Mothers against decapentaplegic homolog 6

SMAD6
Identifiers
Aliases	SMAD6 , AOVD2, HsT17432, MADH6, MADH7, SMAD family member 6
External IDs	OMIM: 602931; MGI: 1336883; HomoloGene: 4079; GeneCards: SMAD6; OMA:SMAD6 - orthologs
Gene location (Human) Chr. Chromosome 15 (human) [1] Band 15q22.31 Start 66,702,236 bp [1] End 66,782,849 bp [1]
Gene location (Mouse) Chr. Chromosome 9 (mouse) [2] Band 9|9 C Start 63,860,358 bp [2] End 63,929,341 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lung glomerulus metanephric glomerulus lower lobe of lung right auricle of heart upper lobe of lung upper lobe of left lung visceral pleura Epithelium of choroid plexus right lobe of thyroid gland Top expressed in right lung right lung lobe molar atrium mesorchium epithelium of stomach choroid plexus of fourth ventricle external carotid artery left lung gastrula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding R-SMAD binding type I transforming growth factor beta receptor binding co-SMAD binding I-SMAD binding DNA-binding transcription factor activity chromatin binding type I activin receptor binding metal ion binding RNA polymerase II cis-regulatory region sequence-specific DNA binding protein binding identical protein binding ubiquitin protein ligase binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component cytoplasm transcription regulator complex intracellular anatomical structure nucleus Golgi apparatus cytosol nuclear body protein-containing complex Biological process ureteric bud development heart valve development regulation of transcription, DNA-templated ventricular septum development zygotic specification of dorsal/ventral axis negative regulation of SMAD protein complex assembly response to laminar fluid shear stress negative regulation of apoptotic process negative regulation of transforming growth factor beta receptor signaling pathway coronary vasculature development BMP signaling pathway transcription, DNA-templated negative regulation of pathway-restricted SMAD protein phosphorylation response to estrogen negative regulation of BMP signaling pathway aorta development cell-substrate adhesion immune response transforming growth factor beta receptor signaling pathway fat cell differentiation negative regulation of cell population proliferation positive regulation of pri-miRNA transcription by RNA polymerase II outflow tract septum morphogenesis mitral valve morphogenesis pulmonary valve morphogenesis negative regulation of ossification aortic valve morphogenesis negative regulation of osteoblast differentiation response to lipopolysaccharide Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4091 17130 Ensembl ENSG00000137834 ENSMUSG00000036867 UniProt O43541 O35182 RefSeq (mRNA) NM_001142861 NM_005585 NM_008542 RefSeq (protein) NP_005576 NP_032568 Location (UCSC) Chr 15: 66.7 – 66.78 Mb Chr 9: 63.86 – 63.93 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

SMAD family member 6, also known as SMAD6, is a protein that in humans is encoded by the SMAD6 gene. ^[5]

SMAD6 is a protein that, as its name describes, is a homolog of the Drosophila gene "mothers against decapentaplegic". It belongs to the SMAD family of proteins, which belong to the TGFβ superfamily of modulators. Like many other TGFβ family members SMAD6 is involved in cell signalling. It acts as a regulator of TGFβ family (such as bone morphogenetic proteins) activity by competing with SMAD4 and preventing the transcription of SMAD4's gene products. There are two known isoforms of this protein.

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 as a humorous take-off on organizations opposing various issues e.g., Mothers Against Drunk Driving, or MADD; and based on a tradition of such unusual naming within the gene research community. ^[6]

Disease associations

Heterozygous, damaging mutations in SMAD6 are the most frequent genetic cause of non-syndromic craniosynostosis identified to date. ^[7]

Interactions

Mothers against decapentaplegic homolog 6 has been shown to interact with:

• HOXC8, ^[8]
• MAP3K7, ^{[9] [10]}
• Mothers against decapentaplegic homolog 7, ^[11]
• PIAS4, ^[12] and
• STRAP. ^[13]

