Mutations in the MH2 domain of SMAD2 and SMAD3 affect their ability to form heterotrimers with SMAD4, thereby impairing TGF-beta signaling (Fleming et al. 2013).
The SMAD2 and SMAD3 MH2 domain residues most frequently targeted by missense mutations are those that are homologous to SMAD4 MH2 domain residues shown to be involved in the formation of SMAD heterotrimers. Asp300 of SMAD2 and Asp258 of SMAD3 correspond to the frequently mutated Asp351 of SMAD4. Pro305 of SMAD2 corresponds to the frequently mutated Pro356 of SMAD4, while Ala354 of SMAD2 corresponds to Ala406 of SMAD4. Arg268 of SMAD3 corresponds to the frequently mutated Arg361 of SMAD4. SMAD2 and SMAD3 MH2 domain mutations have been examined in most detail in colorectal cancer (Fleming et al. 2013).