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Gene Review

SMAD1  -  SMAD family member 1

Homo sapiens

Synonyms: BSP-1, BSP1, JV4-1, JV41, MAD homolog 1, ...
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Disease relevance of SMAD1

  • SMAD signaling may be a mechanism contributing to the characteristic phenotype of scleroderma fibroblasts and playing a role in the pathogenesis of fibrosis [1].
  • These results suggest that TGF-beta production by melanoma cells not only affects the tumor environment but also directly contributes to tumor cell aggressiveness through autocrine activation of Smad signaling [2].
  • In Smad4-deficient breast cancer cells, TGF-beta failed to modulate Smad expression, suggesting that SMADs mediate their own regulation in response to ligand [3].
  • Molecular analyses of the 15q and 18q SMAD genes in pancreatic cancer [4].
  • Expression of Smad proteins in human colorectal cancer [5].

Psychiatry related information on SMAD1

  • Given that a nuclear localization is required to regulate the transcription of TGF-beta target genes to afford neuroprotection, the ectopic localization of phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of TGF-beta in Alzheimer's disease and consequent loss of neuroprotective function [6].

High impact information on SMAD1

  • Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors [7].
  • This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners [7].
  • E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression [8].
  • Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners [8].
  • The type I receptor and Smad proteins that are required in vivo for Müllerian duct regression have not yet been identified [9].

Chemical compound and disease context of SMAD1


Biological context of SMAD1

  • TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus [15].
  • How distinct Smad complexes regulate specific gene expression is not fully understood [16].
  • By 2 hours, TGF-beta induces a marked increase in SnoN expression, resulting in termination of Smad-mediated transactivation [17].
  • Smad proteins mediate transforming growth factor-beta (TGF-beta) signaling to regulate cell growth and differentiation [17].
  • Bioinformatic analysis of the promoter region of these genes reveals diverse configurations of Smad and FoxO binding elements, implying differences in the regulatory properties of this group of genes [18].

Anatomical context of SMAD1

  • Surprisingly, oocytes did not activate the SMAD1/5/8 pathway in transfected GCs although exogenous BMP6 did [19].
  • In conclusion, myricetin increased BMP-2 synthesis, and subsequently activated SMAD1/5/8 and p38 MAPK, and this effect may contribute to its action on the induction of osteoblast maturation and differentiation, followed by an increase of bone mass [20].
  • We report here that DPC4 is essential for the function of Smad1 and Smad2 in pathways that signal mesoderm induction and patterning in Xenopus embryos, as well as antimitogenic and transcriptional responses in breast epithelial cells [21].
  • Transforming growth factor-beta (TGFbeta) regulates the activation state of the endothelium via two opposing type I receptor/Smad pathways [22].
  • To delineate the organization of the TGF-beta response in human keratinocytes, we defined the set of genes whose activation by TGF-beta requires both FoxO and Smad functions [18].

Associations of SMAD1 with chemical compounds

  • Induction of differentiation by myricetin is associated with increased activation of SMAD1/5/8 and p38 mitogen-activated protein kinases [20].
  • Whereas mutations in the C domain disrupt the effector function of the Smad proteins, N-domain arginine mutations inhibit SMAD signalling through a gain of autoinhibitory function [23].
  • As a direct physiological substrate of BMP receptors, Smad1 provides a link between receptor serine/threonine kinases and the nucleus [24].
  • 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 [25].
  • Smad proteins are a family of highly conserved, intracellular proteins that signal cellular responses downstream of transforming growth factor-beta (TGF-beta) family serine/threonine kinase receptors [26].
  • This study suggests that SSc patients with activated Smad1 signaling may benefit from imatinib mesylate treatment [27].

Physical interactions of SMAD1

  • The carboxyl terminus of SNIP1 interacts with Smad1 and Smad2 in yeast two-hybrid as well as in mammalian overexpression systems [28].
  • Consistent with the observation that CHIP induces Smad1 degradation, we further show that the expression of CHIP can inhibit the transcriptional activities of the Smad1/Smad4 complex induced by BMP signals [29].
  • Smad was identified as a component of the CAGACA-binding transcription complex in TGF-beta-treated fibroblasts by antibody supershifting [30].
  • The importance of Smad binding to the CAGACA box of COL1A2 was further established by transcriptional decoy oligonucleotide competition [31].
  • Moreover, when expressed in chicken embryo fibroblasts, mutant Ski or SnoN defective in binding to the Smad proteins failed to induce oncogenic transformation [32].

Enzymatic interactions of SMAD1

  • Members of the SMAD family of intracellular proteins are phosphorylated by TGF-beta receptors and convey signals to specific TGF-beta-inducible genes [3].
  • Smad1 was phosphorylated and underwent nuclear translocation in normal OSE and OC cells upon treatment with BMP4 [33].
  • We investigated the mechanism of phosphorylation-induced Smad complex formation with an activating pseudo-phosphorylated Smad3 [34].
  • Protein Serine/Threonine Phosphatase PPM1A Dephosphorylates Smad1 in the Bone Morphogenetic Protein Signaling Pathway [35].

