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
Gene location (Human)
Chr.	Chromosome 15 (human)
End	66,782,849 bp
Gene location (Mouse)
Chr.	Chromosome 9 (mouse)
End	63,929,341 bp
RNA expression pattern
	Top expressed in
	right lung; ; glomerulus; ; metanephric glomerulus; ; lower lobe of lung; ; upper lobe of lung; ; upper lobe of left lung; ; visceral pleura; ; right lobe of thyroid gland; ; retinal pigment epithelium; ; right coronary artery;
	Top expressed in
	right lung; ; right lung lobe; ; molar; ; atrium; ; epithelium of stomach; ; external carotid artery; ; left lung; ; seminiferous tubule; ; endocardial cushion; ; internal carotid artery;
	More reference expression data
	; ;
	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
	4091
	17130
	ENSG00000137834
	ENSMUSG00000036867
	O43541
	O35182
	NM_001142861 ; NM_005585
	NM_008542
	NP_005576
	NP_032568
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated December 04, 2023

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]

Related Research Articles

Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.

SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, which act as mediators of TGF-β signal transduction. The TGFβ family of cytokines regulates critical processes during the lifecycle of metazoans, with important roles during embryo development, tissue homeostasis, regeneration, and immune regulation.

Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.

Smads comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily, which are critically important for regulating cell development and growth. The abbreviation refers to the homologies to the Caenorhabditis elegans SMA and MAD family of genes in Drosophila.

The bone morphogenetic protein receptor, type IA also known as BMPR1A is a protein which in humans is encoded by the BMPR1A gene. BMPR1A has also been designated as CD292.

Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.

Betaglycan also known as Transforming growth factor beta receptor III (TGFBR3), is a cell-surface chondroitin sulfate / heparan sulfate proteoglycan >300 kDa in molecular weight. Betaglycan binds to various members of the TGF-beta superfamily of ligands via its core protein, and bFGF via its heparan sulfate chains. TGFBR3 is the most widely expressed type of TGF-beta receptor. Its affinity towards all individual isoforms of TGF-beta is similarly high and therefore it plays an important role as a coreceptor mediating the binding of TGF-beta to its other receptors - specifically TGFBR2. The intrinsic kinase activity of this receptor has not yet been described. In regard of TGF-beta signalling it is generally considered a non-signaling receptor or a coreceptor. By binding to various member of the TGF-beta superfamily at the cell surface it acts as a reservoir of TGF-beta.

Transforming growth factor beta receptor I is a membrane-bound TGF beta receptor protein of the TGF-beta receptor family for the TGF beta superfamily of signaling ligands. TGFBR1 is its human gene.

Transforming growth factor, beta receptor II (70/80kDa) is a TGF beta receptor. TGFBR2 is its human gene.

The SKI protein is a nuclear proto-oncogene that is associated with tumors at high cellular concentrations. SKI has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.

E3 SUMO-protein ligase PIAS4 is one of several protein inhibitor of activated STAT (PIAS) proteins. It is also known as protein inhibitor of activated STAT protein gamma, and is an enzyme that in humans is encoded by the PIAS4 gene.

Transcription factor E3 is a protein that in humans is encoded by the TFE3 gene.

Homeobox protein TGIF1 is a protein that, in humans, is encoded by the TGIF1 gene. Alternative splicing has been observed at this locus and eight variants, encoding four distinct isoforms, are described.

Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 is an enzyme that in humans is encoded by the TAB1 gene.

Ski-like protein is a protein that in humans is encoded by the SKIL gene.

Homeobox protein Hox-C8 is a protein that in humans is encoded by the HOXC8 gene.

Serine-threonine kinase receptor-associated protein is an enzyme that in humans is encoded by the STRAP gene.

E3 ubiquitin-protein ligase SMURF2 is an enzyme that in humans is encoded by the SMURF2 gene which is located at chromosome 17q23.3-q24.1.

Krueppel-like factor 10 is a protein that in humans is encoded by the KLF10 gene.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000137834 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036867 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Entrez Gene: SMAD6 SMAD family member 6".
↑ "Sonic Hedgehog, DICER, and the Problem With Naming Genes", Sep 26, 2014, Michael White. psmag.com
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

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. 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.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000137834 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 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.

[entrez-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.

[pmid10722652-8] 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.

[pmid10748100-9] 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.

[pmid11737269-10] 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.

[pmid9256479-11] 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.

[pmid12815042-12] 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.

[pmid10757800-13] 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.

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