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Gene Review

CDH1  -  cadherin 1, type 1, E-cadherin (epithelial)

Homo sapiens

Synonyms: Arc-1, CAM 120/80, CD324, CDHE, Cadherin-1, ...


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Disease relevance of CDH1

  • We screened a series of 66 young gastric cancer probands for germline CDH1 mutations, and two novel missense alterations together with an intronic variant were identified [1].
  • We study the expression and functional correlation of SNAIL, CDH1, VDR and ZEB1 genes and examine their possible involvement in colon cancer [2].
  • We observed a correlation between downregulation of: a) ZEB1 and presence of polyps in surgical resections; b) VDR and poor differentiation and c) CDH1 and poor differentiation, vascular invasion, presence of lymph node metastases and advanced stages; as well as a trend toward a correlation between SNAIL expression in tumors and vascular invasion [2].
  • Finally, allelic imbalances at 8p11.21 and 16q22.1 (CDH1) were significantly more frequent in stage IV metastatic thymomas [3].
  • More recently, mutations in CDH1 have been described in colorectal cancer cell lines [4].
  • No somatic mutations in E-cadherin were identified in noncohesive pancreatic cancers having inactivated E-cadherin [5].

Psychiatry related information on CDH1


High impact information on CDH1

  • Receptor-induced Rac activity causes translocation of p190RhoGAP to adherens junctions (AJs), where it couples to the cadherin complex via interaction with p120 [11].
  • Integration of receptor tyrosine kinase, integrin, and cadherin activities is crucial for normal cell growth, motility, and adhesion [11].
  • Moreover, perturbation of motor neuron segregation with chimeric cadherins depends on EC1 domain identity, suggesting that this region, which includes the structurally defined adhesive interface, encodes type II cadherin functional specificity in vivo [12].
  • Hence, we investigated whether RNA-dependent DNA methylation might operate in human cancers to mediate epigenetic silencing using the endogenous gene CDH1 as a potential target [13].
  • Ectopic expression of Twist results in loss of E-cadherin-mediated cell-cell adhesion, activation of mesenchymal markers, and induction of cell motility, suggesting that Twist contributes to metastasis by promoting an epithelial-mesenchymal transition (EMT) [14].

Chemical compound and disease context of CDH1


Biological context of CDH1


Anatomical context of CDH1


Associations of CDH1 with chemical compounds

  • In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus [22].
  • That PS1 is a constituent of the cadherin/catenin complex makes that complex a potential target for PS1 FAD mutations [26].
  • In addition to their essential role in modulating cadherin adhesivity, catenins have more recently been indicated to participate in cell and developmental signaling pathways. beta-Catenin, for example, associates directly with at least two receptor tyrosine kinases and transduces developmental signals within the Wnt pathway [27].
  • Li+, a GSK3 beta inhibitor, led to E-cadherin induction in an inositol-independent manner [28].
  • In particular, after addition of cisplatin relatively rapid (within 3 h) re-localization of adherens junction proteins from the cell periphery to the cytoplasm was observed whereas little cadherin or catenin degradation occurred until 10 h [29].
  • The effect of Cdh1 siRNA on anaphase spindle dynamics requires Aurora A, and its effect can be mimicked by nondegradable Aurora kinase [30].
  • Our results indicate that the CaR regulates cell survival and Ca(2+)(o)-induced differentiation in keratinocytes at least in part by activating the E-cadherin/PI3K pathway through a Src family tyrosine kinase-mediated signaling [31].

Physical interactions of CDH1

  • Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts [26].
  • p120-catenin stabilizes epithelial cadherin (E-cadherin) in SW48 cells, but the mechanism has not been established [32].
  • IGFs can enhance cell migration, which is known to be influenced via regulation of the E-cadherin/beta-catenin complex [33].
  • Our results may have important therapeutic implications for the treatment of invasive human lung carcinomas via the restoration of the cadherin/catenin complex using inhibitors of EGF-R [34].
  • This appears to be due to the existence of a large pool of cytosolic beta-catenin in SW480 cells that is refractory to both cadherin binding and TCF binding [35].