Regulatory relationships of SMAD1

  • TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300 [36].
  • Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation [37].
  • c-Ski and SnoN are transcriptional co-repressors that inhibit transforming growth factor-beta signaling through interaction with Smad proteins [38].
  • HIPK2 efficiently inhibited Smad1/4-induced transcription from the Smad site-containing promoter [39].
  • In fibroblasts, TGFbeta signals through the activin receptor-like kinase 5 (ALK-5) type I TGFbeta and triggers Smad and MAP kinase signaling pathways [40].
  • Disruption of microtubule networks by nocodazole activates Mps1 and promotes TGF-beta-independent activation of Smad signaling [41].

Other interactions of SMAD1

  • Microinjection of Smad1 messenger RNA into Xenopus embryo animal caps mimics the mesoderm-ventralizing effects of BMP4 [42].
  • Smads regulate transcription of defined genes in response to TGF-beta receptor activation, although the mechanisms of Smad-mediated transcription are not well understood [43].
  • Binding of both TFE3 and the Smad proteins to their cognate sequences is indispensable for TGF-beta-inducible activation of the PE2 promoter [44].
  • Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase [37].
  • MDM2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins [45].

Analytical, diagnostic and therapeutic context of SMAD1


  1. Expression and regulation of intracellular SMAD signaling in scleroderma skin fibroblasts. Mori, Y., Chen, S.J., Varga, J. Arthritis Rheum. (2003) [Pubmed]
  2. Stable overexpression of Smad7 in human melanoma cells inhibits their tumorigenicity in vitro and in vivo. Javelaud, D., Delmas, V., Möller, M., Sextius, P., André, J., Menashi, S., Larue, L., Mauviel, A. Oncogene (2005) [Pubmed]
  3. Modulation of endogenous Smad expression in normal skin fibroblasts by transforming growth factor-beta. Mori, Y., Chen, S.J., Varga, J. Exp. Cell Res. (2000) [Pubmed]
  4. 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]
  5. Expression of Smad proteins in human colorectal cancer. Korchynskyi, O., Landström, M., Stoika, R., Funa, K., Heldin, C.H., ten Dijke, P., Souchelnytskyi, S. Int. J. Cancer (1999) [Pubmed]
  6. Ectopic expression of phospho-Smad2 in Alzheimer's disease: Uncoupling of the transforming growth factor-beta pathway? Lee, H.G., Ueda, M., Zhu, X., Perry, G., Smith, M.A. J. Neurosci. Res. (2006) [Pubmed]
  7. TGF-beta signal transduction. Massagué, J. Annu. Rev. Biochem. (1998) [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. Requirement of Bmpr1a for Müllerian duct regression during male sexual development. Jamin, S.P., Arango, N.A., Mishina, Y., Hanks, M.C., Behringer, R.R. Nat. Genet. (2002) [Pubmed]
  10. Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. Phan, T.T., Lim, I.J., Chan, S.Y., Tan, E.K., Lee, S.T., Longaker, M.T. The Journal of trauma. (2004) [Pubmed]
  11. Changes in Smad expression and subcellular localization in bleomycin-induced pulmonary fibrosis. Venkatesan, N., Pini, L., Ludwig, M.S. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  12. Transforming growth factor-beta and Smad signalling in kidney diseases. Wang, W., Koka, V., Lan, H.Y. Nephrology (Carlton, Vic.) (2005) [Pubmed]
  13. AGEs activate mesangial TGF-beta-Smad signaling via an angiotensin II type I receptor interaction. Fukami, K., Ueda, S., Yamagishi, S., Kato, S., Inagaki, Y., Takeuchi, M., Motomiya, Y., Bucala, R., Iida, S., Tamaki, K., Imaizumi, T., Cooper, M.E., Okuda, S. Kidney Int. (2004) [Pubmed]
  14. Rebamipide inhibits gastric cancer cell growth. Tanigawa, T., Pai, R., Arakawa, T., Tarnawski, A.S. Dig. Dis. Sci. (2007) [Pubmed]
  15. Mammalian twisted gastrulation is essential for skeleto-lymphogenesis. Nosaka, T., Morita, S., Kitamura, H., Nakajima, H., Shibata, F., Morikawa, Y., Kataoka, Y., Ebihara, Y., Kawashima, T., Itoh, T., Ozaki, K., Senba, E., Tsuji, K., Makishima, F., Yoshida, N., Kitamura, T. Mol. Cell. Biol. (2003) [Pubmed]
  16. A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Kato, Y., Habas, R., Katsuyama, Y., Näär, A.M., He, X. Nature (2002) [Pubmed]
  17. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein. Stroschein, S.L., Wang, W., Zhou, S., Zhou, Q., Luo, K. Science (1999) [Pubmed]
  18. A FoxO-Smad synexpression group in human keratinocytes. Gomis, R.R., Alarcón, C., He, W., Wang, Q., Seoane, J., Lash, A., Massagué, J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation. Gilchrist, R.B., Ritter, L.J., Myllymaa, S., Kaivo-Oja, N., Dragovic, R.A., Hickey, T.E., Ritvos, O., Mottershead, D.G. J. Cell. Sci. (2006) [Pubmed]
