The conserved phosphorylation motif Ser-Ser-X-Ser at the C-terminus of SMAD2 and SMAD3 is subject to disruptive mutations in cancer. The last two serine residues in this conserved motif, namely Ser465 and Ser467 in SMAD2 and Ser423 and Ser425 in SMAD3, are phosphorylated by the activated TGF beta receptor complex (Macias Silva et al. 1996, Nakao et al. 1997). Once phosphorylated, SMAD2 and SMAD3 form transcriptionally active heterotrimers with SMAD4 (Chacko et al. 2001, Chacko et al. 2004). Phosphorylation motif mutants of SMAD2 and SMAD3 cannot be activated by the TGF-beta receptor complex either because serine residues are substituted with amino acid residues that cannot be phosphorylated or because the phosphorylation motif is deleted from the protein sequence or truncated (Fleming et al. 2013).