Disease relevance of CDH2

• The present study was carried out to investigate the functional significance of N-cadherin in melanoma cells [1].
• In the present study, E- and N-cadherin, members of the classical cadherin family, are investigated as inducers of epithelial-to-mesenchymal transition (EMT) that is thought to play a fundamental role during the early steps of invasion and metastasis of carcinomas [2].
• The purpose of the study presented here was to investigate whether a gain in N-cadherin in pancreatic cancer is involved in the process of metastasis via EMT and whether its expression is affected by growth factors [2].
• This is reflected by the higher concentrations of soluble N-cadherin in prostate cancer patients than in healthy persons [3].
• The overexpression of N-cad in uterine leiomyomas suggests that this CAM may play a central role in the development of uterine leiomyomas [4].

Psychiatry related information on CDH2

• Presenilin 1 (PS1) is linked to the pathogenesis of early onset familial Alzheimer's disease (FAD) and is localized at the synapse, where it binds N-cadherin and modulates its adhesive activity [5].
• Also, unrelated Caucasian North American patients with bipolar I affective disorder were screened for the B33 and N-cadherin genes (n = 49 and 63, respectively) [6].

High impact information on CDH2

• In this issue of Cell, Marambaud et al. report that PS-1 cleaves the cell adhesion molecule N-cadherin, releasing a C-terminal fragment that promotes degradation of the transcriptional coactivator CBP [7].
• However, the expression of other components of this cascade (Nodal and Lefty) was unchanged after blocking N-cadherin function, suggesting the existence of parallel pathways in the establishment of left-right morphogenesis [8].
• N-Cadherin, a cell adhesion molecule involved in establishment of embryonic left-right asymmetry [8].
• Blocking N-cadherin function randomizes heart looping and alters the expression of Snail and Pitx2, later components of the molecular cascade that regulate left-right asymmetry [8].
• To identify ligands regulating this process, we studied N-cadherin and Ng-CAM/8D9 expression in HVC, a neurogenic region of the canary neostriatum [9].

Chemical compound and disease context of CDH2

• High expression of N-cadherin and alpha5 integrin subunit seems to be associated with the most invasive melanoma phenotype [10].
• Expression of E-cadherin and N-cadherin was examined by immunohistochemistry in 80 colon carcinomas by using paraffin embedded and formalin fixed tissues [11].
• To study the effects of N-cadherin expression on invasion and metastasis in vitro and in vivo, we overexpressed N-cadherin in the rat C6 glioma cell line which normally has low levels of N-cadherin [12].
• Together, the data suggest a novel role for tyrosine phosphorylation of N-cadherin by Src family kinases in the regulation of beta-catenin association during transendothelial migration of melanoma cells [13].
• We analyzed the expression of five cell-surface glycoprotein substrates of GnT-V, matriptase, beta1-integrin, epidermal growth factor receptor, lamp-1, and N-cadherin, on a tissue microarray cohort of 670 breast carcinomas with 30-year follow-up [14].

Biological context of CDH2

• We found that a 69-amino acid portion of EC-4 of N-cadherin was necessary and sufficient to promote both an epithelial to mesenchymal transition in squamous epithelial cells and increased cell motility [15].
• Blocking of N-cadherin-mediated intercellular interaction by N-cadherin-specific antibodies increased the number of cells undergoing apoptosis [1].
• During the process of malignant transformation, nascent melanoma cells escape keratinocyte control through down-regulation of E-cadherin and instead communicate among themselves and with fibroblasts via N-cadherin-based cell-cell contacts [16].
• Classical cadherins such as E-, P- and N-cadherin are transmembrane proteins that mediate cell-cell adhesion, and are important in embryogenesis, maintenance of tissue integrity and cancer [3].
• Genistein-induced neuronal differentiation is associated with activation of extracellular signal-regulated kinases and upregulation of p21 and N-cadherin [17].

Anatomical context of CDH2

• Finally, we have used a transient assay to demonstrate the induction of CDH2 and TGM2 by RASSF1A in NSCLC cell lines [18].
• Differential localization of VE- and N-cadherins in human endothelial cells: VE-cadherin competes with N-cadherin for junctional localization [19].
• Despite similar level of protein expression only VE-cadherin is located at cell-cell contacts, whereas N-cadherin is distributed over the whole cell membrane [19].
• Cotransfection of VE-cadherin and N-cadherin in CHO cells resulted in the same distribution as that observed in endothelial cells indicating that the behavior of the two cadherins was not cell specific but related to their structural characteristics [19].
• Together, these results indicate that the cadherin subtype switching from E- to N-cadherin during melanoma development not only frees melanocytic cells from the control by keratinocytes but also provides growth and possibly metastatic advantages to melanoma cells [1].