Enzymatic interactions of CDH1


Co-localisations of CDH1


Regulatory relationships of CDH1

  • UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells [44].
  • This study provides evidence that RB activates bcl-2 and E-cadherin by binding directly to the respective promoter sequences and not indirectly by repressing an inhibitor [45].
  • beta-Catenin is an ubiquitously expressed cytoplasmic protein that has a crucial role in both cadherin-mediated cell-cell adhesion and as a downstream signaling molecule in the wingless/Wnt pathway [46].
  • Pretreatment of tumor cells with a VEGFR-1 blocking antibody inhibited the VEGFR-1-induced immunohistochemical and molecular changes in E-cadherin [47].
  • Recent studies reveal that IQGAP1 regulates cadherin-mediated cell-cell adhesion both positively and negatively [48].
  • E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a beta-catenin-dependent mechanism [49].
  • Our experiments further revealed that interaction of human KLRG1 to E-cadherin was susceptible to these tumor-associated mutations and that KLRG1(+) NK cells were triggered more easily by K562 target cells carrying these mutations in comparison to target cells expressing wild-type E-cadherin [50].
  • CDH1 has antisense Alu elements in its 3'UTR region, making it susceptible to the regulation of other protein-coding RNAs with sense Alu elements, and Pol-III transcribed Alus [51].

Other interactions of CDH1


Analytical, diagnostic and therapeutic context of CDH1


  1. Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. Suriano, G., Oliveira, C., Ferreira, P., Machado, J.C., Bordin, M.C., De Wever, O., Bruyneel, E.A., Moguilevsky, N., Grehan, N., Porter, T.R., Richards, F.M., Hruban, R.H., Roviello, F., Huntsman, D., Mareel, M., Carneiro, F., Caldas, C., Seruca, R. Hum. Mol. Genet. (2003) [Pubmed]
  2. E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Peña, C., García, J.M., Silva, J., García, V., Rodríguez, R., Alonso, I., Millán, I., Salas, C., de Herreros, A.G., Muñoz, A., Bonilla, F. Hum. Mol. Genet. (2005) [Pubmed]
  3. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Inoue, M., Starostik, P., Zettl, A., Ströbel, P., Schwarz, S., Scaravilli, F., Henry, K., Willcox, N., Müller-Hermelink, H.K., Marx, A. Cancer Res. (2003) [Pubmed]
  4. The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea. Kim, H.C., Wheeler, J.M., Kim, J.C., Ilyas, M., Beck, N.E., Kim, B.S., Park, K.C., Bodmer, W.F. Gut (2000) [Pubmed]
  5. Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Winter, J.M., Ting, A.H., Vilardell, F., Gallmeier, E., Baylin, S.B., Hruban, R.H., Kern, S.E., Iacobuzio-Donahue, C.A. Clin. Cancer Res. (2008) [Pubmed]
  6. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. Marambaud, P., Shioi, J., Serban, G., Georgakopoulos, A., Sarner, S., Nagy, V., Baki, L., Wen, P., Efthimiopoulos, S., Shao, Z., Wisniewski, T., Robakis, N.K. EMBO J. (2002) [Pubmed]
  7. Patterns of gene promoter methylation in squamous cell cancer of the head and neck. Hasegawa, M., Nelson, H.H., Peters, E., Ringstrom, E., Posner, M., Kelsey, K.T. Oncogene (2002) [Pubmed]
  8. Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Lasorella, A., Stegmüller, J., Guardavaccaro, D., Liu, G., Carro, M.S., Rothschild, G., de la Torre-Ubieta, L., Pagano, M., Bonni, A., Iavarone, A. Nature (2006) [Pubmed]
  9. Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele. Blair, I.P., Chetcuti, A.F., Badenhop, R.F., Scimone, A., Moses, M.J., Adams, L.J., Craddock, N., Green, E., Kirov, G., Owen, M.J., Kwok, J.B., Donald, J.A., Mitchell, P.B., Schofield, P.R. Mol. Psychiatry (2006) [Pubmed]
  10. Mutational analysis of the neuronal cadherin gene CELSR1 and exclusion as a candidate for catatonic schizophrenia in a large family. Gross, J., Grimm, O., Ortega, G., Teuber, I., Lesch, K.P., Meyer, J. Psychiatr. Genet. (2001) [Pubmed]
  11. p120-Catenin and p190RhoGAP Regulate Cell-Cell Adhesion by Coordinating Antagonism between Rac and Rho. Wildenberg, G.A., Dohn, M.R., Carnahan, R.H., Davis, M.A., Lobdell, N.A., Settleman, J., Reynolds, A.B. Cell (2006) [Pubmed]
  12. Type II cadherin ectodomain structures: implications for classical cadherin specificity. Patel, S.D., Ciatto, C., Chen, C.P., Bahna, F., Rajebhosale, M., Arkus, N., Schieren, I., Jessell, T.M., Honig, B., Price, S.R., Shapiro, L. Cell (2006) [Pubmed]
  13. Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation. Ting, A.H., Schuebel, K.E., Herman, J.G., Baylin, S.B. Nat. Genet. (2005) [Pubmed]
  14. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Yang, J., Mani, S.A., Donaher, J.L., Ramaswamy, S., Itzykson, R.A., Come, C., Savagner, P., Gitelman, I., Richardson, A., Weinberg, R.A. Cell (2004) [Pubmed]
  15. CDH1 germline mutation in hereditary gastric carcinoma. Wang, H.D., Ren, J., Zhang, L. World J. Gastroenterol. (2004) [Pubmed]
  16. CDH1 associated gastric cancer: a report of a family and review of the literature. Moran, C.J., Joyce, M., McAnena, O.J. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. (2005) [Pubmed]
  17. Extracellular calcium and calcium sensing receptor function in human colon carcinomas: promotion of E-cadherin expression and suppression of beta-catenin/TCF activation. Chakrabarty, S., Radjendirane, V., Appelman, H., Varani, J. Cancer Res. (2003) [Pubmed]
  18. Immunolocalization of the fodrin, E-cadherin, and beta-catenin adhesion complex in infiltrating ductal carcinoma of the breast-comparison with an in vitro model. Sormunen, R.T., Leong, A.S., Vääräniemi, J.P., Fernando, S.S., Eskelinen, S.M. J. Pathol. (1999) [Pubmed]
  19. Recovery of cellular E-cadherin precedes replenishment of estrogen receptor and estrogen-dependent proliferation of breast cancer cells rescued from a death stimulus. Malaguti, C., Rossini, G.P. J. Cell. Physiol. (2002) [Pubmed]
  20. The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Fang, G., Yu, H., Kirschner, M.W. Genes Dev. (1998) [Pubmed]
