Mothers against decapentaplegic homolog 4

From Wikipedia, the free encyclopedia
Jump to: navigation, search
SMAD family member 4
Protein SMAD4 PDB 1dd1.png
PDB rendering based on 1dd1.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols SMAD4 ; DPC4; JIP; MADH4; MYHRS
External IDs OMIM600993 MGI894293 HomoloGene31310 GeneCards: SMAD4 Gene
RNA expression pattern
PBB GE SMAD4 202527 s at tn.png
PBB GE SMAD4 202526 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4089 17128
Ensembl ENSG00000141646 ENSMUSG00000024515
UniProt Q13485 P97471
RefSeq (mRNA) NM_005359 NM_008540
RefSeq (protein) NP_005350 NP_032566
Location (UCSC) Chr 18:
48.49 – 48.61 Mb
Chr 18:
73.64 – 73.7 Mb
PubMed search [1] [2]

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".

Nomenclature[edit]

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]

Structure[edit]

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]

Function[edit]

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.

Mouse KO[edit]

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]

Disease[edit]

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.

Mutations in SMAD4 cause Myhre syndrome .[8]

Disease Database[edit]

SMAD4 gene variant database

References[edit]

  1. ^ "Entrez Gene: SMAD4 SMAD family member 4". 
  2. ^ Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM (March 1995). "Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster". Genetics 139 (3): 1347–58. PMC 1206461. PMID 7768443. 
  3. ^ Roelen BA, Cohen OS, Raychowdhury MK, Chadee DN, Zhang Y, Kyriakis JM, Alessandrini AA, Lin HY (October 2003). "Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor-beta-induced nuclear accumulation". Am. J. Physiol., Cell Physiol. 285 (4): C823–30. doi:10.1152/ajpcell.00053.2003. PMID 12801888. 
  4. ^ a b Inman GJ (February 2005). "Linking Smads and transcriptional activation". Biochem. J. 386 (Pt 1): e1–e3. doi:10.1042/BJ20042133. PMC 1134782. PMID 15702493. 
  5. ^ Shi J, Yoshino O, Osuga Y, Nishii O, Yano T, Taketani Y (March 2010). "Bone morphogenetic protein 7 (BMP-7) increases the expression of follicle-stimulating hormone (FSH) receptor in human granulosa cells". Fertil. Steril. 93 (4): 1273–9. doi:10.1016/j.fertnstert.2008.11.014. PMID 19108831. 
  6. ^ Pangas SA, Li X, Robertson EJ, Matzuk MM (June 2006). "Premature luteinization and cumulus cell defects in ovarian-specific Smad4 knockout mice". Mol. Endocrinol. 20 (6): 1406–22. doi:10.1210/me.2005-0462. PMID 16513794. 
  7. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease (7th ed.). St. Louis, Mo: Elsevier Saunders. ISBN 0-7216-0187-1. 
  8. ^ Caputo, V; Bocchinfuso, G; Castori, M; Traversa, A; Pizzuti, A; Stella, L; Grammatico, P; Tartaglia, M (2014). "Novel SMAD4 mutation causing Myhre syndrome". American Journal of Medical Genetics Part A: n/a. doi:10.1002/ajmg.a.36544. PMID 24715504.  edit

Further reading[edit]

External links[edit]