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Gene Review

Smad2  -  SMAD family member 2

Mus musculus

Synonyms: 7120426M23Rik, MAD homolog 2, Mad-related protein 2, Madh2, Madr2, ...
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Disease relevance of Smad2

  • Compared with sham-operated kidneys, the level of Smad7 protein, but not mRNA, decreased progressively in UUO kidneys, whereas immunoreactivity for nuclear phosphorylated Smad2 and Smad3 and renal fibrosis were inversely increased [1].
  • Compound inactivation of Smad2 in heterozygous Apc mutant mice did not change the total number of intestinal tumors but increased sudden death from intestinal obstruction caused by extremely large tumors [2].
  • Perichondrium was infected with adenoviruses containing dominant-negative forms of Smad2 (Ad-Smad2-3SA) and Smad3 (Ad-Smad3 Delta C) [3].
  • Mice trans-heterozygous for both Smad2 and nodal mutations display a range of phenotypes, including gastrulation defects, complex craniofacial abnormalities such as cyclopia, and defects in left-right patterning, indicating that Smad2 may mediate nodal signalling in these developmental processes [4].
  • Although no mutations were detected in the Smad2 and -4 genes in tumors, proteins of Smad1 through -5 were partially or completely lost in carcinomas [5].

High impact information on Smad2

  • Smad2 function is not required for mesoderm production per se, but, rather unexpectedly, in the absence of Smad2 the entire epiblast adopts a mesodermal fate giving rise to a normal yolk sac and fetal blood cells [6].
  • Smad2 signals serve to restrict the site of primitive streak formation and establish anterior-posterior identity within the epiblast [6].
  • In contrast, Smad2 mutants entirely lack tissues of the embryonic germ layers [6].
  • Moreover, Nodal signals from the epiblast also pattern the visceral endoderm by activating the Smad2-dependent pathway required for specification of anterior identity in overlying epiblast cells [7].
  • About 20 per cent of Smad2 heterozygous embryos have severe gastrulation defects and lack mandibles or eyes, indicating that the gene dosage of Smad2 is critical for signalling [4].

Chemical compound and disease context of Smad2

  • DOX-induced active TGF-beta1 protein and nuclear Smad2 were restricted to cancer cells, suggesting a causal association between autocrine TGF-beta and increased metastases [8].
  • Ang II stimulation caused more prominent cardiac fibrosis in ARKO mice than in WT mice with enhanced expression of types I and III collagen and transforming growth factor-beta1 genes and with increased Smad2 activation [9].
  • Although this activation was most prominent at 24 h after KA administration in neurons, Smad2P immunoreactivity gradually increased in astrocytes and microglial cells at 3 and 5 days, consistent with reactive gliosis [10].
  • Further, the robust induction of tubulointerstitial fibrosis without increase in activated Smad 2 levels in obstructed beta6(-/-) mice by Ang II suggests the existence of a TGF-beta1-independent pathway of induction of fibrosis through angiotensin [11].

Biological context of Smad2


Anatomical context of Smad2

  • Moreover, introducing a human Smad3 cDNA into the mouse Smad2 locus similarly rescues anterior-posterior patterning and definitive endoderm formation and results in adult viability [15].
  • Homozygous Smad2 mutant mice died around E8.5 with impaired visceral endoderm function and deficiency of mesoderm formation [2].
  • Smad2-dependent signals arising in the extraembryonic tissues of early mouse embryos serve to restrict the site of primitive streak formation and establish anteroposterior identity in the epiblast [13].
  • Our data suggest that Gdf11 and Smad2 regulate islet cell differentiation in parallel to the Notch pathway, which previously has been shown to control development of NGN3+ cells [16].
  • Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts [17].

Associations of Smad2 with chemical compounds

  • These results show that Smad2 signaling is a sensitive marker of neuronal activation and CNS injury that can be used to monitor KA-induced neuronal degeneration [10].
  • We therefore used an experimental model of ovalbumin-induced allergic airway inflammation and were able to demonstrate a dramatic increase in the numbers of bronchial epithelial, alveolar, and infiltrating inflammatory cells expressing nuclear phosphorylated Smad2 within the allergen-challenged lungs [18].
  • Importantly, in bleomycin-injected skin, fibroblasts showed predominantly nuclear localization of Smad3 and intense staining for phospho-Smad2/3 [19].
  • During pre-implantation period, Smad2 hybridization signals were accumulated in the luminal and glandular epithelium at a basal level; Smad4 mRNA appeared in the epithelium with a little variation in hybridization signal intensity [14].
  • In amifostine-treated marrows, smad 2/3 and smad4 were not detected in the nucleus but were positive in the cytoplasm of megakaryocytes 10 days after irradiation [20].

