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Journal articles on the topic 'Cadherins'
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1
Klingelhofer, J., R. B. Troyanovsky, O. Y. Laur, and S. Troyanovsky. "Amino-terminal domain of classic cadherins determines the specificity of the adhesive interactions." Journal of Cell Science 113, no. 16 (August 15, 2000): 2829–36. http://dx.doi.org/10.1242/jcs.113.16.2829.
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Classic cadherins are transmembrane receptors involved in cell type-specific calcium-dependent intercellular adhesion. The specificity of adhesion is mediated by homophilic interactions between cadherins extending from opposing cell surfaces. In addition, classic cadherins can self-associate forming lateral dimers. Whereas it is widely excepted that lateral dimerization of cadherins is critical for adhesion, details of this process are not known. Yet, no evidence for physical association between different classic cadherins in cells expressing complex cadherin patterns has been reported. To study lateral and adhesive intercadherin interactions, we examined interactions between two classic cadherins, E- and P-cadherins, in epithelial A-431 cells co-producing both proteins. We showed that these cells exhibited heterocomplexes consisting of laterally assembled E- and P-cadherins. These complexes were formed by a mechanism involving Trp(156) of E-cadherin. Removal of calcium ions from the culture medium triggered a novel Trp(156)-independent type of lateral E-cadherin-P-cadherin association. Notably, an antiparallel (adhesive) mode of interaction between these cadherins was negligible. The specificity of adhesive interaction was localized to the amino-terminal (EC1) domain of both cadherins. Thus, EC1 domain of classic cadherins exposes two determinants responsible for nonspecific lateral and cadherin type-specific adhesive dimerization.
2
SHIMOYAMA, Yutaka, Gozoh TSUJIMOTO, Masaki KITAJIMA, and Michiya NATORI. "Identification of three human type-II classic cadherins and frequent heterophilic interactions between different subclasses of type-II classic cadherins." Biochemical Journal 349, no. 1 (June 26, 2000): 159–67. http://dx.doi.org/10.1042/bj3490159.
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We identified three novel human type-II classic cadherins, cadherin-7, -9 and -10, by cDNA cloning and sequencing, and confirmed that they interact with catenins and function in cell-cell adhesion as do other classic cadherins. Cell-cell binding activities of the eight human type-II classic cadherins, including the three new molecules, were evaluated by long-term cell-aggregation experiments using mouse L fibroblast clones transfected with the individual cadherins. The experiments indicated that all the type-II cadherins appeared to possess similar binding strength, which was virtually equivalent to that of E-cadherin. We next examined the binding specificities of the type-II cadherins using the mixed cell-aggregation assay. Although all of the type-II cadherins exhibited binding specificities distinct from that of E-cadherin, heterophilic interactions ranging from incomplete to complete were frequently observed among them. The combinations of cadherin-6 and -9, cadherin-7 and -14, cadherin-8 and -11, and cadherin-9 and -10 interacted in a complete manner, and in particular cadherin-7 and -14, and cadherin-8 and -11 showed an indistinguishable binding specificity against other cadherin subclasses, at least in this assay system. Although these data were obtained from an in vitro study, they should be useful for understanding cadherin-mediated mechanisms of development, morphogenesis and cell-cell interactions in vivo.
3
Suzuki, S. T. "Protocadherins and diversity of the cadherin superfamily." Journal of Cell Science 109, no. 11 (November 1, 1996): 2609–11. http://dx.doi.org/10.1242/jcs.109.11.2609.
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Recent cadherin studies have revealed that many cadherins and cadherin-related proteins are expressed in various tissues of different multicellular organisms. These proteins are characterized by the multiple repeats of the cadherin motif in their extracellular domains. The members of the cadherin superfamily are divided into two groups: classical cadherin type and protocadherin type. The current cadherins appear to have evolved from a protocadherin type. Recent studies have proved the cell adhesion role of classical cadherins in embryogenesis. In contrast, the biological role of protocadherins is elusive. Circumstantial evidence, however, suggests that protocadherins are involved in a variety of cell-cell interactions. Since protocadherins, and many other new cadherins as well, have unique properties, studies of these cadherins may provide insight into the structure and biological role of the cadherin superfamily.
