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Gene Review

SMAD2  -  SMAD family member 2

Homo sapiens

Synonyms: JV18, JV18-1, MAD homolog 2, MADH2, MADR2, ...
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Disease relevance of SMAD2


High impact information on SMAD2

  • The ubiquitious nuclear protein Transcriptional Intermediary Factor 1gamma (TIF1gamma) selectively binds receptor-phosphorylated Smad2/3 in competition with Smad4 [5].
  • Rapid and robust binding of TIF1gamma to Smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to TGFbeta [5].
  • PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3 [6].
  • Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFbeta signaling [7].
  • We identified the homeodomain protein TGIF as a Smad2-binding protein and a repressor of transcription [8].

Chemical compound and disease context of SMAD2

  • A missense mutation at a conserved arginine residue in the amino-terminal MH1 domain of both Smad2 and Smad4 has been identified in tumors from patients with colorectal and pancreatic cancers, respectively [9].
  • As losartan inhibited the expression of Smad2 on the gene level and reduced the concentration of TGF-beta1 in our study, the results of this in vitro study suggest that the use of angiotensin II receptor blockers might represent a possible way to prevent and treat peritoneal fibrosis in PD patients [10].
  • When compared with sham-nephrectomized animals, subtotally nephrectomized animals had reduced creatinine clearance, proteinuria, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and evidence of TGF-beta activity, as indicated by the abundant nuclear staining of phosphorylated Smad2 [11].

Biological context of SMAD2


Anatomical context of SMAD2


Associations of SMAD2 with chemical compounds

  • This inhibitory function is increased in tumour-derived forms of Smad2 and 4 that carry a missense mutation in a conserved N domain arginine residue [20].
  • The crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the formation of a homotrimer mediated by the C-terminal phosphoserine (pSer) residues [21].
  • Addition of the inhibitor-of-protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-beta-induced phospho-Smad2 and shifts the differentiation toward monocytic end points [19].
  • Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response to receptor tyrosine kinase activation and the gamma interferon pathway and also by the functional interaction of Smad2 with Ca(2+)-calmodulin [22].
  • Thus, in human mesangial cells, the mechanism of decorin-mediated inhibition of TGFbeta signalling may involve activation of Ca(2+) signalling, the subsequent phosphorylation of Smad2 at a key regulatory site, and the sequestration of Smad4 in the nucleus [23].

Physical interactions of SMAD2

  • SnoN physically interacted with activated Smad-2 by forming transcriptionally inactive complex and overrode the profibrotic action of TGF-beta1 [24].
  • These results suggest that Smad2 phosphorylation results in both tighter binding to Smad4 and increased nuclear concentration; those changes may be responsible for transcriptional activation by Smad2 [25].
  • However, under conditions of inhibited endocytosis, Smad2 remains bound to SARA for at least 6 h without a significant decline in associated levels [26].
  • We report here that the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner [27].
  • Although significantly different in sequence from its Xenopus counterpart, hFAST-1 shared with xFAST-1 the ability to bind to human Smad2 and activate an activin response element (ARE) [28].

Enzymatic interactions of SMAD2

  • Numbers of epithelial cell nuclei with Smad4 and phosphorylated Smad2/3 staining were significantly reduced in erythematous oral lichen compared with normal oral mucosa [29].
  • TGF-beta signals through its cell surface receptor serine kinases that phosphorylate Smad2 or Smad3 proteins [30].
  • Additionally, SARA was found to modulate the self-association of partially phosphorylated Smad2, which suggests an added role for this protein in preventing premature release of a monophosphorylated substrate from the receptor complex [31].
  • Activin A significantly increased the expression of phosphorylated Smad2 in JHOC-5 cells [32].

Regulatory relationships of SMAD2


Other interactions of SMAD2

  • This inhibitory function of the N domain is shown here to involve an interaction with the C domain that prevents the association of Smad2 with Smad4 [20].
  • In addition, we observed TbetaR-activation-dependent interaction between Smad2 and Smad3 [18].
  • Vitamin D(3) also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-beta1 [19].
  • In contrast to SMAD2 deletion, for which no clinical relevance was observed, hazard ratios (HR) in a multivariate analysis associated with SMAD7 deletion [overall survival (OS): HR = 0.43, p = 0.0012; disease-free survival (DFS): HR = 0.50, p = 0.0033] indicated a favorable outcome for these patients [37].
  • Significantly, Smurf2 displayed preference to Smad2 as its target for degradation [34].