References

1. GRCh38: Ensembl release 89: ENSG00000137834 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000036867 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: SMAD6 SMAD family member 6".
6. "Sonic Hedgehog, DICER, and the Problem With Naming Genes", Sep 26, 2014, Michael White. psmag.com
7. Timberlake AT, Choi J, Zaidi S, Lu Q, Nelson-Williams C, Brooks ED, et al. (September 2016). "BMP2 alleles". eLife. 5. doi: 10.7554/eLife.20125 . PMC   5045293 . PMID   27606499.
8. Bai S, Shi X, Yang X, Cao X (March 2000). "Smad6 as a transcriptional corepressor". J. Biol. Chem. 275 (12): 8267–70. doi: 10.1074/jbc.275.12.8267 . PMID   10722652.
9. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T (June 2000). "BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6". J. Biol. Chem. 275 (23): 17647–52. doi: 10.1074/jbc.M908622199 . PMID   10748100.
10. Yanagisawa M, Nakashima K, Takeda K, Ochiai W, Takizawa T, Ueno M, Takizawa M, Shibuya H, Taga T (December 2001). "Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7". Genes Cells. 6 (12): 1091–9. doi: 10.1046/j.1365-2443.2001.00483.x . PMID   11737269. S2CID   25476125.
11. Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, Feeley R, Gimeno CJ, Woolf EA, Tayber O, Mays GG, Sampson BA, Schoen FJ, Gimbrone MA, Falb D (August 1997). "Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9314–9. Bibcode:1997PNAS...94.9314T. doi: 10.1073/pnas.94.17.9314 . PMC   23174 . PMID   9256479.
12. Imoto S, Sugiyama K, Muromoto R, Sato N, Yamamoto T, Matsuda T (September 2003). "Regulation of transforming growth factor-beta signaling by protein inhibitor of activated STAT, PIASy through Smad3". J. Biol. Chem. 278 (36): 34253–8. doi: 10.1074/jbc.M304961200 . hdl: 2115/28123 . PMID   12815042.
13. Datta PK, Moses HL (May 2000). "STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling". Mol. Cell. Biol. 20 (9): 3157–67. doi:10.1128/MCB.20.9.3157-3167.2000. PMC   85610 . PMID   10757800.

Further reading

• Massagué J (1998). "TGF-beta signal transduction". Annu. Rev. Biochem. 67: 753–91. doi: 10.1146/annurev.biochem.67.1.753 . PMID   9759503.
• 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.
• 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.
• 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.
• Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (1996). "Mad-related genes in the human". Nat. Genet. 13 (3): 347–9. doi:10.1038/ng0796-347. PMID   8673135. S2CID   10124489.
• Topper JN, Cai J, Qiu Y, Anderson KR, Xu YY, Deeds JD, Feeley R, Gimeno CJ, Woolf EA, Tayber O, Mays GG, Sampson BA, Schoen FJ, Gimbrone MA, Falb D (1997). "Vascular MADs: Two novel MAD-related genes selectively inducible by flow in human vascular endothelium". Proc. Natl. Acad. Sci. U.S.A. 94 (17): 9314–9. Bibcode:1997PNAS...94.9314T. doi: 10.1073/pnas.94.17.9314 . PMC   23174 . PMID   9256479.
• Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A (1998). "Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor". Genes Dev. 12 (2): 186–97. doi:10.1101/gad.12.2.186. PMC   316444 . PMID   9436979.
• Afrakhte M, Morén A, Jossan S, Itoh S, Sampath K, Westermark B, Heldin CH, Heldin NE, ten Dijke P (1998). "Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members". Biochem. Biophys. Res. Commun. 249 (2): 505–11. Bibcode:1998BBRC..249..505A. doi:10.1006/bbrc.1998.9170. PMID   9712726.
• Galvin KM, Donovan MJ, Lynch CA, Meyer RI, Paul RJ, Lorenz JN, Fairchild-Huntress V, Dixon KL, Dunmore JH, Gimbrone MA, Falb D, Huszar D (2000). "A role for smad6 in development and homeostasis of the cardiovascular system". Nat. Genet. 24 (2): 171–4. doi:10.1038/72835. PMID   10655064. S2CID   24365746.
• Bai S, Shi X, Yang X, Cao X (2000). "Smad6 as a transcriptional corepressor". J. Biol. Chem. 275 (12): 8267–70. doi: 10.1074/jbc.275.12.8267 . PMID   10722652.
• Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T (2000). "BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6". J. Biol. Chem. 275 (23): 17647–52. doi: 10.1074/jbc.M908622199 . PMID   10748100.
• Datta PK, Moses HL (2000). "STRAP and Smad7 Synergize in the Inhibition of Transforming Growth Factor β Signaling". Mol. Cell. Biol. 20 (9): 3157–67. doi:10.1128/MCB.20.9.3157-3167.2000. PMC   85610 . PMID   10757800.
• Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K (2001). "Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation". J. Biol. Chem. 276 (16): 12477–80. doi: 10.1074/jbc.C100008200 . PMID   11278251.
• Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (2001). "Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads". EMBO J. 20 (15): 4132–42. doi:10.1093/emboj/20.15.4132. PMC   149146 . PMID   11483516.
• Yanagisawa M, Nakashima K, Takeda K, Ochiai W, Takizawa T, Ueno M, Takizawa M, Shibuya H, Taga T (2002). "Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7". Genes Cells. 6 (12): 1091–9. doi: 10.1046/j.1365-2443.2001.00483.x . PMID   11737269. S2CID   25476125.
• Schiffer M, Schiffer LE, Gupta A, Shaw AS, Roberts IS, Mundel P, Böttinger EP (2003). "Inhibitory smads and tgf-Beta signaling in glomerular cells". J. Am. Soc. Nephrol. 13 (11): 2657–66. doi: 10.1097/01.ASN.0000033276.06451.50 . PMID   12397035.