4
Yanagisawa, Masahiro, and Panos Z. Anastasiadis. "p120 catenin is essential for mesenchymal cadherin–mediated regulation of cell motility and invasiveness." Journal of Cell Biology 174, no. 7 (September 18, 2006): 1087–96. http://dx.doi.org/10.1083/jcb.200605022.
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During epithelial tumor progression, the loss of E-cadherin expression and inappropriate expression of mesenchymal cadherins coincide with increased invasiveness. Reexpression experiments have established E-cadherin as an invasion suppressor. However, the mechanism by which E-cadherin suppresses invasiveness and the role of mesenchymal cadherins are poorly understood. We show that both p120 catenin and mesenchymal cadherins are required for the invasiveness of E-cadherin–deficient cells. p120 binding promotes the up-regulation of mesenchymal cadherins and the activation of Rac1, which are essential for cell migration and invasiveness. p120 also promotes invasiveness by inhibiting RhoA activity, independently of cadherin association. Furthermore, association of endogenous p120 with E-cadherin is required for E-cadherin–mediated suppression of invasiveness and is accompanied by a reduction in mesenchymal cadherin levels. The data indicate that p120 acts as a rheostat, promoting a sessile cellular phenotype when associated with E-cadherin or a motile phenotype when associated with mesenchymal cadherins.
5
Suzuki, S., K. Sano, and H. Tanihara. "Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue." Cell Regulation 2, no. 4 (April 1991): 261–70. http://dx.doi.org/10.1091/mbc.2.4.261.
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To examine the diversity of the cadherin family, we isolated cDNAs from brain and retina cDNA preparations with the aid of polymerase chain reaction. The products obtained included cDNAs for two of three known cadherins as well as eight distinct cDNAs, of which deduced amino acid sequences show significant similarity with the known cadherin sequences. Larger cDNA clones were isolated from human cDNA libraries for six of the eight new molecules. The deduced amino acid sequences show that the overall structure of these molecules is very similar to that of the known cadherins, indicating that these molecules are new members of the cadherin family. We have tentatively designated these cadherins as cadherin-4 through -11. The new molecules, with the exception of cadherin-4, exhibit features that distinguish them as a group from previously cloned cadherins; they may belong to a new subfamily of cadherins. Northern blot analysis showed that most of these cadherins are expressed mainly in brain, although some are expressed in other tissues as well. These findings show that the cadherin family of adhesion molecules is much larger than previously thought, and suggest that the new cadherins may play an important role in cell-cell interactions within the central nervous system.
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Vestal, D. J., and B. Ranscht. "Glycosyl phosphatidylinositol--anchored T-cadherin mediates calcium-dependent, homophilic cell adhesion." Journal of Cell Biology 119, no. 2 (October 15, 1992): 451–61. http://dx.doi.org/10.1083/jcb.119.2.451.
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Cadherins are a family of cell adhesion molecules that exhibit calcium-dependent, homophilic binding. Their function depends on both an HisAlaVal sequence in the first extracellular domain, EC1, and the interaction of a conserved cytoplasmic region with intracellular proteins. T-cadherin is an unusual member of the cadherin family that lacks the HisAlaVal motif and is anchored to the membrane through a glycosyl phosphatidylinositol moiety (Ranscht, B., and M. T. Dours-Zimmermann. 1991. Neuron. 7:391-402). To assay the function of T-cadherin in cell adhesion, we have transfected T-cadherin cDNA into CHO cells. Two proteins, mature T-cadherin and the uncleaved T-cadherin precursor, were produced from T-cadherin cDNA. The T-cadherin proteins differed from classical cadherins in several aspects. First, the uncleaved T-cadherin precursor was expressed, together with mature T-cadherin, on the surface of the transfected cells. Second, in the absence of calcium, T-cadherin was more resistant to proteolytic cleavage than other cadherins. Lastly, in contrast to classical cadherins, T-cadherin was not concentrated into cell-cell contacts between transfected cells in monolayer cultures. In cellular aggregation assays, T-cadherin induced calcium-dependent, homophilic adhesion which was abolished by treatment of T-cadherin-transfected cells with phosphatidylinositol-specific phospholipase C. These results demonstrate that T-cadherin is a functional cadherin that differs in several properties from classical cadherins. The function of T-cadherin in homophilic cell recognition implies that the mechanism of T-cadherin-induced adhesion is distinct from that of classical cadherins.
