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Gene Review

SMAD3  -  SMAD family member 3

Homo sapiens

Synonyms: HSPC193, HsT17436, JV15-2, LDS1C, LDS3, ...
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Disease relevance of SMAD3


Psychiatry related information on SMAD3


High impact information on SMAD3

  • (2006) answer one of the long-standing questions in the TGFbeta field by identifying a phosphatase, PPM1A, that directly dephosphorylates Smad2 and Smad3 to limit their activation [7].
  • Smad3 is a direct mediator of transcriptional activation by the TGFbeta receptor [8].
  • We defined how, in the same context, Smad3 can also mediate transcriptional repression of the growth-promoting gene c-myc [8].
  • The crystal structure of a Smad3 MH1 domain bound to an optimal DNA sequence determined at 2.8 A resolution reveals a novel DNA-binding motif [9].
  • These interactions complement interactions between c-Jun and c-Fos, and between Smad3 and Smad4 [10].

Chemical compound and disease context of SMAD3


Biological context of SMAD3

  • SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor beta [14].
  • Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3 [15].
  • Cotransfection of SMAD3-SMAD4 along with hepatocyte nuclear factor-4 resulted in a strong synergistic transactivation of the -890/+24 apoCIII promoter, proximal promoter segments, or synthetic promoters containing either the apoCIII enhancer or the proximal apoCIII hormone response element [16].
  • IL-1beta and its downstream mediator TAK1 inhibit SMAD3-mediated TGFbeta target gene activation, whereas SMAD3 nuclear translocation and DNA binding in response to TGFbeta are not affected [15].
  • Radioresistance was abrogated by reinsertion of the human SMAD3 transgene, resulting in a D(0)=1.49 0.10 (P=0.028) for Smad3(-/-)(3) cells [17].

Anatomical context of SMAD3


Associations of SMAD3 with chemical compounds

  • Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor-beta Signaling by Repressing SMAD3 Transactivation [20].
  • Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism [21].
  • TGF-beta signals through its cell surface receptor serine kinases that phosphorylate Smad2 or Smad3 proteins [22].
  • Using transient transfection systems, we demonstrated that Smad3 specifically represses transcriptional activation mediated by AR on two natural androgen-responsive promoters [23].
  • The induction of MMP-13 expression by Smad3 and constitutively active mutants of MKK3b or MKK6b was blocked by specific p38 inhibitor SB203580 and by the dominant negative form of p38alpha [24].

Physical interactions of SMAD3

  • In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes [25].
  • In conclusion, our data demonstrate for the first time that ligand-bound AR inhibits TGF-beta transcriptional responses through selectively repressing the binding of Smad3 to SBE [26].
  • UV irradiation reduced protein binding to the Smad3 enhancer and increased binding to the AP-1 enhancer [27].
  • Finally, we show that GR interacts with Smad3 both in vitro and in vivo [28].
  • Here, we show that c-Ski and SnoN bind to the "SE" sequence in the C-terminal MH2 domain of Smad3, which is exposed on the N-terminal upper side of the toroidal structure of the MH2 oligomer [29].

Enzymatic interactions of SMAD3


Co-localisations of SMAD3

  • In the absence of ligand stimulation, Axin was colocalized with Smad3 in the cytoplasm in vivo [33].

Regulatory relationships of SMAD3


Other interactions of SMAD3

  • Smad2 and Smad3 are structurally highly similar and mediate TGF-beta signals [34].
  • In addition, we observed TbetaR-activation-dependent interaction between Smad2 and Smad3 [34].
  • Evi-1 interacted with and repressed the receptor-activated transcription through Smad1 and Smad2, similarly to Smad3 [36].
  • RESULTS: Protein and mRNA levels of SMAD3, but not of SMAD4 or SMAD7, were variably elevated in scleroderma fibroblasts compared with those from healthy controls [37].
  • Modifying the interaction between Smad3 and TERT gene may, thus, lead to novel strategies to regulate telomerase [38].
  • Reduction in the expression or activity of Axin/GSK3-beta leads to increased Smad3 stability and transcriptional activity without affecting TGF-beta receptors or Smad2, whereas overexpression of these proteins promotes Smad3 basal degradation and desensitizes cells to TGF-beta [39].

