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Gene Review

Smad6  -  SMAD family member 6

Mus musculus

Synonyms: MAD homolog 6, Mad homolog 7, Madh6, Madh7, Mothers against DPP homolog 6, ...
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Disease relevance of Smad6


High impact information on Smad6


Biological context of Smad6


Anatomical context of Smad6

  • AMSH interacts with Smad6, but not with R- and Co-Smads, upon BMP receptor activation in cultured cells [8].
  • In contrast, Smad6 was selectively expressed at high levels, e.g. in intramembranous bone whereas Smad7 was prominent in seminiferous tubules of the testis, demonstrating distinct expression of these genes in non-cardiovascular tissues [9].
  • Over-expression of Smad6 in chondrocytes causes delays in chondrocyte differentiation and maturation (<citeref rid="bib21">Horiki et al., 2004</citeref>) [10].
  • Smad6 appears to play a modulatory role in the regulation of Dlx3-dependent gene transcription within placental trophoblasts [3].
  • To elucidate the mechanism by which oxygen tension influences chondrocyte differentiation, the Smad pathway was examined using Smad6 overexpression adenovirus and Smad6 transgenic mice embryo forelimbs [11].

Regulatory relationships of Smad6

  • Smad-6 overexpression significantly inhibited TGF-beta-stimulated chondrocyte proliferation, although proliferation was not completely abolished [12].

Other interactions of Smad6

  • Smad5 knock-down also reduces the rise in Smad6 upon BMP7 [13].
  • The expression of inhibitory Smads (Smad6 and 7) largely overlaps with receptor regulated Smads, indicating that negative feedback on BMP/TGF-beta signaling is critical throughout all stages of tooth morphogenesis [14].
  • Specific inhibitors for p38 kinase inhibited BMP2-induced adipocytic differentiation and transcriptional activation of PPARgamma, whereas overexpression of Smad6 had no effect on transcriptional activity of PPARgamma [15].

Analytical, diagnostic and therapeutic context of Smad6


  1. A role for smad6 in development and homeostasis of the cardiovascular system. Galvin, K.M., Donovan, M.J., Lynch, C.A., Meyer, R.I., Paul, R.J., Lorenz, J.N., Fairchild-Huntress, V., Dixon, K.L., Dunmore, J.H., Gimbrone, M.A., Falb, D., Huszar, D. Nat. Genet. (2000) [Pubmed]
  2. Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia. Horiki, M., Imamura, T., Okamoto, M., Hayashi, M., Murai, J., Myoui, A., Ochi, T., Miyazono, K., Yoshikawa, H., Tsumaki, N. J. Cell Biol. (2004) [Pubmed]
  3. Smad6 represses Dlx3 transcriptional activity through inhibition of DNA binding. Berghorn, K.A., Clark-Campbell, P.A., Han, L., McGrattan, M., Weiss, R.S., Roberson, M.S. J. Biol. Chem. (2006) [Pubmed]
  4. Smad6 is a Smad1/5-induced smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter. Ishida, W., Hamamoto, T., Kusanagi, K., Yagi, K., Kawabata, M., Takehara, K., Sampath, T.K., Kato, M., Miyazono, K. J. Biol. Chem. (2000) [Pubmed]
  5. Smad7 and Smad6 differentially modulate transforming growth factor beta -induced inhibition of embryonic lung morphogenesis. Zhao, J., Shi, W., Chen, H., Warburton, D. J. Biol. Chem. (2000) [Pubmed]
  6. 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]
  7. Methylation of Smad6 by protein arginine N-methyltransferase 1. Inamitsu, M., Itoh, S., Hellman, U., Ten Dijke, P., Kato, M. FEBS Lett. (2006) [Pubmed]
  8. Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads. Itoh, F., Asao, H., Sugamura, K., Heldin, C.H., ten Dijke, P., Itoh, S. EMBO J. (2001) [Pubmed]
  9. Developmentally regulated expression of Smad3, Smad4, Smad6, and Smad7 involved in TGF-beta signaling. Luukko, K., Ylikorkala, A., Mäkelä, T.P. Mech. Dev. (2001) [Pubmed]
  10. Bone morphogenetic proteins. Chen, D., Zhao, M., Mundy, G.R. Growth Factors (2004) [Pubmed]
  11. Oxygen Tension Regulates Chondrocyte Differentiation and Function during Endochondral Ossification. Hirao, M., Tamai, N., Tsumaki, N., Yoshikawa, H., Myoui, A. J. Biol. Chem. (2006) [Pubmed]
  12. Adenoviral overexpression of Smad-7 and Smad-6 differentially regulates TGF-beta-mediated chondrocyte proliferation and proteoglycan synthesis. Scharstuhl, A., Diepens, R., Lensen, J., Vitters, E., van Beuningen, H., van der Kraan, P., van den Berg, W. Osteoarthr. Cartil. (2003) [Pubmed]
  13. Bone morphogenetic protein-7 signals opposing transforming growth factor beta in mesangial cells. Wang, S., Hirschberg, R. J. Biol. Chem. (2004) [Pubmed]
  14. Developmental expression of Smad1-7 suggests critical function of TGF-beta/BMP signaling in regulating epithelial-mesenchymal interaction during tooth morphogenesis. Xu, X., Jeong, L., Han, J., Ito, Y., Bringas, P., Chai, Y. Int. J. Dev. Biol. (2003) [Pubmed]
  15. Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Hata, K., Nishimura, R., Ikeda, F., Yamashita, K., Matsubara, T., Nokubi, T., Yoneda, T. Mol. Biol. Cell (2003) [Pubmed]
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