7
Tanihara, H., M. Kido, S. Obata, R. L. Heimark, M. Davidson, T. St John, and S. Suzuki. "Characterization of cadherin-4 and cadherin-5 reveals new aspects of cadherins." Journal of Cell Science 107, no. 6 (June 1, 1994): 1697–704. http://dx.doi.org/10.1242/jcs.107.6.1697.
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Several properties of cadherin-4 and cadherin-5 were characterized by using the cDNA transfection approach. The proteins of both cadherins had a relative molecular mass of about 130 kDa and were present at the cell periphery, especially at cell-cell contact sites. These cadherins were easily digested with trypsin, and Ca2+ protected cadherin-4, but not cadherin-5, from the digestion. In immunoprecipitation, cadherin-4 co-precipitated with two major proteins of 105 kDa and 95 kDa, respectively. The 105 kDa and the 95 kDa proteins are likely to correspond to alpha- and beta-catenins. Cadherin-5 co-precipitated with only one major protein of 95 kDa, but seems to associate with the 105 kDa protein. On the other hand, plakoglobin or gamma-catenin did not co-precipitate well with either cadherin-4 or cadherin-5 in immunoprecipitation, but plakoglobin also appears to associated weakly with these cadherins. Cadherin-4 transfectants aggregated within 30 minutes in a cell aggregation assay, but cadherin-5 transfectants did not aggregate under the same conditions. Furthermore, the transfectants of chimeric cadherin-4 with cadherin-5 cytoplasmic domain showed cell aggregation activity comparable to that of wild-type cadherin-4 transfectants, whereas the transfectants of chimeric cadherin-5 with cadherin-4 cytoplasmic domain did not show appreciable cell aggregation, suggesting that the extracellular domains of cadherins, in conjunction with their cytoplasmic domains, play an important role in cell aggregation activity. These results show that cadherin-4 is very similar to the classical cadherins, whereas cadherin-5 is functionally as well as structurally distinct from classical cadherins.
8
Kreft, Bertolt, Dietmar Berndorff, Anja Böttinger, Silvia Finnemann, Doris Wedlich, Michael Hortsch, Rudolf Tauber, and Reinhard Geßner. "LI-Cadherin–mediated Cell–Cell Adhesion Does Not Require Cytoplasmic Interactions." Journal of Cell Biology 136, no. 5 (March 10, 1997): 1109–21. http://dx.doi.org/10.1083/jcb.136.5.1109.
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The adhesive function of classical cadherins depends on the association with cytoplasmic proteins, termed catenins, which serve as a link between cadherins and the actin cytoskeleton. LI-cadherin, a structurally different member of the cadherin family, mediates Ca2+-dependent cell–cell adhesion, although its markedly short cytoplasmic domain exhibits no homology to this highly conserved region of classical cadherins. We now examined whether the adhesive function of LI-cadherin depends on the interaction with catenins, the actin cytoskeleton or other cytoplasmic components. In contrast to classical cadherins, LI-cadherin, when expressed in mouse L cells, was neither associated with catenins nor did it induce an upregulation of β-catenin. Consistent with these findings, LI-cadherin was not resistant to detergent extraction and did not induce a reorganization of the actin cytoskeleton. However, LI-cadherin was still able to mediate Ca2+dependent cell–cell adhesion. To analyze whether this function requires any interaction with proteins other than catenins, a glycosyl phosphatidylinositol–anchored form of LI-cadherin (LI-cadherinGPI) was constructed and expressed in Drosophila S2 cells. The mutant protein was able to induce Ca2+-dependent, homophilic cell–cell adhesion, and its adhesive properties were indistinguishable from those of wild type LI-cadherin. These findings indicate that the adhesive function of LI-cadherin is independent of any interaction with cytoplasmic components, and consequently should not be sensitive to regulatory mechanisms affecting the binding of classical cadherins to catenins and to the cytoskeleton. Thus, we postulate that the adhesive function of LI-cadherin is complementary to that of coexpressed classical cadherins ensuring cell–cell contacts even under conditions that downregulate the function of classical cadherins.