  21. E-cadherin missense mutations, associated with hereditary diffuse gastric cancer (HDGC) syndrome, display distinct invasive behaviors and genetic interactions with the Wnt and Notch pathways in Drosophila epithelia. Pereira, P.S., Teixeira, A., Pinho, S., Ferreira, P., Fernandes, J., Oliveira, C., Seruca, R., Suriano, G., Casares, F. Hum. Mol. Genet. (2006) [Pubmed]
  22. Nuclear localization of the cell cycle regulator CDH1 and its regulation by phosphorylation. Zhou, Y., Ching, Y.P., Chun, A.C., Jin, D.Y. J. Biol. Chem. (2003) [Pubmed]
  23. Characterization of a recurrent germ line mutation of the E-cadherin gene: implications for genetic testing and clinical management. Suriano, G., Yew, S., Ferreira, P., Senz, J., Kaurah, P., Ford, J.M., Longacre, T.A., Norton, J.A., Chun, N., Young, S., Oliveira, M.J., Macgillivray, B., Rao, A., Sears, D., Jackson, C.E., Boyd, J., Yee, C., Deters, C., Pai, G.S., Hammond, L.S., McGivern, B.J., Medgyesy, D., Sartz, D., Arun, B., Oelschlager, B.K., Upton, M.P., Neufeld-Kaiser, W., Silva, O.E., Donenberg, T.R., Kooby, D.A., Sharma, S., Jonsson, B.A., Gronberg, H., Gallinger, S., Seruca, R., Lynch, H., Huntsman, D.G. Clin. Cancer Res. (2005) [Pubmed]
  24. E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Lombaerts, M., van Wezel, T., Philippo, K., Dierssen, J.W., Zimmerman, R.M., Oosting, J., van Eijk, R., Eilers, P.H., van de Water, B., Cornelisse, C.J., Cleton-Jansen, A.M. Br. J. Cancer (2006) [Pubmed]
  25. Infiltrating leukocytes confound the detection of E-cadherin promoter methylation in tumors. Lombaerts, M., Middeldorp, J.W., van der Weide, E., Philippo, K., van Wezel, T., Smit, V.T., Cornelisse, C.J., Cleton-Jansen, A.M. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  26. Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Georgakopoulos, A., Marambaud, P., Efthimiopoulos, S., Shioi, J., Cui, W., Li, H.C., Schütte, M., Gordon, R., Holstein, G.R., Martinelli, G., Mehta, P., Friedrich, V.L., Robakis, N.K. Mol. Cell (1999) [Pubmed]
  27. beta-Catenin associates with the actin-bundling protein fascin in a noncadherin complex. Tao, Y.S., Edwards, R.A., Tubb, B., Wang, S., Bryan, J., McCrea, P.D. J. Cell Biol. (1996) [Pubmed]
  28. WNT7a induces E-cadherin in lung cancer cells. Ohira, T., Gemmill, R.M., Ferguson, K., Kusy, S., Roche, J., Brambilla, E., Zeng, C., Baron, A., Bemis, L., Erickson, P., Wilder, E., Rustgi, A., Kitajewski, J., Gabrielson, E., Bremnes, R., Franklin, W., Drabkin, H.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  29. The fate of E- and P-cadherin during the early stages of apoptosis. Schmeiser, K., Grand, R.J. Cell Death Differ. (1999) [Pubmed]
  30. APC/C Cdh1 targets aurora kinase to control reorganization of the mitotic spindle at anaphase. Floyd, S., Pines, J., Lindon, C. Curr. Biol. (2008) [Pubmed]
  31. Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes. Tu, C.L., Chang, W., Xie, Z., Bikle, D.D. J. Biol. Chem. (2008) [Pubmed]
  32. A core function for p120-catenin in cadherin turnover. Davis, M.A., Ireton, R.C., Reynolds, A.B. J. Cell Biol. (2003) [Pubmed]
  33. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Playford, M.P., Bicknell, D., Bodmer, W.F., Macaulay, V.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  34. Regulation of E-cadherin/catenin complex patterns by epidermal growth factor receptor modulation in human lung cancer cells. Al Moustafa, A.E., Yen, L., Benlimame, N., Alaoui-Jamali, M.A. Lung Cancer (2002) [Pubmed]
  35. E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. Gottardi, C.J., Wong, E., Gumbiner, B.M. J. Cell Biol. (2001) [Pubmed]
  36. Sequential changes in cadherin-catenin expression associated with the progression and heterogeneity of primary oesophageal squamous carcinoma. Sanders, D.S., Bruton, R., Darnton, S.J., Casson, A.G., Hanson, I., Williams, H.K., Jankowski, J. Int. J. Cancer (1998) [Pubmed]
  37. Hypermethylation of E-cadherin gene is frequent and independent of p16INK4A methylation in non-small cell lung cancer: potential prognostic implication. Shimamoto, T., Ohyashiki, J.H., Hirano, T., Kato, H., Ohyashiki, K. Oncol. Rep. (2004) [Pubmed]
  38. E-cadherin phosphorylation by protein kinase D1/protein kinase C{mu} is associated with altered cellular aggregation and motility in prostate cancer. Jaggi, M., Rao, P.S., Smith, D.J., Wheelock, M.J., Johnson, K.R., Hemstreet, G.P., Balaji, K.C. Cancer Res. (2005) [Pubmed]
  39. Shigella flexneri regulates tight junction-associated proteins in human intestinal epithelial cells. Sakaguchi, T., Köhler, H., Gu, X., McCormick, B.A., Reinecker, H.C. Cell. Microbiol. (2002) [Pubmed]
  40. Novel membrane protein shrew-1 targets to cadherin-mediated junctions in polarized epithelial cells. Bharti, S., Handrow-Metzmacher, H., Zickenheiner, S., Zeitvogel, A., Baumann, R., Starzinski-Powitz, A. Mol. Biol. Cell (2004) [Pubmed]
  41. Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells. Laprise, P., Viel, A., Rivard, N. J. Biol. Chem. (2004) [Pubmed]
  42. Disruption of adherens junctions liberates nectin-1 to serve as receptor for herpes simplex virus and pseudorabies virus entry. Yoon, M., Spear, P.G. J. Virol. (2002) [Pubmed]
  43. Snail and slug play distinct roles during breast carcinoma progression. C??me, C., Magnino, F., Bibeau, F., De Santa Barbara, P., Becker, K.F., Theillet, C., Savagner, P. Clin. Cancer Res. (2006) [Pubmed]
  44. UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells. Jamal, S., Schneider, R.J. J. Clin. Invest. (2002) [Pubmed]
  45. The retinoblastoma protein binds the promoter of the survival gene bcl-2 and regulates its transcription in epithelial cells through transcription factor AP-2. Decary, S., Decesse, J.T., Ogryzko, V., Reed, J.C., Naguibneva, I., Harel-Bellan, A., Cremisi, C.E. Mol. Cell. Biol. (2002) [Pubmed]
  46. Beta-catenin mutations in biliary tract cancers: a population-based study in China. Rashid, A., Gao, Y.T., Bhakta, S., Shen, M.C., Wang, B.S., Deng, J., Fraumeni, J.F., Hsing, A.W. Cancer Res. (2001) [Pubmed]
  47. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Yang, A.D., Camp, E.R., Fan, F., Shen, L., Gray, M.J., Liu, W., Somcio, R., Bauer, T.W., Wu, Y., Hicklin, D.J., Ellis, L.M. Cancer Res. (2006) [Pubmed]
  48. IQGAP1: a key regulator of adhesion and migration. Noritake, J., Watanabe, T., Sato, K., Wang, S., Kaibuchi, K. J. Cell. Sci. (2005) [Pubmed]
  49. E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. Perrais, M., Chen, X., Perez-Moreno, M., Gumbiner, B.M. Mol. Biol. Cell (2007) [Pubmed]
  50. Tumor-associated E-cadherin mutations affect binding to the killer cell lectin-like receptor G1 in humans. Schwartzkopff, S., Gründemann, C., Schweier, O., Rosshart, S., Karjalainen, K.E., Becker, K.F., Pircher, H. J. Immunol. (2007) [Pubmed]
  51. A gene expression restriction network mediated by sense and antisense Alu sequences located on protein-coding messenger RNAs WikiGenes. Publication
  52. Molecular mechanisms of beta-catenin recognition by adenomatous polyposis coli revealed by the structure of an APC-beta-catenin complex. Eklof Spink, K., Fridman, S.G., Weis, W.I. EMBO J. (2001) [Pubmed]
  53. Rac-dependent cyclin D1 gene expression regulated by cadherin- and integrin-mediated adhesion. Fournier, A.K., Campbell, L.E., Castagnino, P., Liu, W.F., Chung, B.M., Weaver, V.M., Chen, C.S., Assoian, R.K. J. Cell. Sci. (2008) [Pubmed]
  54. CagA associates with c-Met, E-cadherin, and p120-catenin in a multiproteic complex that suppresses Helicobacter pylori-induced cell-invasive phenotype. Oliveira, M.J., Costa, A.M., Costa, A.C., Ferreira, R.M., Sampaio, P., Machado, J.C., Seruca, R., Mareel, M., Figueiredo, C. J. Infect. Dis. (2009) [Pubmed]
  55. Association of E-cadherin germ-line alterations with prostate cancer. Ikonen, T., Matikainen, M., Mononen, N., Hyytinen, E.R., Helin, H.J., Tommola, S., Tammela, T.L., Pukkala, E., Schleutker, J., Kallioniemi, O.P., Koivisto, P.A. Clin. Cancer Res. (2001) [Pubmed]
  56. Prognostic analysis of E-cadherin gene promoter hypermethylation in patients with surgically resected, node-positive, diffuse gastric cancer. Graziano, F., Arduini, F., Ruzzo, A., Bearzi, I., Humar, B., More, H., Silva, R., Muretto, P., Guilford, P., Testa, E., Mari, D., Magnani, M., Cascinu, S. Clin. Cancer Res. (2004) [Pubmed]
  57. CDH1 c-160a promotor polymorphism is not associated with risk of stomach cancer. Pharoah, P.D., Oliveira, C., Machado, J.C., Keller, G., Vogelsang, H., Laux, H., Becker, K.F., Hahn, H., Paproski, S.M., Brown, L.A., Caldas, C., Huntsman, D. Int. J. Cancer (2002) [Pubmed]
  58. E-cadherin expression in sporadic gastric cancer from Mexico: exon 8 and 9 deletions are infrequent events associated with poor survival. Gamboa-Dominguez, A., Dominguez-Fonseca, C., Chavarri-Guerra, Y., Vargas, R., Reyes-Gutierrez, E., Green, D., Quintanilla-Martinez, L., Luber, B., Busch, R., Becker, K.F., Becker, I., Höfler, H., Fend, F. Hum. Pathol. (2005) [Pubmed]
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