Analytical, diagnostic and therapeutic context of SMAD2

  • By quantitative PCR analysis, a relative loss of copy number of SMAD2, SMAD4, and DCC were detected in 40%, 57%, and 53%, respectively, of the colitis-related cancers [14].
  • Cells were stimulated with TGFbeta1 and the expression of SMAD2, 3, 4, 6 and 7 mRNA was analysed by real time RT-PCR [38].
  • Transforming growth factor-beta signal transducer SMAD2 but not SMAD1 moved from the cytoplasm to the nucleus after TGF-beta stimulation [39].
  • The results of the screen and subsequent co-immunoprecipitation studies identified Smad2 and Smad3, two transcriptional activators that mediate the type beta transforming growth factor (TGF-beta) response, as Ski-interacting proteins [40].
  • Performing electrophoretic mobility shift assay and cotransfection experiments, we were able to delineate DNA-binding complexes and identified Smad3, Smad4, and Smad2 [41].


  1. Allelic analysis of serous ovarian carcinoma reveals two putative tumor suppressor loci at 18q22-q23 distal to SMAD4, SMAD2, and DCC. Lassus, H., Salovaara, R., Aaltonen, L.A., Butzow, R. Am. J. Pathol. (2001) [Pubmed]
  2. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4. Qiu, W., Sch??nleben, F., Li, X., Su, G.H. Cancer Lett. (2007) [Pubmed]
  3. 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]
  4. Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Xie, W., Mertens, J.C., Reiss, D.J., Rimm, D.L., Camp, R.L., Haffty, B.G., Reiss, M. Cancer Res. (2002) [Pubmed]
  5. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. He, W., Dorn, D.C., Erdjument-Bromage, H., Tempst, P., Moore, M.A., Massagué, J. Cell (2006) [Pubmed]
  6. PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling. Lin, X., Duan, X., Liang, Y.Y., Su, Y., Wrighton, K.H., Long, J., Hu, M., Davis, C.M., Wang, J., Brunicardi, F.C., Shi, Y., Chen, Y.G., Meng, A., Feng, X.H. Cell (2006) [Pubmed]
  7. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Loeys, B.L., Chen, J., Neptune, E.R., Judge, D.P., Podowski, M., Holm, T., Meyers, J., Leitch, C.C., Katsanis, N., Sharifi, N., Xu, F.L., Myers, L.A., Spevak, P.J., Cameron, D.E., De Backer, J., Hellemans, J., Chen, Y., Davis, E.C., Webb, C.L., Kress, W., Coucke, P., Rifkin, D.B., De Paepe, A.M., Dietz, H.C. Nat. Genet. (2005) [Pubmed]
  8. A Smad transcriptional corepressor. Wotton, D., Lo, R.S., Lee, S., Massagué, J. Cell (1999) [Pubmed]
  9. Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Xu, J., Attisano, L. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  10. Inhibition of the effect of high glucose on the expression of Smad in human peritoneal mesothelial cells. Yao, Q., Qian, J.Q., Lin, X.H., Lindholm, B. The International journal of artificial organs. (2004) [Pubmed]
  11. Combination therapy with tranilast and angiotensin-converting enzyme inhibition provides additional renoprotection in the remnant kidney model. Kelly, D.J., Zhang, Y., Cox, A.J., Gilbert, R.E. Kidney Int. (2006) [Pubmed]
  12. Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis. Santiago, B., Gutierrez-Cañas, I., Dotor, J., Palao, G., Lasarte, J.J., Ruiz, J., Prieto, J., Borrás-Cuesta, F., Pablos, J.L. J. Invest. Dermatol. (2005) [Pubmed]
  13. Inhibition of SMAD2 expression prevents murine palatal fusion. Shiomi, N., Cui, X.M., Yamamoto, T., Saito, T., Shuler, C.F. Dev. Dyn. (2006) [Pubmed]
  14. High resolution analysis of chromosome 18 alterations in ulcerative colitis-related colorectal cancer. Terdiman, J.P., Aust, D.E., Chang, C.G., Willenbucher, R.F., Baretton, G.B., Waldman, F.M. Cancer Genet. Cytogenet. (2002) [Pubmed]
  15. Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Mori, Y., Chen, S.J., Varga, J. Arthritis Rheum. (2003) [Pubmed]
  16. Involvement of SMAD4, but not of SMAD2, in transforming growth factor-beta1-induced trophoblast expression of matrix metalloproteinase-2. Lin, H.Y., Yang, Q., Wang, H.M., Qi, J.G., Zhang, H., Wang, H.X., Tsang, B.K., Zhu, C. Front. Biosci. (2006) [Pubmed]
  17. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Lagna, G., Hata, A., Hemmati-Brivanlou, A., Massagué, J. Nature (1996) [Pubmed]
  18. 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]
  19. 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]