9
Strale, Pierre-Olivier, Laurence Duchesne, Grégoire Peyret, Lorraine Montel, Thao Nguyen, Evelyn Png, Robert Tampé, et al. "The formation of ordered nanoclusters controls cadherin anchoring to actin and cell–cell contact fluidity." Journal of Cell Biology 210, no. 2 (July 20, 2015): 333–46. http://dx.doi.org/10.1083/jcb.201410111.
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Oligomerization of cadherins could provide the stability to ensure tissue cohesion. Cadherins mediate cell–cell adhesion by forming trans-interactions. They form cis-interactions whose role could be essential to stabilize intercellular junctions by shifting cadherin clusters from a fluid to an ordered phase. However, no evidence has been provided so far for cadherin oligomerization in cellulo and for its impact on cell–cell contact stability. Visualizing single cadherins within cell membrane at a nanometric resolution, we show that E-cadherins arrange in ordered clusters, providing the first demonstration of the existence of oligomeric cadherins at cell–cell contacts. Studying the consequences of the disruption of the cis-interface, we show that it is not essential for adherens junction formation. Its disruption, however, increased the mobility of junctional E-cadherin. This destabilization strongly affected E-cadherin anchoring to actin and cell–cell rearrangement during collective cell migration, indicating that the formation of oligomeric clusters controls the anchoring of cadherin to actin and cell–cell contact fluidity.
10
Takeichi, M. "The cadherins: cell-cell adhesion molecules controlling animal morphogenesis." Development 102, no. 4 (April 1, 1988): 639–55. http://dx.doi.org/10.1242/dev.102.4.639.
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Cadherins are a family of glycoproteins involved in the Ca2+-dependent cell-cell adhesion mechanism which is detected in most kinds of tissues. Inhibition of the cadherin activity with antibodies induces dissociation of cell layers, indicating a fundamental importance of these molecules in maintaining the multicellular structure. Cadherins are divided into subclasses, including E-, N- and P-cadherins. While all subclasses are similar in molecular weight, Ca2+- and protease-sensitivity, each subclass is characterized by a unique tissue distribution pattern and immunological specificity. Analysis of amino acid sequences deduced from cDNA encoding these molecules showed that they are integral membrane proteins of 723–748 amino acids long and share common sequences; similarity in the sequences between subclasses is in a range of 50–60% when compared within a single animal species. L cells, with very little endogenous cadherin activity, transfected with the cadherin cDNA acquired high cadherin-mediated aggregating activity. Their colony morphology was altered by the ectopic expression of cadherins from the dispersed type to the compact type, providing direct evidence for a key role of cadherins in cell-cell adhesion. It has been suggested that cadherins bind cells by their homophilic interactions at the extracellular domain and are associated with actin bundles at the cytoplasmic domain. It appears that each cadherin subclass has binding specificity and this molecular family is involved in selective cell-cell adhesion. In development, the expression of each cadherin subclass is spatiotemporally regulated and associated with a variety of morphogenetic events; e.g. the termination or initiation of expression of a cadherin subclass in a given cell collective is correlated with its segregation from or connection with other cell collectives. Antibodies to cadherins were shown to perturb the morphogenesis of some embryonic organs in vitro. These observations suggest that cadherins play a crucial role in construction of tissues and the whole animal body.
11
Shan, Wei-Song, Hidekazu Tanaka, Greg R. Phillips, Kirsten Arndt, Mika Yoshida, David R. Colman, and Lawrence Shapiro. "Functional Cis-Heterodimers of N- and R-Cadherins." Journal of Cell Biology 148, no. 3 (February 7, 2000): 579–90. http://dx.doi.org/10.1083/jcb.148.3.579.
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Classical cadherins form parallel cis-dimers that emanate from a single cell surface. It is thought that the cis-dimeric form is active in cell–cell adhesion, whereas cadherin monomers are likely to be inactive. Currently, cis-dimers have been shown to exist only between cadherins of the same type. Here, we show the specific formation of cis-heterodimers between N- and R-cadherins. E-cadherin cannot participate in these complexes. Cells coexpressing N- and R-cadherins show homophilic adhesion in which these proteins coassociate at cell–cell interfaces. We performed site- directed mutagenesis studies, the results of which support the strand dimer model for cis-dimerization. Furthermore, we show that when N- and R-cadherins are coexpressed in neurons in vitro, the two cadherins colocalize at certain neural synapses, implying biological relevance for these complexes. The present study provides a novel paradigm for cadherin interaction whereby selective cis-heterodimer formation may generate new functional units to mediate cell–cell adhesion.
