Mothers against decapentaplegic homolog 6 explained

SMAD family member 6, also known as SMAD6, is a protein that in humans is encoded by the SMAD6 gene.^[1]

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.^[2]

Disease associations

Heterozygous, damaging mutations in SMAD6 are the most frequent genetic cause of non-syndromic craniosynostosis identified to date.^[3]

Interactions

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

• HOXC8,^[4]
• MAP3K7,^{[5] [6]}
• Mothers against decapentaplegic homolog 7,^[7]
• PIAS4,^[8] and
• STRAP.^[9]

Further reading

• Massagué J . TGF-beta signal transduction . Annu. Rev. Biochem. . 67 . 753–91 . 1998 . 9759503 . 10.1146/annurev.biochem.67.1.753 . free .
• Verschueren K, Huylebroeck D . Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells . Cytokine Growth Factor Rev. . 10 . 3–4 . 187–99 . 2000 . 10647776 . 10.1016/S1359-6101(99)00012-X .
• Wrana JL, Attisano L . The Smad pathway . Cytokine Growth Factor Rev. . 11 . 1–2 . 5–13 . 2000 . 10708948 . 10.1016/S1359-6101(99)00024-6 .
• Miyazono K . TGF-beta signaling by Smad proteins . Cytokine Growth Factor Rev. . 11 . 1–2 . 15–22 . 2000 . 10708949 . 10.1016/S1359-6101(99)00025-8 .
• Riggins GJ, Thiagalingam S, Rozenblum E, Weinstein CL, Kern SE, Hamilton SR, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B . Mad-related genes in the human . Nat. Genet. . 13 . 3 . 347–9 . 1996 . 8673135 . 10.1038/ng0796-347 . 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 . 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 . 1997 . 9256479 . 23174 . 10.1073/pnas.94.17.9314 . 1997PNAS...94.9314T . free .
• Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A . Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor . Genes Dev. . 12 . 2 . 186–97 . 1998 . 9436979 . 316444 . 10.1101/gad.12.2.186 .
• Afrakhte M, Morén A, Jossan S, Itoh S, Sampath K, Westermark B, Heldin CH, Heldin NE, ten Dijke P . Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members . Biochem. Biophys. Res. Commun. . 249 . 2 . 505–11 . 1998 . 9712726 . 10.1006/bbrc.1998.9170 .
• 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 . A role for smad6 in development and homeostasis of the cardiovascular system . Nat. Genet. . 24 . 2 . 171–4 . 2000 . 10655064 . 10.1038/72835 . 24365746 .
• Bai S, Shi X, Yang X, Cao X . Smad6 as a transcriptional corepressor . J. Biol. Chem. . 275 . 12 . 8267–70 . 2000 . 10722652 . 10.1074/jbc.275.12.8267 . free .
• Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T . 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 . 2000 . 10748100 . 10.1074/jbc.M908622199 . free .
• Datta PK, Moses HL . STRAP and Smad7 Synergize in the Inhibition of Transforming Growth Factor β Signaling . Mol. Cell. Biol. . 20 . 9 . 3157–67 . 2000 . 10757800 . 85610 . 10.1128/MCB.20.9.3157-3167.2000 .
• Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K . Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation . J. Biol. Chem. . 276 . 16 . 12477–80 . 2001 . 11278251 . 10.1074/jbc.C100008200 . free .
• Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S . Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads . EMBO J. . 20 . 15 . 4132–42 . 2001 . 11483516 . 149146 . 10.1093/emboj/20.15.4132 .
• Yanagisawa M, Nakashima K, Takeda K, Ochiai W, Takizawa T, Ueno M, Takizawa M, Shibuya H, Taga T . Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7 . Genes Cells . 6 . 12 . 1091–9 . 2002 . 11737269 . 10.1046/j.1365-2443.2001.00483.x . 25476125 . free .
• Schiffer M, Schiffer LE, Gupta A, Shaw AS, Roberts IS, Mundel P, Böttinger EP . Inhibitory smads and tgf-Beta signaling in glomerular cells . J. Am. Soc. Nephrol. . 13 . 11 . 2657–66 . 2003 . 12397035 . 10.1097/01.ASN.0000033276.06451.50 . free .

Notes and References

1. Web site: Entrez Gene: SMAD6 SMAD family member 6.
2. https://psmag.com/sonic-hedgehog-dicer-and-the-problem-with-naming-genes-113c58df8f7a#.os08udsyk "Sonic Hedgehog, DICER, and the Problem With Naming Genes"
3. Timberlake AT, Choi J, Zaidi S, Lu Q, Nelson-Williams C, Brooks ED, Bilguvar K, Tikhonova I, Mane S, Yang JF, Sawh-Martinez R, Persing S, Zellner EG, Loring E, Chuang C, Galm A, Hashim PW, Steinbacher DM, DiLuna ML, Duncan CC, Pelphrey KA, Zhao H, Persing JA, Lifton RP . 6 . BMP2 alleles . eLife . 5 . September 2016 . 27606499 . 5045293 . 10.7554/eLife.20125 . free .
4. Bai S, Shi X, Yang X, Cao X . Smad6 as a transcriptional corepressor . J. Biol. Chem. . 275 . 12 . 8267–70 . March 2000 . 10722652 . 10.1074/jbc.275.12.8267 . free .
5. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T . 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 . June 2000 . 10748100 . 10.1074/jbc.M908622199 . free .
6. Yanagisawa M, Nakashima K, Takeda K, Ochiai W, Takizawa T, Ueno M, Takizawa M, Shibuya H, Taga T . Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7 . Genes Cells . 6 . 12 . 1091–9 . December 2001 . 11737269 . 10.1046/j.1365-2443.2001.00483.x . 25476125 . free .
7. 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 . 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 . August 1997 . 9256479 . 23174 . 10.1073/pnas.94.17.9314 . 1997PNAS...94.9314T . free .
8. Imoto S, Sugiyama K, Muromoto R, Sato N, Yamamoto T, Matsuda T . Regulation of transforming growth factor-beta signaling by protein inhibitor of activated STAT, PIASy through Smad3 . J. Biol. Chem. . 278 . 36 . 34253–8 . September 2003 . 12815042 . 10.1074/jbc.M304961200 . 2115/28123 . free . free .
9. Datta PK, Moses HL . STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling . Mol. Cell. Biol. . 20 . 9 . 3157–67 . May 2000 . 10757800 . 85610 . 10.1128/MCB.20.9.3157-3167.2000 .