Analytical, diagnostic and therapeutic context of SMAD3


  1. Isoprenoid-mediated control of SMAD3 expression in a cultured model of cystic fibrosis epithelial cells. Lee, J.Y., Elmer, H.L., Ross, K.R., Kelley, T.J. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  2. Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer. Jonson, T., Gorunova, L., Dawiskiba, S., Andrén-Sandberg, A., Stenman, G., ten Dijke, P., Johansson, B., Höglund, M. Genes Chromosomes Cancer (1999) [Pubmed]
  3. SMAD3 expression is regulated by mitogen-activated protein kinase kinase-1 in epithelial and smooth muscle cells. Ross, K.R., Corey, D.A., Dunn, J.M., Kelley, T.J. Cell. Signal. (2007) [Pubmed]
  4. Immunohistochemical evaluation of phosphorylated SMAD2/SMAD3 and the co-activator P300 in human glomerulonephritis: correlation with renal injury. Kassimatis, T.I., Giannopoulou, I., Koumoundourou, D., Theodorakopoulou, E., Varakis, I., Nakopoulou, L. J. Cell. Mol. Med. (2006) [Pubmed]
  5. Cellular response to hypoxia involves signaling via Smad proteins. Zhang, H., Akman, H.O., Smith, E.L., Zhao, J., Murphy-Ullrich, J.E., Batuman, O.A. Blood (2003) [Pubmed]
  6. The TGF{beta} intracellular effector Smad3 regulates neuronal differentiation and cell fate specification in the developing spinal cord. Garc??a-Campmany, L., Mart??, E. Development (2007) [Pubmed]
  7. A phosphatase controls the fate of receptor-regulated Smads. Schilling, S.H., Datto, M.B., Wang, X.F. Cell (2006) [Pubmed]
  8. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Chen, C.R., Kang, Y., Siegel, P.M., Massagué, J. Cell (2002) [Pubmed]
  9. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Shi, Y., Wang, Y.F., Jayaraman, L., Yang, H., Massagué, J., Pavletich, N.P. Cell (1998) [Pubmed]
  10. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Zhang, Y., Feng, X.H., Derynck, R. Nature (1998) [Pubmed]
  11. From transforming growth factor-beta signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. Kang, H.Y., Lin, H.K., Hu, Y.C., Yeh, S., Huang, K.E., Chang, C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  12. Smad3 mediates angiotensin II- and TGF-beta1-induced vascular fibrosis: Smad3 thickens the plot. Sorescu, D. Circ. Res. (2006) [Pubmed]
  13. Smad3 signaling involved in pulmonary fibrosis and emphysema. Gauldie, J., Kolb, M., Ask, K., Martin, G., Bonniaud, P., Warburton, D. Proceedings of the American Thoracic Society. (2006) [Pubmed]
  14. SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor beta. Vindevoghel, L., Lechleider, R.J., Kon, A., de Caestecker, M.P., Uitto, J., Roberts, A.B., Mauviel, A. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  15. Inhibition of the transforming growth factor beta (TGFbeta) pathway by interleukin-1beta is mediated through TGFbeta-activated kinase 1 phosphorylation of SMAD3. Benus, G.F., Wierenga, A.T., de Gorter, D.J., Schuringa, J.J., van Bennekum, A.M., Drenth-Diephuis, L., Vellenga, E., Eggen, B.J. Mol. Biol. Cell (2005) [Pubmed]
  16. SMAD proteins transactivate the human ApoCIII promoter by interacting physically and functionally with hepatocyte nuclear factor 4. Kardassis, D., Pardali, K., Zannis, V.I. J. Biol. Chem. (2000) [Pubmed]
  17. Increased radioresistance, g(2)/m checkpoint inhibition, and impaired migration of bone marrow stromal cell lines derived from Smad3(-/-) mice. Epperly, M.W., Goff, J.P., Zhang, X., Niu, Y., Shields, D.S., Wang, H., Shen, H., Franicola, D., Bahnson, A.B., Nie, S., Greenberger, E.E., Greenberger, J.S. Radiat. Res. (2006) [Pubmed]
  18. Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells. Cao, Z., Flanders, K.C., Bertolette, D., Lyakh, L.A., Wurthner, J.U., Parks, W.T., Letterio, J.J., Ruscetti, F.W., Roberts, A.B. Blood (2003) [Pubmed]
  19. Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment. Furumatsu, T., Tsuda, M., Taniguchi, N., Tajima, Y., Asahara, H. J. Biol. Chem. (2005) [Pubmed]
  20. Orphan Nuclear Receptor Small Heterodimer Partner Inhibits Transforming Growth Factor-beta Signaling by Repressing SMAD3 Transactivation. Suh, J.H., Huang, J., Park, Y.Y., Seong, H.A., Kim, D., Shong, M., Ha, H., Lee, I.K., Lee, K., Wang, L., Choi, H.S. J. Biol. Chem. (2006) [Pubmed]
  21. Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced SMAD3/4-dependent transcription via a protein kinase A-dependent mechanism. Schiller, M., Verrecchia, F., Mauviel, A. Oncogene (2003) [Pubmed]
