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

• Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, controls a gamma-secretase-like cleavage of E-cadherin [6].
• In order to study the association of tumor suppressor gene promoter methylation in HNSCC with patient clinical characteristics, especially alcohol consumption and tobacco smoking, we examined promoter methylation of the p16(INK4a), DAP-kinase, E-Cadherin, and RASSF1A genes using methylation-specific PCR (MSP) in 80 patients [7].
• Depletion of Cdh1 stabilizes Id proteins in neurons, whereas Id2 D-box mutants are impaired for Cdh1 binding and remain stable in cells that exit from the cell cycle and contain active APC/C(Cdh1) [8].
• Positional cloning, association analysis and expression studies provide convergent evidence that the cadherin gene FAT contains a bipolar disorder susceptibility allele [9].
• Mutational analysis of the neuronal cadherin gene CELSR1 and exclusion as a candidate for catatonic schizophrenia in a large family [10].

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

• E-cadherin, a product of CDH1 gene, belonging to the functionally related trans-membrane glycoprotein family, is responsible for the Ca(2+)-dependent cell-cell adhesion mechanism and contributes to dissociation followed by acquisition of cell motility, which usually occurs in the first step of cancer invasion and metastasis [15].
• METHODS: A search was conducted of Medline and the National Library of Medicine to identify key articles concerning CDH1 gene mutations, familial gastric cancer and gastrectomy [16].
• In addition, the promotion of E-cadherin and suppression of beta-catenin/T cell factor may be an important mechanism underlying the chemopreventive action of Ca(2+) in colon cancer [17].
• Membranous localization of E-cadherin showed a positive correlation with oestrogen and progesterone expression, whereas loss of membranous E-cadherin and cytoplasmic accumulation of fodrin was more often observed in high-grade carcinomas and showed a positive correlation with p53 expression [18].
• Loss of estrogen-responsiveness and impaired E-cadherin expression/function has been linked to increased metastatic potential of breast cancer cells [19].

Biological context of CDH1

• Activation of the anaphase-promoting complex (APC) by binding of CDC20 and CDH1 is required for exit from mitosis, and APC has been implicated as a target for the checkpoint intervention [20].
• SNAIL expression was associated with downregulation of CDH1 (P < 0.001) and VDR (P < 0.001) gene products [2].
• Germline mutations in the human E-cadherin (hEcad) gene, CDH1, are initiating events in cases of human hereditary diffuse gastric cancer (HDGC) indicating that hEcad is a tumor suppressor [21].
• E-cadherin (CDH1) gene expression is strictly regulated [2].
• Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands [1].

Anatomical context of CDH1

• CDH1 localizes dynamically to the nucleus during interphase and to the centrosome during metaphase and anaphase [22].
• RESULTS: We identified eight inactivating and one missense CDH1 germ line mutation [23].
• Three non-tumorigenic mammary cell lines derived from normal breast epithelium also showed CDH1 promoter methylation, a fibroblastic phenotype and expression profile [24].
• Since in normal breast tissue no CDH1 promoter methylation is detected, infiltrating leukocytes, often present in tumors, might account for these methylation-specific fragments [25].
• In MDCK cells, presenilin-1 (PS1) accumulates at intercellular contacts where it colocalizes with components of the cadherin-based adherens junctions [26].

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

• Beta catenin may be phosphorylated with implied loss of cadherin binding [36].
• In contrast, NSCLC patients with hypermethylated p16INK4a but un-methylated E-cadherin gene (discordant pattern) had a significantly poor prognosis [37].
• In vitro kinase assays have shown that PKD1 phosphorylates E-cadherin [38].
• S. flexneri serotype 2a and 5, but not the non-invasive Escherichia coli strain F-18, share the ability to regulate expression of ZO-1, ZO-2, E-cadherin and to dephosphorylate occludin [39].

Co-localisations of CDH1

• Interestingly, shrew-1 was partially translocated in response to scatter factor (ligand of receptor tyrosine kinase c-met) from the plasma membrane to the cytoplasm where it still colocalized with endogenous E-cadherin [40].
• 1) hDlg co-localizes with E-cadherin, but not with ZO-1, at the sites of cell-cell contact in intestinal epithelial cells [41].
• Our study shows that PKD1 colocalizes with E-cadherin at cell junctions in LNCaP prostate cancer cells and coimmunoprecipitates with E-cadherin from lysates of LNCaP cells [38].
• Nectin-1 colocalizes with E-cadherin at adherens junctions in epithelial cells [42].
• RESULTS: In contrast with transformed cell lines, Slug was found to colocalize with E-cadherin at the cellular level in normal mammary epithelial cells and all tested carcinomas [43].

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

• PS1 fragments form complexes with E-cadherin, beta-catenin, and alpha-catenin, all components of adherens junctions [26].
• Together, these data show that PS1 incorporates into the cadherin/catenin adhesion system and regulates cell-cell adhesion [26].
• Downregulation of E-cadherin by ET-1/ET(B) involves the downstream activation of caspase-8 but not of distal, executioner caspases, and does not lead to apoptosis [44].
• Although it lacks significant sequence homology, the N-terminal half of the repeat binds in a manner similar to portions of E-cadherin and XTcf3, but the remaining interactions are unique to APC [52].
• A core function for p120-catenin in cadherin turnover [32].
• We show that the increased expression of cyclin D1 mRNA associated with E-cadherin-dependent cell-cell adhesion is causally linked to an increased entry into S phase [53].
• E-cadherin was sufficient to suppress not only H. pylori-mediated cell-invasive phenotype but also c-Met and p120-catenin tyrosine phosphorylation [54].

Analytical, diagnostic and therapeutic context of CDH1

• No truncating or splice site CDH1 mutations were identified by PCR single-strand conformational polymorphism in these families or in eight individual patients who had both prostate and gastric cancer [55].
• CDH1 promoter hypermethylation retained its prognostic role for disease-free survival (P < 0.001) and overall survival (P < 0.001) in multivariate analysis [56].
• Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing [23].
• We have combined data from case control studies designed to test the hypothesis that the c-160a promotor polymorphism in the gene coding for the cell adhesion molecule E-cadherin (CDH1) is associated with stomach cancer [57].
• Immunohistochemistry against wild-type E-cadherin (clone 36) and against 2 mutation-specific antibodies (MSA) recognizing mutant CDH1 lacking exon-8 (del 8) or exon-9 (del 9) were performed [58].

References