  20. Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Hata, A., Lo, R.S., Wotton, D., Lagna, G., Massagué, J. Nature (1997) [Pubmed]
  21. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Wu, J.W., Hu, M., Chai, J., Seoane, J., Huse, M., Li, C., Rigotti, D.J., Kyin, S., Muir, T.W., Fairman, R., Massagué, J., Shi, Y. Mol. Cell (2001) [Pubmed]
  22. Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II. Wicks, S.J., Lui, S., Abdel-Wahab, N., Mason, R.M., Chantry, A. Mol. Cell. Biol. (2000) [Pubmed]
  23. Decorin suppresses transforming growth factor-beta-induced expression of plasminogen activator inhibitor-1 in human mesangial cells through a mechanism that involves Ca2+-dependent phosphorylation of Smad2 at serine-240. Abdel-Wahab, N., Wicks, S.J., Mason, R.M., Chantry, A. Biochem. J. (2002) [Pubmed]
  24. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. Yang, J., Dai, C., Liu, Y. J. Am. Soc. Nephrol. (2005) [Pubmed]
  25. Identification and characterization of constitutively active Smad2 mutants: evaluation of formation of Smad complex and subcellular distribution. Funaba, M., Mathews, L.S. Mol. Endocrinol. (2000) [Pubmed]
  26. The role of internalization in transforming growth factor beta1-induced Smad2 association with Smad anchor for receptor activation (SARA) and Smad2-dependent signaling in human mesangial cells. Runyan, C.E., Schnaper, H.W., Poncelet, A.C. J. Biol. Chem. (2005) [Pubmed]
  27. Roles of pathway-specific and inhibitory Smads in activin receptor signaling. Lebrun, J.J., Takabe, K., Chen, Y., Vale, W. Mol. Endocrinol. (1999) [Pubmed]
  28. Characterization of human FAST-1, a TGF beta and activin signal transducer. Zhou, S., Zawel, L., Lengauer, C., Kinzler, K.W., Vogelstein, B. Mol. Cell (1998) [Pubmed]
  29. Inhibition of the transforming growth factor-beta/Smad signaling pathway in the epithelium of oral lichen. Karatsaidis, A., Schreurs, O., Axéll, T., Helgeland, K., Schenck, K. J. Invest. Dermatol. (2003) [Pubmed]
  30. 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]
  31. Semisynthesis of phosphovariants of Smad2 reveals a substrate preference of the activated T beta RI kinase. Ottesen, J.J., Huse, M., Sekedat, M.D., Muir, T.W. Biochemistry (2004) [Pubmed]
  32. The autocrine effect of activin A on human ovarian clear cell adenocarcinoma cells. Mabuchi, Y., Yamoto, M., Minami, S., Umesaki, N. Oncol. Rep. (2006) [Pubmed]
  33. Modulation of the TGFbeta/Smad signaling pathway in mesangial cells by CTGF/CCN2. Wahab, N.A., Weston, B.S., Mason, R.M. Exp. Cell Res. (2005) [Pubmed]
  34. Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. Lin, X., Liang, M., Feng, X.H. J. Biol. Chem. (2000) [Pubmed]
  35. TGF beta-induced focal complex formation in epithelial cells is mediated by activated ERK and JNK MAP kinases and is independent of Smad4. Imamichi, Y., Waidmann, O., Hein, R., Eleftheriou, P., Giehl, K., Menke, A. Biol. Chem. (2005) [Pubmed]
  36. c-Jun interacts with the corepressor TG-interacting factor (TGIF) to suppress Smad2 transcriptional activity. Pessah, M., Prunier, C., Marais, J., Ferrand, N., Mazars, A., Lallemand, F., Gauthier, J.M., Atfi, A. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  37. SMAD7 is a prognostic marker in patients with colorectal cancer. Boulay, J.L., Mild, G., Lowy, A., Reuter, J., Lagrange, M., Terracciano, L., Laffer, U., Herrmann, R., Rochlitz, C. Int. J. Cancer (2003) [Pubmed]
  38. 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]
  39. Regulation mechanisms of retinal pigment epithelial cell migration by the TGF-beta superfamily. Mitsuhiro, M.R., Eguchi, S., Yamashita, H. Acta ophthalmologica Scandinavica. (2003) [Pubmed]
  40. Ski acts as a co-repressor with Smad2 and Smad3 to regulate the response to type beta transforming growth factor. Xu, W., Angelis, K., Danielpour, D., Haddad, M.M., Bischof, O., Campisi, J., Stavnezer, E., Medrano, E.E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  41. Participation of Smad2, Smad3, and Smad4 in transforming growth factor beta (TGF-beta)-induced activation of Smad7. THE TGF-beta response element of the promoter requires functional Smad binding element and E-box sequences for transcriptional regulation. Stopa, M., Anhuf, D., Terstegen, L., Gatsios, P., Gressner, A.M., Dooley, S. J. Biol. Chem. (2000) [Pubmed]
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