the cell surface recruiting the type I receptor (TßRI) to form a heterocomplex. Consequently, after phosphorylation and activation of TßRI, the transcription factors R-Smad2 and Smad3 are recruited and activated through phosphorylation of C terminal residues. Smad2/3 and co-Smad4 have overall similar structures consisting of three regions an N-terminal MH1 domain, a C-terminal MH2 domain and a central linker region. 2. Smad linker region phosphorylation appears to have an important role in the regulation of Smad activity and function. MAP kinase family, CDK 2, CDK4 and calcium-calmodulin dependent (CAM) kinase are the main kinases that phosphorylate sites in the linker region. The role of linker region includes enabling the formation of Smad homo-oligomers and provision of phosphorylation sites for MAP-kinase and other kinases. In some instances linker region phosphorylation regulates inhibition of nuclear translocation of Smads. 3. In this review we describe TGF-ß signalling through Smad2/3 and the importance of linker region role in regulation and expression of genes induced by TGF-ß super family ligands in the context of vascular smooth muscle.