Physical interactions of Smad2


Enzymatic interactions of Smad2

  • Neither TGFbeta-dependent nor endogenously phosphorylated Smad2/3 was detectable in comparable amounts in transdifferentiated MFB, indicating loss of TGFbeta sensitivity [22].
  • Endogenous Smad pathway was activated in the obstructed kidney after UUO in wild-type mice as judged by the increase of phosphorylated Smad2 or phosphorylated Smad2/3-positive cells in renal interstitial area [23].

Regulatory relationships of Smad2


Other interactions of Smad2

  • Antisense oligodeoxynucleotides were designed to attenuate Smad3 and Smad2 gene expression in embryonic (E11) mouse lungs over 4 days in culture [27].
  • After implantation, on day 5 of pregnancy, Smad2 signals were localized to the subluminal stroma surrounding the implanting blastocyst, and Smad4 mRNA were accumulated in the decidua near the luminal epithelium [14].
  • Previously, we excluded Smad4 and Smad2 as candidates for Par2 based on the lack of functional polymorphism(s) and differential expression in lungs from A/J and BALB/c mice [28].
  • These findings suggest that the two FYVE domain proteins, Hgs and SARA, are prerequisites for receptor-mediated activation of Smad2 [29].
  • These experiments provide the first evidence that TGFbeta signaling pathways are required for specification of the definitive endoderm lineage in mammals and identify Smad2 as a key mediator that directs epiblast derivatives towards an endodermal as opposed to a mesodermal fate [13].
  • This acetylation event is required for the ability of Smad2 to mediate activin and TGFbeta signaling [30].

