Phosphorylated SMAD2 and SMAD3 MH2 domain mutants cannot form heterotrimers with SMAD4 (Fleming et al. 2013), leading to the loss of TGF-beta-induced regulation of gene expression and aberrant cell differentiation and proliferation.
SMAD2 MH2 domain mutants SMAD2 A354T, SMAD2 D300A, SMAD2 D300N and SMAD2 P305L, as well as SMAD3 MH2 domain mutants SMAD3 D258N and SMAD3 R268C are annotated as characterized mutant set members based on structural and/or functional studies (Fleming et al. 2013). SMAD2 mutants SMAD2 D300V and SMAD2 P305Q, and SMAD3 mutant SMAD2 R268C are annotated as candidate members of the mutant set, based on sequence similarity with characterized mutants.