SMAD family member 4, also known as SMAD4, is a protein that in humans is encoded by the SMAD4 gene.[1]
SMAD4 is a 552-amino acid protein involved in cell signaling. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily. It binds receptor-regulated SMADs such as SMAD1 and SMAD2, and forms a complex that binds to DNA and serves as a transcription factor. It is the only known mammalian coSMAD. It is a homolog of the Drosophila protein: "Mothers against decapentaplegic".
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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, e.g., Mothers Against Drunk Driving (MADD), reflecting "the maternal-effect enhancement of dpp".[2]
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.[3]
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′.[4] These associations are weak and require additional transcription factors such as members of the AP-1 family, TFE3 and FoxG1 to regulate gene expression.[4]
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.
In ovarian conditional mouse knockout of SMAD4, the granulosa cells undergo premature luteinization and express lower levels of follicle-stimulating hormone receptors (FSHR) and higher levels of luteinizing hormone receptors (LHR). This may be due in part to impairment of bone morphogenetic protein-7 effects as BMP-7 uses the SMAD4 signaling pathway.[5][6]
SMAD4, is often found mutated in many cancers. It acts as a tumor suppressor that functions in the regulation of the TGF-β signal transduction pathway, which negatively regulates growth of epithelial cells and the extracellular matrix (ECM). SMAD4 alterations have been found in multiploid colorectal cancer and pancreatic carcinoma. It is found inactivated in at least 50% of pancreatic cancers.[7] It is also found mutated in the autosomal dominant disease juvenile polyposis syndrome (JPS). JPS is 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.
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