  20. Myricetin induces human osteoblast differentiation through bone morphogenetic protein-2/p38 mitogen-activated protein kinase pathway. Hsu, Y.L., Chang, J.K., Tsai, C.H., Chien, T.T., Kuo, P.L. Biochem. Pharmacol. (2007) [Pubmed]
  21. Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Lagna, G., Hata, A., Hemmati-Brivanlou, A., Massagué, J. Nature (1996) [Pubmed]
  22. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Goumans, M.J., Valdimarsdottir, G., Itoh, S., Lebrin, F., Larsson, J., Mummery, C., Karlsson, S., ten Dijke, P. Mol. Cell (2003) [Pubmed]
  23. Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Hata, A., Lo, R.S., Wotton, D., Lagna, G., Massagué, J. Nature (1997) [Pubmed]
  24. The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Kretzschmar, M., Liu, F., Hata, A., Doody, J., Massagué, J. Genes Dev. (1997) [Pubmed]
  25. 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]
  26. Characterization of functional domains within Smad4/DPC4. de Caestecker, M.P., Hemmati, P., Larisch-Bloch, S., Ajmera, R., Roberts, A.B., Lechleider, R.J. J. Biol. Chem. (1997) [Pubmed]
  27. Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate. Pannu, J., Asano, Y., Nakerakanti, S., Smith, E., Jablonska, S., Blaszczyk, M., ten Dijke, P., Trojanowska, M. Arthritis Rheum. (2008) [Pubmed]
  28. A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Kim, R.H., Wang, D., Tsang, M., Martin, J., Huff, C., de Caestecker, M.P., Parks, W.T., Meng, X., Lechleider, R.J., Wang, T., Roberts, A.B. Genes Dev. (2000) [Pubmed]
  29. CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription. Li, L., Xin, H., Xu, X., Huang, M., Zhang, X., Chen, Y., Zhang, S., Fu, X.Y., Chang, Z. Mol. Cell. Biol. (2004) [Pubmed]
  30. Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: involvement of Smad 3. Chen, S.J., Yuan, W., Mori, Y., Levenson, A., Trojanowska, M., Varga, J. J. Invest. Dermatol. (1999) [Pubmed]
  31. Interaction of smad3 with a proximal smad-binding element of the human alpha2(I) procollagen gene promoter required for transcriptional activation by TGF-beta. Chen, S.J., Yuan, W., Lo, S., Trojanowska, M., Varga, J. J. Cell. Physiol. (2000) [Pubmed]
  32. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. He, J., Tegen, S.B., Krawitz, A.R., Martin, G.S., Luo, K. J. Biol. Chem. (2003) [Pubmed]
  33. Identification of a putative autocrine bone morphogenetic protein-signaling pathway in human ovarian surface epithelium and ovarian cancer cells. Shepherd, T.G., Nachtigal, M.W. Endocrinology (2003) [Pubmed]
  34. 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]
  35. Protein Serine/Threonine Phosphatase PPM1A Dephosphorylates Smad1 in the Bone Morphogenetic Protein Signaling Pathway. Duan, X., Liang, Y.Y., Feng, X.H., Lin, X. J. Biol. Chem. (2006) [Pubmed]
  36. TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Janknecht, R., Wells, N.J., Hunter, T. Genes Dev. (1998) [Pubmed]
  37. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Zhang, Y., Chang, C., Gehling, D.J., Hemmati-Brivanlou, A., Derynck, R. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  38. 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]
  39. Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation. Harada, J., Kokura, K., Kanei-Ishii, C., Nomura, T., Khan, M.M., Kim, Y., Ishii, S. J. Biol. Chem. (2003) [Pubmed]
  40. Selective inhibition of activin receptor-like kinase 5 signaling blocks profibrotic transforming growth factor beta responses in skin fibroblasts. Mori, Y., Ishida, W., Bhattacharyya, S., Li, Y., Platanias, L.C., Varga, J. Arthritis Rheum. (2004) [Pubmed]
  41. Activation of Mps1 promotes transforming growth factor-beta-independent Smad signaling. Zhu, S., Wang, W., Clarke, D.C., Liu, X. J. Biol. Chem. (2007) [Pubmed]
  42. A human Mad protein acting as a BMP-regulated transcriptional activator. Liu, F., Hata, A., Baker, J.C., Doody, J., Cárcamo, J., Harland, R.M., Massagué, J. Nature (1996) [Pubmed]
  43. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Feng, X.H., Zhang, Y., Wu, R.Y., Derynck, R. Genes Dev. (1998) [Pubmed]
  44. Synergistic cooperation of TFE3 and smad proteins in TGF-beta-induced transcription of the plasminogen activator inhibitor-1 gene. Hua, X., Liu, X., Ansari, D.O., Lodish, H.F. Genes Dev. (1998) [Pubmed]
  45. MDM2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins. Yam, C.H., Siu, W.Y., Arooz, T., Chiu, C.H., Lau, A., Wang, X.Q., Poon, R.Y. Cancer Res. (1999) [Pubmed]
  46. 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]
  47. 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]
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