Mothers against decapentaplegic homolog 4

Overview
SMAD4 or Mothers against decapentaplegic homolog 4 is a 552 amino acid polypeptide that is a homolog of the Drosophila protein: "Mothers against decapentaplegic". It belongs to the Darfwin family of proteins which modulate members of the TGFβ superfamily of proteins, such as Activin or Nodal. It is the only known mammalian coSMAD. Like many other TGFβ family modulators SMAD4 is involved in cell signaling. It binds receptor regulated SMADs such as SMAD1 or SMAD2 and forms a complex that serves as a transcription factor. It promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA.

Nomenclature
The SMAD proteins are homologs of both the drosophila protein, mothers against decapentaplegic (MAD) and the C. elegans protein SMA. The name is a combination of the two. During Drosophila research, it was found that a mutation in the gene, MAD, in the mother, repressed the gene, decapentaplegic, in the embryo. The phrase "Mothers against" was added since mothers often form organizations opposing various issues eg. Mothers Against Drunk Driving or (MADD).

Structure
SMADs are highly conserved across species, especially in the N terminal MH1 domain and the C terminal MH2 domain. The MH1 domain has DNA specific binding properties, where it binds to specific nucleotide sequences. It also facilitates the binding of SMAD4 to the phosphorylated C-terminus of R-SMADs. The MH2 domain is responsible for receptor recognition and oligomerization with other SMADs as well as DNA binding. The MH2 domain directly interacts with the MH1 domain of R-SMADs.

Function
SMAD4 binds to receptor regulated SMADs (R-SMADs), such as SMAD1 or SMAD2 and facilitates the translocation of the heteromeric complex into the nucleus. SMAD4 may form heterotrimeric, heterohexameric or heterodimeric complexes with R-SMADs.

In the nucleus the heteromeric complex binds promoters and interact with transcriptional activators. SMAD3/SMAD4 complexes can directly bind the SBE (Smad-binding DNA element) which is a four base pair sequence 5′-GTCT-3' or the complement 5′-AGAC-3′. These associations are weak and require additional transcription factors such as members of the AP-1 family, TFE3 and FoxG1 to regulate gene expression.

Many TGFβ ligands use this pathway and subsequently SMAD4 is involved in many cell functions such as differentiation, apoptosis, gastrulation, embryonic development and the cell cycle.

Disease
SMAD4, is often found mutated in many cancers. SMAD4 alterations have been found in multiploid colorectal cancer and pancreatic carcinoma. It is found inactivated in at least 50% of pancreatic cancers. It is also found mutated in the autosomal dominant disease juvenile polyposis syndrome (JPS). JPS is characterized by characterized by hamartomatous polyps in the gastrointestinal (GI) tract. These polyps are usually benign, however they are at greater risk of developing gastrointestinal cancers, in particular colon cancer.

Somatic mutations found in human cancers of the MH1 domain of Smad4 have been shown to inhibit the DNA-binding function of this domain.