madh-4

SMAD Family Member 4 (SMAD4) is a cytoplasmic protein that belongs to the Dwarfin SMAD family. SMAD4 contains one MH1 (MAD homology 1) domain and one MH2 (MAD homology 2) domain. It is the component of the heterotrimeric SMAD2 SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. SMAD4 promotes binding of the SMAD2 SMAD4 FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. SMAD4 may act as a tumor suppressor. It positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. Mutations or deletions in SMAD4 have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome.