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Gene Review

SMAD4  -  SMAD family member 4

Homo sapiens

Synonyms: DPC4, Deletion target in pancreatic carcinoma 4, JIP, MAD homolog 4, MADH4, ...
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Disease relevance of SMAD4


Psychiatry related information on SMAD4

  • Reciprocally, both full-length wild-type and familial Alzheimer's disease mutant APPs were precipitated by PID-containing JIP constructs [7].

High impact information on SMAD4


Chemical compound and disease context of SMAD4


Biological context of SMAD4

  • Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN [17].
  • Germline mutations of MADH4 (SMAD4) have been described in a variable number of probands with JPS [18].
  • Maximal transactivation of COL7A1 SBS-driven promoters in either MDA-MB-468 carcinoma cells or fibroblasts requires concomitant overexpression of SMAD3 and SMAD4 [19].
  • Of the 18 MSI(-) cancers with retained SMAD4 expression, four harbored missense mutations in the 3' part of the gene and showed allele loss [2].
  • Fourteen of thirty-two MSI(-) lines showed loss of SMAD4 protein expression; usually, one allele was lost and the other was mutated in one of a number of ways, including deletions of various sizes, splice site changes, and missense and nonsense point mutations (although no frameshifts) [2].

Anatomical context of SMAD4

  • Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology [1].
  • In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age [17].
  • A novel SMAD4 gene mutation in seminoma germ cell tumors [3].
  • Furthermore HA decreased TGF-beta1 activation of a luciferase-SMAD responsive construct, and decreased translocation of SMAD4 into the cell nucleus [20].
  • 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 [21].

Associations of SMAD4 with chemical compounds

  • Using reverse transcription-PCR, single-strand conformational polymorphism, and sequencing analysis, the COOH-terminal domain of SMAD4 was found to be mutated: a single thymine was inserted between nt 1521 and 1522 in 2 of 20 tumors analyzed [3].
  • MATERIALS AND METHOD: The protein expression of SMAD4 was evaluated immunohistochemically in 86 formalin-fixed and paraffin-embedded CRC samples [22].
  • In response to tetracycline, Smad4 expression is effectively silenced [23].
  • Infection with Ad-Smad4 in the presence of TGF-beta1 also resulted in an altered cell morphology that coincided with enhanced beta1 integrin expression and reduced efficiency of colony formation in soft agar [24].
  • In addition, we showed that the NH2-terminal domain of Smad4 augments ligand-dependent activation associated with the middle-linker region, indicating that there is a distinct ligand-response domain within the N terminus of this molecule [25].

Physical interactions of SMAD4

  • In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes [26].
  • Smad2/3 and Smad4 coimmunoprecipitate only after TGF-beta1 treatment [27].
  • 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 [28].
  • We found that the mutations at Lys-113 and Lys-159 did not alter the ability of Smad4 to form a complex with Smad2 and FAST on the Mix.2 promoter [29].
  • DACH1 inhibits transforming growth factor-beta signaling through binding Smad4 [30].

Enzymatic interactions of SMAD4


Regulatory relationships of SMAD4

  • We report here that, in addition to the previously reported regions/cells, DLX1 is expressed in hematopoietic cells in a lineage-dependent manner and that DLX1 interacts with Smad4 through its homeodomain [32].
  • These results suggest that the abnormalities of TRII and Smad4 play an important role inhibiting TGF-beta signaling in colorectal carcinogenesis [33].
  • Here we describe the involvement of the small ubiquitin-like modifier-1 (SUMO-1) conjugation pathway in regulating the growth inhibitory and transcriptional responses of Smad4 [29].
  • Sumoylation of Smad4 was enhanced by the conjugating enzyme Ubc9 and members of the PIAS family of SUMO ligases [34].
  • Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling pathway from activin A in hematopoietic cells [32].
  • We further determined that Smad4-dependent signaling regulated RON expression at the transcriptional level by real-time reverse transcription PCR and RON promoter luciferase reporter assays [35].

Other interactions of SMAD4

  • 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 [36].
  • Smad4 was found to be constitutively phosphorylated in Mv1Lu cells, the phosphorylation level remaining unchanged upon TGF-beta1 stimulation [37].
  • Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene [26].
  • A series of familial and isolated European probands without MADH4 mutations were analyzed for germline mutations in BMPR1A, a member of the transforming growth-factor beta-receptor superfamily, upstream from the SMAD pathway [18].
  • Yeast 2-hybrid interaction assays reveal the lack of physical interactions between SMAD5beta and SMAD5 or SMAD4 [38].

Analytical, diagnostic and therapeutic context of SMAD4


  1. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Bardeesy, N., Cheng, K.H., Berger, J.H., Chu, G.C., Pahler, J., Olson, P., Hezel, A.F., Horner, J., Lauwers, G.Y., Hanahan, D., Depinho, R.A. Genes Dev. (2006) [Pubmed]
  2. SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway. Woodford-Richens, K.L., Rowan, A.J., Gorman, P., Halford, S., Bicknell, D.C., Wasan, H.S., Roylance, R.R., Bodmer, W.F., Tomlinson, I.P. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. A novel SMAD4 gene mutation in seminoma germ cell tumors. Bouras, M., Tabone, E., Bertholon, J., Sommer, P., Bouvier, R., Droz, J.P., Benahmed, M. Cancer Res. (2000) [Pubmed]
  4. 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]
  5. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Blackford, A., Serrano, O.K., Wolfgang, C.L., Parmigiani, G., Jones, S., Zhang, X., Parsons, D.W., Lin, J.C., Leary, R.J., Eshleman, J.R., Goggins, M., Jaffee, E.M., Iacobuzio-Donahue, C.A., Maitra, A., Cameron, J.L., Olino, K., Schulick, R., Winter, J., Herman, J.M., Laheru, D., Klein, A.P., Vogelstein, B., Kinzler, K.W., Velculescu, V.E., Hruban, R.H. Clin. Cancer Res. (2009) [Pubmed]
  6. SMAD4 immunohistochemistry reflects genetic status in juvenile polyposis syndrome. Langeveld, D., van Hattem, W.A., de Leng, W.W., Morsink, F.H., Ten Kate, F.J., Giardiello, F.M., Offerhaus, G.J., Brosens, L.A. Clin. Cancer Res. (2010) [Pubmed]
  7. c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer's amyloid precursor protein with JNK. Matsuda, S., Yasukawa, T., Homma, Y., Ito, Y., Niikura, T., Hiraki, T., Hirai, S., Ohno, S., Kita, Y., Kawasumi, M., Kouyama, K., Yamamoto, T., Kyriakis, J.M., Nishimoto, I. J. Neurosci. (2001) [Pubmed]
  8. SMAD4-deficient intestinal tumors recruit CCR1(+) myeloid cells that promote invasion. Kitamura, T., Kometani, K., Hashida, H., Matsunaga, A., Miyoshi, H., Hosogi, H., Aoki, M., Oshima, M., Hattori, M., Takabayashi, A., Minato, N., Taketo, M.M. Nat. Genet. (2007) [Pubmed]
  9. 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]
  10. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Dupont, S., Zacchigna, L., Cordenonsi, M., Soligo, S., Adorno, M., Rugge, M., Piccolo, S. Cell (2005) [Pubmed]
  11. A Smad transcriptional corepressor. Wotton, D., Lo, R.S., Lee, S., Massagué, J. Cell (1999) [Pubmed]
  12. 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]
  13. SMAD4 levels and response to 5-fluorouracil in colorectal cancer. Alhopuro, P., Alazzouzi, H., Sammalkorpi, H., Dávalos, V., Salovaara, R., Hemminki, A., Järvinen, H., Mecklin, J.P., Schwartz, S., Aaltonen, L.A., Arango, D. Clin. Cancer Res. (2005) [Pubmed]
  14. Smad4 as a transcription corepressor for estrogen receptor alpha. Wu, L., Wu, Y., Gathings, B., Wan, M., Li, X., Grizzle, W., Liu, Z., Lu, C., Mao, Z., Cao, X. J. Biol. Chem. (2003) [Pubmed]
  15. Loss of Smad4 protein expression occurs infrequently in endometrial carcinomas. Liu, F.S., Chen, J.T., Hsieh, Y.T., Ho, E.S., Hung, M.J., Lu, C.H., Chiou, L.C. Int. J. Gynecol. Pathol. (2003) [Pubmed]
  16. Inhibitory effect of retroviral vector containing anti-sense Smad4 gene on Ito cell line, LI90. Xu, X.B., Leng, X.S., He, Z.P., Liang, Z.Q., Lin, K., Wei, Y.H., Yu, X., Peng, J.R. Chin. Med. J. (2004) [Pubmed]
  17. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. Xu, X., Kobayashi, S., Qiao, W., Li, C., Xiao, C., Radaeva, S., Stiles, B., Wang, R.H., Ohara, N., Yoshino, T., LeRoith, D., Torbenson, M.S., Gores, G.J., Wu, H., Gao, B., Deng, C.X. J. Clin. Invest. (2006) [Pubmed]
