Mothers against decapentaplegic homolog 4
|SMAD family member 4|
PDB rendering based on 1dd1.
|RNA expression pattern|
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".
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".
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.
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.
Mouse KO 
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.
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. 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.
Disease Database 
- "Entrez Gene: SMAD4 SMAD family member 4".
- 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.
- 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.
- Inman GJ (February 2005). "Linking Smads and transcriptional activation". Biochem. J. 386 (Pt 1): e1–e3. doi:10.1042/BJ20042133. PMC 1134782. PMID 15702493.
- 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.
- 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.
- 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.
Further reading 
- Miyazono K (2000). "TGF-beta signaling by Smad proteins". Cytokine Growth Factor Rev. 11 (1–2): 15–22. doi:10.1016/S1359-6101(99)00025-8. PMID 10708949.
- Wrana JL, Attisano L (2000). "The Smad pathway". Cytokine Growth Factor Rev. 11 (1–2): 5–13. doi:10.1016/S1359-6101(99)00024-6. PMID 10708948.
- Verschueren K, Huylebroeck D (2000). "Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells". Cytokine Growth Factor Rev. 10 (3–4): 187–99. doi:10.1016/S1359-6101(99)00012-X. PMID 10647776.
- Massagué J (1998). "TGF-beta signal transduction". Annu. Rev. Biochem. 67: 753–91. doi:10.1146/annurev.biochem.67.1.753. PMID 9759503.
- Klein-Scory S, Zapatka M, Eilert-Micus C et al. (2008). "High-level inducible Smad4-reexpression in the cervical cancer cell line C4-II is associated with a gene expression profile that predicts a preferential role of Smad4 in extracellular matrix composition". BMC Cancer 7: 209. doi:10.1186/1471-2407-7-209. PMC 2186346. PMID 17997817.
- Kalo E, Buganim Y, Shapira KE et al. (2007). "Mutant p53 Attenuates the SMAD-Dependent Transforming Growth Factor β1 (TGF-β1) Signaling Pathway by Repressing the Expression of TGF-β Receptor Type II". Mol. Cell. Biol. 27 (23): 8228–42. doi:10.1128/MCB.00374-07. PMC 2169171. PMID 17875924.
- Aretz S, Stienen D, Uhlhaas S et al. (2007). "High proportion of large genomic deletions and a genotype–phenotype update in 80 unrelated families with juvenile polyposis syndrome". J. Med. Genet. 44 (11): 702–9. doi:10.1136/jmg.2007.052506. PMC 2752176. PMID 17873119.
- Ali S, Cohen C, Little JV et al. (2007). "The utility of SMAD4 as a diagnostic immunohistochemical marker for pancreatic adenocarcinoma, and its expression in other solid tumors". Diagn. Cytopathol. 35 (10): 644–8. doi:10.1002/dc.20715. PMID 17854080.
- Milet J, Dehais V, Bourgain C et al. (2007). "Common Variants in the BMP2, BMP4, and HJV Genes of the Hepcidin Regulation Pathway Modulate HFE Hemochromatosis Penetrance". Am. J. Hum. Genet. 81 (4): 799–807. doi:10.1086/520001. PMC 2227929. PMID 17847004.
- Salek C, Benesova L, Zavoral M et al. (2007). "Evaluation of clinical relevance of examining K-ras, p16 and p53 mutations along with allelic losses at 9p and 18q in EUS-guided fine needle aspiration samples of patients with chronic pancreatitis and pancreatic cancer". World J. Gastroenterol. 13 (27): 3714–20. PMID 17659731.
- Sebestyén A, Hajdu M, Kis L et al. (2007). "Smad4-independent, PP2A-dependent apoptotic effect of exogenous transforming growth factor beta 1 in lymphoma cells". Exp. Cell Res. 313 (15): 3167–74. doi:10.1016/j.yexcr.2007.05.028. PMID 17643425.
- Martin MM, Buckenberger JA, Jiang J et al. (2007). "TGF-β1 stimulates human AT1 receptor expression in lung fibroblasts by cross talk between the Smad, p38 MAPK, JNK, and PI3K signaling pathways". Am. J. Physiol. Lung Cell Mol. Physiol. 293 (3): L790–9. doi:10.1152/ajplung.00099.2007. PMC 2413071. PMID 17601799.
- Levy L, Howell M, Das D et al. (2007). "Arkadia Activates Smad3/Smad4-Dependent Transcription by Triggering Signal-Induced SnoN Degradation". Mol. Cell. Biol. 27 (17): 6068–83. doi:10.1128/MCB.00664-07. PMC 1952153. PMID 17591695.
- Grijelmo C, Rodrigue C, Svrcek M et al. (2007). "Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells". Cell. Signal. 19 (8): 1722–32. doi:10.1016/j.cellsig.2007.03.008. PMID 17478078.
- Sonegawa H, Nukui T, Li DW et al. (2007). "Involvement of deterioration in S100C/A11-mediated pathway in resistance of human squamous cancer cell lines to TGFbeta-induced growth suppression". J. Mol. Med. 85 (7): 753–62. doi:10.1007/s00109-007-0180-7. PMID 17476473.
- Sheikh AA, Vimalachandran D, Thompson CC et al. (2007). "The expression of S100A8 in pancreatic cancer-associated monocytes is associated with the Smad4 status of pancreatic cancer cells". Proteomics 7 (11): 1929–40. doi:10.1002/pmic.200700072. PMID 17469085.
- Popović Hadzija M, Korolija M, Jakić Razumović J et al. (2007). "K-Ras and Dpc4 Mutations in Chronic Pancreatitis: Case Series". Croat. Med. J. 48 (2): 218–24. PMC 2080529. PMID 17436386.
- Losi L, Bouzourene H, Benhattar J (2007). "Loss of Smad4 expression predicts liver metastasis in human colorectal cancer". Oncol. Rep. 17 (5): 1095–9. PMID 17390050.
- Karlsson G, Blank U, Moody JL et al. (2007). "Smad4 is critical for self-renewal of hematopoietic stem cells". J. Exp. Med. 204 (3): 467–74. doi:10.1084/jem.20060465. PMC 2137898. PMID 17353364.
- Takano S, Kanai F, Jazag A et al. (2007). "Smad4 is essential for down-regulation of E-cadherin induced by TGF-beta in pancreatic cancer cell line PANC-1". J. Biochem. 141 (3): 345–51. doi:10.1093/jb/mvm039. PMID 17301079.
- GeneReviews/NCBI/NIH/UW entry on Hereditary Hemorrhagic Telangiectasia
- GeneReviews/NCBI/NIH/UW entry on Juvenile Polyposis Syndrome