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Shewan, Annette M., Madhavi Maddugoda, Astrid Kraemer, Samantha J. Stehbens, Suzie Verma, Eva M. Kovacs, and Alpha S. Yap. "Myosin 2 Is a Key Rho Kinase Target Necessary for the Local Concentration of E-Cadherin at Cell–Cell Contacts." Molecular Biology of the Cell 16, no. 10 (October 2005): 4531–42. http://dx.doi.org/10.1091/mbc.e05-04-0330.
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Classical cadherins accumulate at cell–cell contacts as a characteristic response to productive adhesive ligation. Such local accumulation of cadherins is a developmentally regulated process that supports cell adhesiveness and cell–cell cohesion. Yet the molecular effectors responsible for cadherin accumulation remain incompletely understood. We now report that Myosin 2 is critical for cells to concentrate E-cadherin at cell–cell contacts. Myosin 2 is found at cadherin-based cell–cell contacts and its recruitment requires E-cadherin activity. Indeed, both Myosin 2 recruitment and its activation were stimulated by E-cadherin homophilic ligation alone. Inhibition of Myosin 2 activity by blebbistatin or ML-7 rapidly impaired the ability of cells to concentrate E-cadherin at adhesive contacts, accompanied by decreased cadherin-based cell adhesiveness. The total surface expression of cadherins was unaffected, suggesting that Myosin 2 principally regulates the regional distribution of cadherins at the cell surface. The recruitment of Myosin 2 to cadherin contacts, and its activation, required Rho kinase; furthermore, inhibition of Rho kinase signaling effectively phenocopied the effects of Myosin 2 inhibition. We propose that Myosin 2 is a key effector of Rho-Rho kinase signaling that regulates cell–cell adhesion by determining the ability of cells to concentrate cadherins at contacts in response to homophilic ligation.
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Casal, J. Ignacio, and Rubén A. Bartolomé. "Beyond N-Cadherin, Relevance of Cadherins 5, 6 and 17 in Cancer Progression and Metastasis." International Journal of Molecular Sciences 20, no. 13 (July 9, 2019): 3373. http://dx.doi.org/10.3390/ijms20133373.
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Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and metastasis. Although significant progress has been made in the characterization of multiple members of the cadherin superfamily, most of the published work continues to focus in the switch E-/N-cadherin and its role in the epithelial–mesenchymal transition. Here, we will discuss the structural and functional properties of a subset of cadherins (cadherin 17, cadherin 5 and cadherin 6) that have an RGD motif in the extracellular domains. This RGD motif is critical for the interaction with α2β1 integrin and posterior integrin pathway activation in cancer metastatic cells. However, other signaling pathways seem to be affected by RGD cadherin interactions, as will be discussed. The range of solid tumors with overexpression or “de novo” expression of one or more of these three cadherins is very wide (gastrointestinal, gynaecological and melanoma, among others), underscoring the relevance of these cadherins in cancer metastasis. Finally, we will discuss different evidences that support the therapeutic use of these cadherins by blocking their capacity to work as integrin ligands in order to develop new cures for metastatic patients.
14
Johnson, Kamin J., Sutchin R. Patel, and Kim Boekelheide. "Multiple Cadherin Superfamily Members with Unique Expression Profiles Are Produced in Rat Testis1." Endocrinology 141, no. 2 (February 1, 2000): 675–83. http://dx.doi.org/10.1210/endo.141.2.7334.
