DPC4/Smad4 Tumor Suppressor

The Smad family of proteins mediate TGF-beta signaling from the cell membrane to the nucleus, propagating the signal by the formation of homo- and hetero-oligomers and by cooperating with other transcription factors to regulate the expression of genes. Smads are frequently targeted by tumorigenic mutations in cancer; and DPC4 is found inactivated in nearly half of all pancreatic carcinomas.

[Enlarge Image] DPC4/Smad4 Trimer

The Smad4/DPC4 C-terminal domain forms a trimer in the crystal, and is capable of forming hetero-hexamers with the related Smad2 protein in vitro. Mutation of residues in the Smad4 L3 loop may disrupt such hexamers and effect transmission of the TGF-beta signal to the nucleus.

[Enlarge Image] Smad3-MH1 Domain in Complex with DNA

The Smad3-MH1 domain bound to the Smad binding element on DNA is shown above. Two copies of the domain bind to this element independently.