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HMDB Protein ID HMDBP14504
Secondary Accession Numbers None
Name Mothers against decapentaplegic homolog 6
  1. MAD homolog 6
  2. Mothers against DPP homolog 6
  3. SMAD family member 6
  4. SMAD 6
  5. Smad6
  6. hSMAD6
Gene Name SMAD6
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators. SMAD6 is an inhibitory Smad (i-Smad) that negatively regulates signaling downstream of type I transforming growth factor-beta (PubMed:9436979, PubMed:16951688, PubMed:22275001, PubMed:9759503, PubMed:10647776, PubMed:10708948, PubMed:10708949, PubMed:30848080). Acts as a mediator of TGF-beta and BMP anti-inflammatory activities. Suppresses IL1R-TLR signaling through its direct interaction with PEL1, preventing NF-kappa-B activation, nuclear transport and NF-kappa-B-mediated expression of proinflammatory genes (PubMed:16951688). Blocks the BMP-SMAD1 signaling pathway by competing with SMAD4 for receptor-activated SMAD1-binding (PubMed:9436979, PubMed:30848080). Binds to regulatory elements in target promoter regions (PubMed:16491121).
  • TGF-beta signaling pathway
Reactions Not Available
GO Classification
Biological Process
fat cell differentiation
response to laminar fluid shear stress
negative regulation of apoptotic process
response to lipopolysaccharide
SMAD protein signal transduction
BMP signaling pathway
anatomical structure morphogenesis
coronary vasculature development
aortic valve morphogenesis
positive regulation of pri-miRNA transcription by RNA polymerase II
pulmonary valve morphogenesis
aorta development
mitral valve morphogenesis
zygotic specification of dorsal/ventral axis
negative regulation of BMP signaling pathway
ventricular septum development
immune response
cell differentiation
negative regulation of ossification
negative regulation of osteoblast differentiation
outflow tract septum morphogenesis
negative regulation of transforming growth factor beta receptor signaling pathway
transforming growth factor beta receptor signaling pathway
negative regulation of cell proliferation
cell-substrate adhesion
ureteric bud development
negative regulation of SMAD protein complex assembly
negative regulation of pathway-restricted SMAD protein phosphorylation
response to estrogen stimulus
Cellular Component
protein-containing complex
Golgi apparatus
heteromeric SMAD protein complex
nuclear body
Molecular Function
metal ion binding
co-SMAD binding
R-SMAD binding
ubiquitin protein ligase binding
transcription regulator inhibitor activity
type I activin receptor binding
chromatin binding
I-SMAD binding
identical protein binding
transcription regulatory region sequence-specific DNA binding
type I transforming growth factor beta receptor binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 496
Molecular Weight 53496.635
Theoretical pI 8.104
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID O43541
UniProtKB/Swiss-Prot Entry Name SMAD6_HUMAN
PDB IDs Not Available
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
General References
  1. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  2. 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. 1996 Jul;13(3):347-9. [PubMed:8673135 ]
  3. Massague J: TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753-91. [PubMed:9759503 ]
  4. Verschueren K, Huylebroeck D: Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells. Cytokine Growth Factor Rev. 1999 Sep-Dec;10(3-4):187-99. [PubMed:10647776 ]
  5. Wrana JL, Attisano L: The Smad pathway. Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):5-13. [PubMed:10708948 ]
  6. Miyazono K: TGF-beta signaling by Smad proteins. Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):15-22. [PubMed:10708949 ]
  7. Hata A, Lagna G, Massague J, Hemmati-Brivanlou A: Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998 Jan 15;12(2):186-97. [PubMed:9436979 ]
  8. Afrakhte M, Moren 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. 1998 Aug 19;249(2):505-11. [PubMed:9712726 ]
  9. Bai S, Shi X, Yang X, Cao X: Smad6 as a transcriptional corepressor. J Biol Chem. 2000 Mar 24;275(12):8267-70. [PubMed:10722652 ]
  10. Krishnan P, King MW, Neff AW, Sandusky GE, Bierman KL, Grinnell B, Smith RC: Human truncated Smad 6 (Smad 6s) inhibits the BMP pathway in Xenopus laevis. Dev Growth Differ. 2001 Apr;43(2):115-32. [PubMed:11284962 ]
  11. 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. 2001 Aug 1;20(15):4132-42. [PubMed:11483516 ]
  12. Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T, Miyazono K: Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. EMBO J. 2003 Dec 15;22(24):6458-70. [PubMed:14657019 ]
  13. Liu W, Rui H, Wang J, Lin S, He Y, Chen M, Li Q, Ye Z, Zhang S, Chan SC, Chen YG, Han J, Lin SC: Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006 Apr 19;25(8):1646-58. Epub 2006 Apr 6. [PubMed:16601693 ]
  14. Glesne D, Huberman E: Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation. Oncogene. 2006 Jul 6;25(29):4086-98. Epub 2006 Feb 20. [PubMed:16491121 ]
  15. Choi KC, Lee YS, Lim S, Choi HK, Lee CH, Lee EK, Hong S, Kim IH, Kim SJ, Park SH: Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1. Nat Immunol. 2006 Oct;7(10):1057-65. doi: 10.1038/ni1383. Epub 2006 Sep 3. [PubMed:16951688 ]
  16. Tan HL, Glen E, Topf A, Hall D, O'Sullivan JJ, Sneddon L, Wren C, Avery P, Lewis RJ, ten Dijke P, Arthur HM, Goodship JA, Keavney BD: Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Hum Mutat. 2012 Apr;33(4):720-7. doi: 10.1002/humu.22030. Epub 2012 Feb 14. [PubMed:22275001 ]
  17. Zhang X, Zhang J, Bauer A, Zhang L, Selinger DW, Lu CX, Ten Dijke P: Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. EMBO J. 2013 Apr 3;32(7):996-1007. doi: 10.1038/emboj.2013.38. Epub 2013 Mar 1. [PubMed:23455153 ]
  18. Yang Y, Zheng Y, Li W, Li L, Tu M, Zhao L, Mei H, Zhu G, Zhu Y: SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis. Genet Med. 2019 Nov;21(11):2577-2585. doi: 10.1038/s41436-019-0552-8. Epub 2019 May 29. [PubMed:31138930 ]
  19. Luyckx I, MacCarrick G, Kempers M, Meester J, Geryl C, Rombouts O, Peeters N, Claes C, Boeckx N, Sakalihasan N, Jacquinet A, Hoischen A, Vandeweyer G, Van Lent S, Saenen J, Van Craenenbroeck E, Timmermans J, Duijnhouwer A, Dietz H, Van Laer L, Loeys B, Verstraeten A: Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy. Eur J Hum Genet. 2019 Jul;27(7):1044-1053. doi: 10.1038/s41431-019-0363-z. Epub 2019 Feb 22. [PubMed:30796334 ]
  20. Park JE, Park JS, Jang SY, Park SH, Kim JW, Ki CS, Kim DK: A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm. Mol Genet Genomic Med. 2019 May;7(5):e620. doi: 10.1002/mgg3.620. Epub 2019 Mar 8. [PubMed:30848080 ]