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Abstract Adhesion between germ and Sertoli cells is thought to be crucial for spermatogenesis. Cadherin superfamily proteins, including classic cadherins and protocadherins, are important mediators of cell-cell adhesion. Using a degenerate PCR cloning strategy, we surveyed the expression of cadherin superfamily members in rat testis. Similar to brain, testis expressed a large number of cadherin superfamily members: 7 classic cadherins of both types I and II, 14 protocadherins, 2 protocadherin-related cadherins, and 1 cadherin-related receptor-like protein. All three protocadherin families (α, β, and γ) were found in testis. Using a semiquantitative RT-PCR assay, messenger RNA expression was determined for each cadherin superfamily member during a postnatal developmental time-course and following ablation of specific testis cell types by ethanedimethanesulfonate, methoxyacetic acid, and 2,5-hexanedione. Diverse expression patterns were observed among the cadherins, suggesting that cadherin expression is cell type-specific in testis. The large number and variety of cadherin superfamily members found in testis supports a critical function for cadherin-mediated cell-cell adhesion in spermatogenesis.
15
Sisto, Margherita, Domenico Ribatti, and Sabrina Lisi. "Cadherin Signaling in Cancer and Autoimmune Diseases." International Journal of Molecular Sciences 22, no. 24 (December 12, 2021): 13358. http://dx.doi.org/10.3390/ijms222413358.
Full textAbstract:
Cadherins mediate cell–cell adhesion through a dynamic process that is strongly dependent on the cellular context and signaling. Cadherin regulation reflects the interplay between fundamental cellular processes, including morphogenesis, proliferation, programmed cell death, surface organization of receptors, cytoskeletal organization, and cell trafficking. The variety of molecular mechanisms and cellular functions regulated by cadherins suggests that we have only scratched the surface in terms of clarifying the functions mediated by these versatile proteins. Altered cadherins expression is closely connected with tumorigenesis, epithelial–mesenchymal transition (EMT)-dependent fibrosis, and autoimmunity. We review the current understanding of how cadherins contribute to human health and disease, considering the mechanisms of cadherin involvement in diseases progression, as well as the clinical significance of cadherins as therapeutic targets.
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Gray, Michelle E., and Marcos Sotomayor. "Crystal structure of the nonclassical cadherin-17 N-terminus and implications for its adhesive binding mechanism." Acta Crystallographica Section F Structural Biology Communications 77, no. 3 (March 1, 2021): 85–94. http://dx.doi.org/10.1107/s2053230x21002247.
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The cadherin superfamily of calcium-dependent cell-adhesion proteins has over 100 members in the human genome. All members of the superfamily feature at least a pair of extracellular cadherin (EC) repeats with calcium-binding sites in the EC linker region. The EC repeats across family members form distinct complexes that mediate cellular adhesion. For instance, classical cadherins (five EC repeats) strand-swap their N-termini and exchange tryptophan residues in EC1, while the clustered protocadherins (six EC repeats) use an extended antiparallel `forearm handshake' involving repeats EC1–EC4. The 7D-cadherins, cadherin-16 (CDH16) and cadherin-17 (CDH17), are the most similar to classical cadherins and have seven EC repeats, two of which are likely to have arisen from gene duplication of EC1–2 from a classical ancestor. However, CDH16 and CDH17 lack the EC1 tryptophan residue used by classical cadherins to mediate adhesion. The structure of human CDH17 EC1–2 presented here reveals features that are not seen in classical cadherins and that are incompatible with the EC1 strand-swap mechanism for adhesion. Analyses of crystal contacts, predicted glycosylation and disease-related mutations are presented along with sequence alignments suggesting that the novel features in the CDH17 EC1–2 structure are well conserved. These results hint at distinct adhesive properties for 7D-cadherins.
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Dufour, S., J. P. Saint-Jeannet, F. Broders, D. Wedlich, and J. P. Thiery. "Differential perturbations in the morphogenesis of anterior structures induced by overexpression of truncated XB- and N-cadherins in Xenopus embryos." Journal of Cell Biology 127, no. 2 (October 15, 1994): 521–35. http://dx.doi.org/10.1083/jcb.127.2.521.