  22. Specificity in transforming growth factor beta-induced transcription of the plasminogen activator inhibitor-1 gene: interactions of promoter DNA, transcription factor muE3, and Smad proteins. Hua, X., Miller, Z.A., Wu, G., Shi, Y., Lodish, H.F. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  23. SMAD3 represses androgen receptor-mediated transcription. Hayes, S.A., Zarnegar, M., Sharma, M., Yang, F., Peehl, D.M., ten Dijke, P., Sun, Z. Cancer Res. (2001) [Pubmed]
  24. Smad3 mediates transforming growth factor-beta-induced collagenase-3 (matrix metalloproteinase-13) expression in human gingival fibroblasts. Evidence for cross-talk between Smad3 and p38 signaling pathways. Leivonen, S.K., Chantry, A., Hakkinen, L., Han, J., Kahari, V.M. J. Biol. Chem. (2002) [Pubmed]
  25. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., Gauthier, J.M. EMBO J. (1998) [Pubmed]
  26. The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. Chipuk, J.E., Cornelius, S.C., Pultz, N.J., Jorgensen, J.S., Bonham, M.J., Kim, S.J., Danielpour, D. J. Biol. Chem. (2002) [Pubmed]
  27. Ultraviolet irradiation induces Smad7 via induction of transcription factor AP-1 in human skin fibroblasts. Quan, T., He, T., Voorhees, J.J., Fisher, G.J. J. Biol. Chem. (2005) [Pubmed]
  28. Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3. Song, C.Z., Tian, X., Gelehrter, T.D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  29. Two short segments of Smad3 are important for specific interaction of Smad3 with c-Ski and SnoN. Mizuide, M., Hara, T., Furuya, T., Takeda, M., Kusanagi, K., Inada, Y., Mori, M., Imamura, T., Miyazawa, K., Miyazono, K. J. Biol. Chem. (2003) [Pubmed]
  30. The transforming growth factor-beta/SMAD signaling pathway is present and functional in human mesangial cells. Poncelet, A.C., de Caestecker, M.P., Schnaper, H.W. Kidney Int. (1999) [Pubmed]
  31. Activin A mediates growth inhibition and cell cycle arrest through Smads in human breast cancer cells. Burdette, J.E., Jeruss, J.S., Kurley, S.J., Lee, E.J., Woodruff, T.K. Cancer Res. (2005) [Pubmed]
  32. The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization. Chacko, B.M., Qin, B., Correia, J.J., Lam, S.S., de Caestecker, M.P., Lin, K. Nat. Struct. Biol. (2001) [Pubmed]
  33. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway. Furuhashi, M., Yagi, K., Yamamoto, H., Furukawa, Y., Shimada, S., Nakamura, Y., Kikuchi, A., Miyazono, K., Kato, M. Mol. Cell. Biol. (2001) [Pubmed]
  34. TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. Nakao, A., Imamura, T., Souchelnytskyi, S., Kawabata, M., Ishisaki, A., Oeda, E., Tamaki, K., Hanai, J., Heldin, C.H., Miyazono, K., ten Dijke, P. EMBO J. (1997) [Pubmed]
  35. Transforming growth factor beta regulates parathyroid hormone-related protein expression in MDA-MB-231 breast cancer cells through a novel Smad/Ets synergism. Lindemann, R.K., Ballschmieter, P., Nordheim, A., Dittmer, J. J. Biol. Chem. (2001) [Pubmed]
  36. Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1. Alliston, T., Ko, T.C., Cao, Y., Liang, Y.Y., Feng, X.H., Chang, C., Derynck, R. J. Biol. Chem. (2005) [Pubmed]
  37. Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Mori, Y., Chen, S.J., Varga, J. Arthritis Rheum. (2003) [Pubmed]
  38. Transforming growth factor beta suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene. Li, H., Xu, D., Li, J., Berndt, M.C., Liu, J.P. J. Biol. Chem. (2006) [Pubmed]
  39. Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling. Guo, X., Ramirez, A., Waddell, D.S., Li, Z., Liu, X., Wang, X.F. Genes Dev. (2008) [Pubmed]
  40. Transforming growth factor-beta inhibits pulmonary surfactant protein B gene transcription through SMAD3 interactions with NKX2.1 and HNF-3 transcription factors. Li, C., Zhu, N.L., Tan, R.C., Ballard, P.L., Derynck, R., Minoo, P. J. Biol. Chem. (2002) [Pubmed]
  41. The mechanism of nuclear export of Smad3 involves exportin 4 and Ran. Kurisaki, A., Kurisaki, K., Kowanetz, M., Sugino, H., Yoneda, Y., Heldin, C.H., Moustakas, A. Mol. Cell. Biol. (2006) [Pubmed]
  42. Smad3 interacts with JunB and Cbfa1/Runx2 for transforming growth factor-beta1-stimulated collagenase-3 expression in human breast cancer cells. Selvamurugan, N., Kwok, S., Partridge, N.C. J. Biol. Chem. (2004) [Pubmed]
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