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Gene Review

SMAD6  -  SMAD family member 6

Homo sapiens

Synonyms: AOVD2, HsT17432, MAD homolog 6, MADH6, MADH7, ...
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Disease relevance of SMAD6


High impact information on SMAD6


Biological context of SMAD6


Anatomical context of SMAD6


Associations of SMAD6 with chemical compounds


Physical interactions of SMAD6

  • Endogenous HDAC-1 was also shown to interact with both Smad6 and Hoxc-8 [11].
  • Smad1 and Smad6 interact with Hoxc8 and regulate its repression activities [15].
  • Here we show that Smad6 interacts with homeobox (Hox) c-8 as a transcriptional corepressor, inhibiting BMP signaling in the nucleus [16].

Regulatory relationships of SMAD6


Other interactions of SMAD6

  • Here we demonstrate that STRAP synergizes specifically with Smad7, but not with Smad6, in the inhibition of TGF-beta-induced transcriptional responses [20].
  • Here, the expression of the regulatory SMAD2, 3, the co-SMAD4 and the inhibitory SMAD6 and 7 was assessed in bronchial biopsies of COPD patients and controls by quantitative RT-PCR [2].
  • Here, we report the completion of cloning of the six known human Smads, providing novel sequences for Smad5 and Smad6 [21].
  • Adrenomedullin impairs the profibrotic effects of transforming growth factor-beta1 through recruiting Smad6 protein in human renal tubular cells [22].
  • The interaction between Smad6 and Hoxc-8 was identified by a yeast two-hybrid approach and further demonstrated by co-immunoprecipitation assays in cells [16].

Analytical, diagnostic and therapeutic context of SMAD6

  • Immunostaining (including confocal microscopy) confirmed the presence of Smad6 and Smad7 in the majority of normal and degenerated articular chondrocytes; localization was mostly cytoplasmic [9].
  • Furthermore, detection of phosphorylated Smad1/5/8 on Western blotting analysis was prolonged, suggesting prolonged kinase activity of BMP receptors through suppressed expression of Smad6 [13].
  • By using in vitro electrophoretic mobility shift assays and in vivo chromatin immunoprecipitation, we also demonstrate that during macrophage differentiation Smad6 displays an increased binding to the human osteopontin, Id2, and Hex gene promoters, which correlates to an observed increased expression of these genes [14].


  1. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. Yu, H., Bock, O., Bayat, A., Ferguson, M.W., Mrowietz, U. Journal of plastic, reconstructive & aesthetic surgery : JPRAS. (2006) [Pubmed]
  2. SMAD-signaling in chronic obstructive pulmonary disease: transcriptional down-regulation of inhibitory SMAD 6 and 7 by cigarette smoke. Springer, J., Scholz, F.R., Peiser, C., Groneberg, D.A., Fischer, A. Biol. Chem. (2004) [Pubmed]
  3. Prognostic value of the expression of Smad6 and Smad7, as inhibitory Smads of the TGF-beta superfamily, in esophageal squamous cell carcinoma. Osawa, H., Nakajima, M., Kato, H., Fukuchi, M., Kuwano, H. Anticancer Res. (2004) [Pubmed]
  4. Smad7 but not Smad6 cooperates with oncogenic ras to cause malignant conversion in a mouse model for squamous cell carcinoma. Liu, X., Lee, J., Cooley, M., Bhogte, E., Hartley, S., Glick, A. Cancer Res. (2003) [Pubmed]
  5. Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice. Nakao, A., Fujii, M., Matsumura, R., Kumano, K., Saito, Y., Miyazono, K., Iwamoto, I. J. Clin. Invest. (1999) [Pubmed]
  6. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Hata, A., Lagna, G., Massagué, J., Hemmati-Brivanlou, A. Genes Dev. (1998) [Pubmed]
  7. The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity. Pimanda, J.E., Donaldson, I.J., de Bruijn, M.F., Kinston, S., Knezevic, K., Huckle, L., Piltz, S., Landry, J.R., Green, A.R., Tannahill, D., Göttgens, B. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  8. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Topper, J.N., Cai, J., Qiu, Y., Anderson, K.R., Xu, Y.Y., Deeds, J.D., Feeley, R., Gimeno, C.J., Woolf, E.A., Tayber, O., Mays, G.G., Sampson, B.A., Schoen, F.J., Gimbrone, M.A., Falb, D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  9. Bone morphogenetic protein and transforming growth factor beta inhibitory Smads 6 and 7 are expressed in human adult normal and osteoarthritic cartilage in vivo and are differentially regulated in vitro by interleukin-1beta. Kaiser, M., Haag, J., Söder, S., Bau, B., Aigner, T. Arthritis Rheum. (2004) [Pubmed]
  10. Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. Ishisaki, A., Yamato, K., Hashimoto, S., Nakao, A., Tamaki, K., Nonaka, K., ten Dijke, P., Sugino, H., Nishihara, T. J. Biol. Chem. (1999) [Pubmed]
  11. A nuclear antagonistic mechanism of inhibitory Smads in transforming growth factor-beta signaling. Bai, S., Cao, X. J. Biol. Chem. (2002) [Pubmed]
  12. The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor: potential clinical implications. Ichijo, T., Voutetakis, A., Cotrim, A.P., Bhattachryya, N., Fujii, M., Chrousos, G.P., Kino, T. J. Biol. Chem. (2005) [Pubmed]
  13. Bone morphogenetic protein activities are enhanced by 3',5'-cyclic adenosine monophosphate through suppression of Smad6 expression in osteoprogenitor cells. Sugama, R., Koike, T., Imai, Y., Nomura-Furuwatari, C., Takaoka, K. Bone (2006) [Pubmed]
  14. Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation. Glesne, D., Huberman, E. Oncogene (2006) [Pubmed]
  15. Smads oppose Hox transcriptional activities. Li, X., Nie, S., Chang, C., Qiu, T., Cao, X. Exp. Cell Res. (2006) [Pubmed]
  16. Smad6 as a transcriptional corepressor. Bai, S., Shi, X., Yang, X., Cao, X. J. Biol. Chem. (2000) [Pubmed]
  17. Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21(WAF1/Cip1). Pardali, K., Kowanetz, M., Heldin, C.H., Moustakas, A. J. Cell. Physiol. (2005) [Pubmed]
  18. Expressions of inhibitory Smads, Smad6 and Smad7, are differentially regulated by TPA in human lung fibroblast cells. Tsunobuchi, H., Ishisaki, A., Imamura, T. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  19. Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation. Nguyen, L.N., Furuya, M.H., Wolfraim, L.A., Nguyen, A.P., Holdren, M.S., Campbell, J.S., Knight, B., Yeoh, G.C., Fausto, N., Parks, W.T. Hepatology (2007) [Pubmed]
  20. STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling. Datta, P.K., Moses, H.L. Mol. Cell. Biol. (2000) [Pubmed]
  21. Frequency of Smad gene mutations in human cancers. Riggins, G.J., Kinzler, K.W., Vogelstein, B., Thiagalingam, S. Cancer Res. (1997) [Pubmed]
  22. Adrenomedullin impairs the profibrotic effects of transforming growth factor-beta1 through recruiting Smad6 protein in human renal tubular cells. Huang, H., Ma, C., Yang, M., Tang, C., Wang, H. Cell. Physiol. Biochem. (2005) [Pubmed]
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