SMAD4 MH2 domain mutants are not able to form heterotrimers with phosphorylated SMAD2 and SMAD3 (Shi et al. 1997, Fleming et al. 2013) and regulate transcription of TGF-beta responsive genes, leading to aberrant cell differentiation and proliferation even in the presence of tumor suppressive TGF-beta signaling.

The following SMAD4 MH2 domain mutants are annotated as members of the SMAD4 MH2 Domain Mutants set, based on functional and structural studies: SMAD4 A406T, SMAD4 D351G, SMAD4 D351H, SMAD4 D351Y, SMAD4 D351del, SMAD4 K428T, SMAD4 P356L, SMAD4 P356R, SMAD4 R361C, SMAD4 R361H and SMAD4 R515T (Shi et al. 1997, Fleming et al. 2013). Additional SMAD4 MH2 domain mutants are annotated as candidates of the SMAD4 MH2 Domain Mutants set based on their similarity with characterized mutants: SMAD4 K428R, SMAD4 R361G, SMAD4 R361S and SMAD4 R515*.