Mothers against decapentaplegic homolog 4

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SMAD, Mothers against decapentaplegic homolog 4
Crystal Structure Of The Phosphorylated Smad2SMAD4 Heterotrimeric Complex
Symbol(s):	SMAD4 MADH4
Other names:	SMAD 4, Mothers against DPP homolog 4, Deletion target in pancreatic carcinoma 4, hSMAD4
Genetic data
Locus:	Chr. 18 q21.1
Protein Structure/Function
Protein length:	552 (Amino Acids)
Molecular Weight:	60439 (Da)
Structure:	Crystal Structure Of The Phosphorylated Smad2SMAD4 Heterotrimeric Complex.
Protein type:	transcription factor, coSMAD
Functions:	signal transduction, transcription regulator
Domains:	MH1 domain, MH2 domain, SAD domain
Other
Taxa expressing:	Homo sapiens; homologs many metazoan phyla
Cell types:	ubiquitous; pancreas, Skin fibroblast, Uterus, Colon epithelium
Subcellular localization:	Primary:nucleus, Alternative:cytoplasm
Covalent modifications:	Sumoylation, phosphorylation
Pathway(s):	TGF-beta signaling pathway KEGG; Cell cycle KEGG ; Wnt signaling pathway KEGG; Adherens junction KEGG
Molecular interactions:	There are 61 known interacting proteins
Medical/Biotechnological data
Diseases:	pancreatic carcinoma (Mendelian Inheritance in Man (OMIM) 260350), juvenile polyposis syndrome (JPS) (Mendelian Inheritance in Man (OMIM) 174900), juvenile polyposis/ hereditary hemorrhagic telangiectasia syndrome (JP/HHT)(Mendelian Inheritance in Man (OMIM) 175050)
Database Links
Codes:	EntrezGene 4089; Mendelian Inheritance in Man (OMIM) 600993; RefSeq NM_005359; UniProt Q13485
Related information
Recent publications:	role in colorectal cancer

SMAD4 or Mothers against decapentaplegic homolog 4 is a 552 amino acid polypeptide that, as its name describes, is a homolog of the Drosophila protein: "Mothers against decepentaplegic". 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.

Contents 1 Nomenclature 2 Structure 3 Function 4 Disease 5 References

[edit] 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).

[edit] 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^[1].

[edit] 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′^[2]. These associations are weak and require additional transcription factors such as members of the AP-1 family, TFE3 and FoxG1 to regulate gene expression^[2].

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.

[edit] Disease

SMAD4, is often found mutated in many cancers. SMAD4 alterations have been found in multiploid colorectal cancer and pancreatic carcinoma. 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.

[edit] References

1. ^ (Oct 2003) "Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor-beta-induced nuclear accumulation". Am J Physiol Cell Physiol.. Entrez PubMed 12801888 12801888.
2. ^ ^{a b} Inman, Gareth J. (Feb 2005). "Linking Smads and transcriptional activation". Biochem J.. Entrez PubMed 15702493 15702493.