  18. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Zhou, X.P., Woodford-Richens, K., Lehtonen, R., Kurose, K., Aldred, M., Hampel, H., Launonen, V., Virta, S., Pilarski, R., Salovaara, R., Bodmer, W.F., Conrad, B.A., Dunlop, M., Hodgson, S.V., Iwama, T., Järvinen, H., Kellokumpu, I., Kim, J.C., Leggett, B., Markie, D., Mecklin, J.P., Neale, K., Phillips, R., Piris, J., Rozen, P., Houlston, R.S., Aaltonen, L.A., Tomlinson, I.P., Eng, C. Am. J. Hum. Genet. (2001) [Pubmed]
  19. 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]
  20. Hyaluronan attenuates transforming growth factor-beta1-mediated signaling in renal proximal tubular epithelial cells. Ito, T., Williams, J.D., Fraser, D., Phillips, A.O. Am. J. Pathol. (2004) [Pubmed]
  21. 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]
  22. SMAD4/DPC4 expression and prognosis in human colorectal cancer. Isaksson-Mettävainio, M., Palmqvist, R., Forssell, J., Stenling, R., Oberg, A. Anticancer Res. (2006) [Pubmed]
  23. Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Levy, L., Hill, C.S. Mol. Cell. Biol. (2005) [Pubmed]
  24. Restoration of transforming growth factor Beta signaling by functional expression of smad4 induces anoikis. Ramachandra, M., Atencio, I., Rahman, A., Vaillancourt, M., Zou, A., Avanzini, J., Wills, K., Bookstein, R., Shabram, P. Cancer Res. (2002) [Pubmed]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4. Lin, X., Liang, M., Liang, Y.Y., Brunicardi, F.C., Melchior, F., Feng, X.H. J. Biol. Chem. (2003) [Pubmed]
  30. DACH1 inhibits transforming growth factor-beta signaling through binding Smad4. Wu, K., Yang, Y., Wang, C., Davoli, M.A., D'Amico, M., Li, A., Cveklova, K., Kozmik, Z., Lisanti, M.P., Russell, R.G., Cvekl, A., Pestell, R.G. J. Biol. Chem. (2003) [Pubmed]
  31. 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]
  32. Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling pathway from activin A in hematopoietic cells. Chiba, S., Takeshita, K., Imai, Y., Kumano, K., Kurokawa, M., Masuda, S., Shimizu, K., Nakamura, S., Ruddle, F.H., Hirai, H. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  33. Mutational analysis of TGF-beta type II receptor, Smad2, Smad3, Smad4, Smad6 and Smad7 genes in colorectal cancer. Fukushima, T., Mashiko, M., Takita, K., Otake, T., Endo, Y., Sekikawa, K., Takenoshita, S. J. Exp. Clin. Cancer Res. (2003) [Pubmed]
  34. Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling. Lee, P.S., Chang, C., Liu, D., Derynck, R. J. Biol. Chem. (2003) [Pubmed]
  35. Smad4-dependent TGF-beta signaling suppresses RON receptor tyrosine kinase-dependent motility and invasion of pancreatic cancer cells. Zhao, S., Ammanamanchi, S., Brattain, M., Cao, L., Thangasamy, A., Wang, J., Freeman, J.W. J. Biol. Chem. (2008) [Pubmed]
  36. Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Hata, A., Lo, R.S., Wotton, D., Lagna, G., Massagué, J. Nature (1997) [Pubmed]
  37. 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]
  38. Differential expression of a novel C-terminally truncated splice form of SMAD5 in hematopoietic stem cells and leukemia. Jiang, Y., Liang, H., Guo, W., Kottickal, L.V., Nagarajan, L. Blood (2000) [Pubmed]
  39. 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]
  40. Different pattern of allelic loss in Epstein-Barr virus-positive gastric cancer with emphasis on the p53 tumor suppressor pathway. van Rees, B.P., Caspers, E., zur Hausen, A., van den Brule, A., Drillenburg, P., Weterman, M.A., Offerhaus, G.J. Am. J. Pathol. (2002) [Pubmed]
  41. Up-regulation of transforming growth factor (TGF)-beta receptors by TGF-beta1 in COLO-357 cells. Kleeff, J., Korc, M. J. Biol. Chem. (1998) [Pubmed]
  42. Impaired transforming growth factor beta signalling in Barrett's carcinogenesis due to frequent SMAD4 inactivation. Onwuegbusi, B.A., Aitchison, A., Chin, S.F., Kranjac, T., Mills, I., Huang, Y., Lao-Sirieix, P., Caldas, C., Fitzgerald, R.C. Gut (2006) [Pubmed]
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