Associations of CDH2 with chemical compounds

• The method presented here should prove useful for the further investigation of the N-cadherin expression and function in several disease conditions on formalin-fixed, paraffin-embedded archival tissues [20].
• On the other hand, at the transcriptional level, the addition of actinomycin D abolished the cAMP-mediated decrease in N-cadherin mRNA but did not change its stability [21].
• Gonadotropins regulate N-cadherin-mediated human ovarian surface epithelial cell survival at both post-translational and transcriptional levels through a cyclic AMP/protein kinase A pathway [21].
• In contrast, monoclonal antibodies directed against the extracellular domain of N-cadherin, the alphavbeta3 integrin, and PECAM-1 failed to inhibit capillary tube formation [22].
• The src-family tyrosine kinase inhibitor PP1 also blocked rhFGF-2-promoted N-cadherin expression [23].

Physical interactions of CDH2

• A truncated mutant of VE-cadherin retaining the full extracellular domain and a short cytoplasmic tail (Arg621-Pro702) lacking the catenin-binding region was able to exclude N-cadherin from junctions [19].
• Moreover, we show that alpha-actinin coimmunoprecipitates with the N-cadherin/catenin complex in an actin-independent manner [24].
• Increased cell surface N-cadherin in the disease cells in turn stabilized the continued plasma membrane localization of beta-catenin in the absence of E-cadherin [25].
• Overall, the results indicate that E- and N-cadherin assemble stoichiometrically different complexes with p120 in the same cells [26].
• AP-1 transcription factor complex is a target of signals from both WnT-7a and N-cadherin-dependent cell-cell adhesion complex during the regulation of limb mesenchymal chondrogenesis [27].

Co-localisations of CDH2

• Immunostaining experiments revealed that for all the cell types PS1 is present at the plasma membrane and co-localizes with N-cadherin, a component of the cell-cell adhesion complex [28].
• MOCA colocalizes with N-cadherin and actin in areas of cell-cell and cell substratum contact and is expressed in neuronal processes [29].

Regulatory relationships of CDH2

• A decapeptide containing the HAV motif of human N-cad partially inhibited Ca2+-dependent cell-cell adhesion and completely prevented BMP-2-induced stimulation of alkaline phosphatase activity by BMCs [30].
• These results indicate that Sp1/Sp3 and MZF1 are important transcription factors regulating N-cadherin promoter activity and expression in osteoblasts [31].
• These results suggest that protection of the FGFR-1 from ligand-induced downregulation by N-cadherin enhances receptor signaling and provides a mechanism by which tumor cells can acquire metastatic properties [32].
• E-, P-, and N-cadherin are co-expressed in the nasopharyngeal carcinoma cell line TW-039 [33].
• As a result of complex mechanisms of tissue selectivity, N-cadherin is expressed by the developing pleural mesothelial cells and E-cadherin is expressed by the epithelial cells of the lung [34].

Other interactions of CDH2

• PS1 concentrates at intercellular contacts in epithelial tissue; in brain, it forms complexes with both E- and N-cadherin and concentrates at synaptic adhesions [35].
• Our present study was designed to determine which domains of N-cadherin make it different from E-cadherin, with respect to altering cellular behavior, such as which domains are responsible for the epithelial to mesenchymal transition and increased cell motility and invasion [15].
• Up-regulated expression of zonula occludens protein-1 in human melanoma associates with N-cadherin and contributes to invasion and adhesion [16].
• Likewise, N-cad mRNA did not change during BMP-2 incubation [30].
• RT-PCR analysis showed that human osteoblastic cells express MZF1 and that Sp1/MZF1 overexpression increased N-cadherin expression [31].

Analytical, diagnostic and therapeutic context of CDH2

• Immunofluorescence and co-immunoprecipitation studies showed co-localization of ZO-1 with N-cadherin [16].
• The expression of CD44 variant isoforms, beta-catenin, E, P and N-cadherin were evaluated by immunohistochemistry [36].
• N-cadherin immunofluorescence was detected at cell membranous adherents junctions where co-localization with immunofluorescent staining of inner surface adhesion proteins alpha- and beta-catenins was observed [37].
• Flow cytometry indicated abundant expression of E-cadherin but marginal P- and N-cadherin in cultured melanocytes [38].
• On the other hand, Western blot analyses of six tumors showed that the secreted form was strongly expressed, and furthermore, expression of N-cadherin was extremely low [39].

References