Brief:
TGFβ signalling is a major signalling pathway and regulates many cellular functions like cell differentiation, proliferation, and apoptosis. Research in TGFβ signalling has provided a lot of insight into how it is initiated but very little is understood about its termination. My study focuses on understanding TGFβ signal termination via regulation of its signal transducer proteins Smad2 and Smad3.
Smad2/3 structure has a linker region, which was considered just as a connector between the other 2 domains MH1 and MH2, but recent studies show that they have important regulatory functions in TGFβ signalling. Smad2/3 linker has certain Ser and Thr residues which are phosphorylated by other kinases like PI3K, Erk, MAPKs, CDKs etc, which can further regulate TGFβ signalling.
These linker Ser and Thr residues are generally considered to have a collective function in TGFβ signalling. However, we found in our lab that Smad2/3 linker Thr and Ser are differently regulated. Our data suggests that linker serine residues are phosphorylated mainly by CDKs in human embryonic stem cells (hESCs) and PC3 cells. Also, this CDK-mediated linker Ser phosphorylation of Smad2/3 results in its degradation upon prolonged CDK inhibition. Therefore, I am investigating how differential phosphorylation of Smad2/3 linker Ser and Thr has an important role in Smad2/3 degradation and termination of TGFβ signalling.