Analytical, diagnostic and therapeutic context of Smad2


  1. Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., Hishida, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. Compound disruption of smad2 accelerates malignant progression of intestinal tumors in apc knockout mice. Hamamoto, T., Beppu, H., Okada, H., Kawabata, M., Kitamura, T., Miyazono, K., Kato, M. Cancer Res. (2002) [Pubmed]
  3. Unique and redundant roles of Smad3 in TGF-beta-mediated regulation of long bone development in organ culture. Alvarez, J., Serra, R. Dev. Dyn. (2004) [Pubmed]
  4. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nomura, M., Li, E. Nature (1998) [Pubmed]
  5. Smads mediate signaling of the TGFbeta superfamily in normal keratinocytes but are lost during skin chemical carcinogenesis. He, W., Cao, T., Smith, D.A., Myers, T.E., Wang, X.J. Oncogene (2001) [Pubmed]
  6. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Waldrip, W.R., Bikoff, E.K., Hoodless, P.A., Wrana, J.L., Robertson, E.J. Cell (1998) [Pubmed]
  7. Nodal signalling in the epiblast patterns the early mouse embryo. Brennan, J., Lu, C.C., Norris, D.P., Rodriguez, T.A., Beddington, R.S., Robertson, E.J. Nature (2001) [Pubmed]
  8. Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors. Muraoka-Cook, R.S., Kurokawa, H., Koh, Y., Forbes, J.T., Roebuck, L.R., Barcellos-Hoff, M.H., Moody, S.E., Chodosh, L.A., Arteaga, C.L. Cancer Res. (2004) [Pubmed]
  9. Androgen receptor gene knockout male mice exhibit impaired cardiac growth and exacerbation of angiotensin II-induced cardiac fibrosis. Ikeda, Y., Aihara, K., Sato, T., Akaike, M., Yoshizumi, M., Suzaki, Y., Izawa, Y., Fujimura, M., Hashizume, S., Kato, M., Yagi, S., Tamaki, T., Kawano, H., Matsumoto, T., Azuma, H., Kato, S., Matsumoto, T. J. Biol. Chem. (2005) [Pubmed]
  10. Bioluminescence imaging of Smad signaling in living mice shows correlation with excitotoxic neurodegeneration. Luo, J., Lin, A.H., Masliah, E., Wyss-Coray, T. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  11. Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice. Ma, L.J., Yang, H., Gaspert, A., Carlesso, G., Barty, M.M., Davidson, J.M., Sheppard, D., Fogo, A.B. Am. J. Pathol. (2003) [Pubmed]
  12. Itch E3 ligase-mediated regulation of TGF-beta signaling by modulating smad2 phosphorylation. Bai, Y., Yang, C., Hu, K., Elly, C., Liu, Y.C. Mol. Cell (2004) [Pubmed]
  13. Formation of the definitive endoderm in mouse is a Smad2-dependent process. Tremblay, K.D., Hoodless, P.A., Bikoff, E.K., Robertson, E.J. Development (2000) [Pubmed]
  14. Expression of Smad2 and Smad4 in mouse uterus during the oestrous cycle and early pregnancy. Liu, G., Lin, H., Zhang, X., Li, Q., Wang, H., Qian, D., Ni, J., Zhu, C. Placenta (2004) [Pubmed]
  15. Mice exclusively expressing the short isoform of Smad2 develop normally and are viable and fertile. Dunn, N.R., Koonce, C.H., Anderson, D.C., Islam, A., Bikoff, E.K., Robertson, E.J. Genes Dev. (2005) [Pubmed]
  16. GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Harmon, E.B., Apelqvist, A.A., Smart, N.G., Gu, X., Osborne, D.H., Kim, S.K. Development (2004) [Pubmed]
  17. Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. Piek, E., Ju, W.J., Heyer, J., Escalante-Alcalde, D., Stewart, C.L., Weinstein, M., Deng, C., Kucherlapati, R., Bottinger, E.P., Roberts, A.B. J. Biol. Chem. (2001) [Pubmed]
  18. Activation of the TGF-beta/activin-Smad2 pathway during allergic airway inflammation. Rosendahl, A., Checchin, D., Fehniger, T.E., ten Dijke, P., Heldin, C.H., Sideras, P. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  19. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. Takagawa, S., Lakos, G., Mori, Y., Yamamoto, T., Nishioka, K., Varga, J. J. Invest. Dermatol. (2003) [Pubmed]
  20. Amifostine does not prevent activation of TGFbeta1 but induces smad 7 activation in megakaryocytes irradiated in vivo. Segreto, H.R., Ferreira, A.T., Kimura, E.T., Franco, M., Egami, M.I., Silva, M.R., Segreto, R.A. Am. J. Hematol. (2002) [Pubmed]
  21. A novel Xenopus Smad-interacting forkhead transcription factor (XFast-3) cooperates with XFast-1 in regulating gastrulation movements. Howell, M., Inman, G.J., Hill, C.S. Development (2002) [Pubmed]
  22. Transforming growth factor beta signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myofibroblasts. TGFbeta signal transduction during transdifferentiation of hepatic stellate cells. Dooley, S., Delvoux, B., Streckert, M., Bonzel, L., Stopa, M., ten Dijke, P., Gressner, A.M. FEBS Lett. (2001) [Pubmed]
  23. Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction. Inazaki, K., Kanamaru, Y., Kojima, Y., Sueyoshi, N., Okumura, K., Kaneko, K., Yamashiro, Y., Ogawa, H., Nakao, A. Kidney Int. (2004) [Pubmed]
  24. Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Ju, W., Ogawa, A., Heyer, J., Nierhof, D., Yu, L., Kucherlapati, R., Shafritz, D.A., Böttinger, E.P. Mol. Cell. Biol. (2006) [Pubmed]
  25. Transforming growth factor-beta stimulates vascular endothelial growth factor production by folliculostellate pituitary cells. Renner, U., Lohrer, P., Schaaf, L., Feirer, M., Schmitt, K., Onofri, C., Arzt, E., Stalla, G.K. Endocrinology (2002) [Pubmed]
  26. A novel mesoderm inducer, Madr2, functions in the activin signal transduction pathway. Baker, J.C., Harland, R.M. Genes Dev. (1996) [Pubmed]
  27. Abrogation of Smad3 and Smad2 or of Smad4 gene expression positively regulates murine embryonic lung branching morphogenesis in culture. Zhao, J., Lee, M., Smith, S., Warburton, D. Dev. Biol. (1998) [Pubmed]
  28. Fine mapping and characterization of candidate lung tumor resistance genes for the Par2 locus on mouse chromosome 18. Zhang, Z., Lin, L., Liu, G., Wang, M., Hill, J., Wang, Y., You, M., Devereux, T.R. Exp. Lung Res. (2000) [Pubmed]
  29. Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA. Miura, S., Takeshita, T., Asao, H., Kimura, Y., Murata, K., Sasaki, Y., Hanai, J.I., Beppu, H., Tsukazaki, T., Wrana, J.L., Miyazono, K., Sugamura, K. Mol. Cell. Biol. (2000) [Pubmed]
  30. Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor beta response. Tu, A.W., Luo, K. J. Biol. Chem. (2007) [Pubmed]
  31. Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. Goumans, M.J., Mummery, C. Int. J. Dev. Biol. (2000) [Pubmed]
  32. Reduced transforming growth factor-beta signaling in cartilage of old mice: role in impaired repair capacity. Blaney Davidson, E.N., Scharstuhl, A., Vitters, E.L., van der Kraan, P.M., van den Berg, W.B. Arthritis Res. Ther. (2005) [Pubmed]
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