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Cadherins, a family of Ca-dependent adhesion molecules, have been proposed to act as regulators of morphogenetic processes and to be major effectors in the maintenance of tissue integrity. In this study, we have compared the effects of the expression of two truncated cadherins during early neurogenesis in Xenopus laevis. mRNA encoding deleted forms of XB- and N-cadherin lacking most of the extracellular domain were injected into the four animal dorsal blastomeres of 32-cell stage Xenopus embryos. These truncated cadherins altered the cohesion of cells derived from the injected blastomeres and induced morphogenetic defects in the anterior neural tissue to which they chiefly contributed. Truncated XB-cadherin was more efficient than N-cadherin in inducing these perturbations. Moreover, the coexpression of both truncated cadherins had additive perturbation effects on neural development. The two truncated cadherins can interact with the three known catenins, but with distinct affinities. These results suggest that the adhesive signal mediated by cadherins can be perturbed by overexpressing their cytoplasmic domains by competing with different affinity with catenins and/or a common anchor structure. Therefore, the correct regulation of cadherin function through the cytoplasmic domain appears to be a crucial step in the formation of the neural tissue.
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Berndorff, D., R. Gessner, B. Kreft, N. Schnoy, A. M. Lajous-Petter, N. Loch, W. Reutter, M. Hortsch, and R. Tauber. "Liver-intestine cadherin: molecular cloning and characterization of a novel Ca(2+)-dependent cell adhesion molecule expressed in liver and intestine." Journal of Cell Biology 125, no. 6 (June 15, 1994): 1353–69. http://dx.doi.org/10.1083/jcb.125.6.1353.
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A novel member of the cadherin family of cell adhesion molecules has been characterized by cloning from rat liver, sequencing of the corresponding cDNA, and functional analysis after heterologous expression in nonadhesive S2 cells. cDNA clones were isolated using a polyclonal antibody inhibiting Ca(2+)-dependent intercellular adhesion of hepatoma cells. As inferred from the deduced amino acid sequence, the novel molecule has homologies with E-, P-, and N-cadherins, but differs from these classical cadherins in four characteristics. Its extracellular domain is composed of five homologous repeated domains instead of four characteristic for the classical cadherins. Four of the five domains are characterized by the sequence motifs DXNDN and DXD or modifications thereof representing putative Ca(2+)-binding sites of classical cadherins. In its NH2-terminal region, this cadherin lacks both the precursor segment and the endogenous protease cleavage site RXKR found in classical cadherins. In the extracellular EC1 domain, the novel cadherin contains an AAL sequence in place of the HAV sequence motif representing the common cell adhesion recognition sequence of E-, P-, and N-cadherin. In contrast to the conserved cytoplasmic domain of classical cadherins with a length of 150-160 amino acid residues, that of the novel cadherin has only 18 amino acids. Examination of transfected S2 cells showed that despite these structural differences, this cadherin mediates intercellular adhesion in a Ca(2+)-dependent manner. The novel cadherin is solely expressed in liver and intestine and was, hence, assigned the name LI-cadherin. In these tissues, LI-cadherin is localized to the basolateral domain of hepatocytes and enterocytes. These results suggest that LI-cadherin represents a new cadherin subtype and may have a role in the morphological organization of liver and intestine.
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Jia, Liwei, Fengming Liu, Steen H. Hansen, Martin B. A. ter Beest, and Mirjam M. P. Zegers. "Distinct roles of cadherin-6 and E-cadherin in tubulogenesis and lumen formation." Molecular Biology of the Cell 22, no. 12 (June 15, 2011): 2031–41. http://dx.doi.org/10.1091/mbc.e11-01-0038.
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Classic cadherins are important regulators of tissue morphogenesis. The predominant cadherin in epithelial cells, E-cadherin, has been extensively studied because of its critical role in normal epithelial development and carcinogenesis. Epithelial cells may also coexpress other cadherins, but their roles are less clear. The Madin Darby canine kidney (MDCK) cell line has been a popular mammalian model to investigate the role of E-cadherin in epithelial polarization and tubulogenesis. However, MDCK cells also express relatively high levels of cadherin-6, and it is unclear whether the functions of this cadherin are redundant to those of E-cadherin. We investigate the specific roles of both cadherins using a knockdown approach. Although we find that both cadherins are able to form adherens junctions at the basolateral surface, we show that they have specific and mutually exclusive roles in epithelial morphogenesis. Specifically, we find that cadherin-6 functions as an inhibitor of tubulogenesis, whereas E-cadherin is required for lumen formation. Ablation of cadherin-6 leads to the spontaneous formation of tubules, which depends on increased phosphoinositide 3-kinase (PI3K) activity. In contrast, loss of E-cadherin inhibits lumen formation by a mechanism independent of PI3K.
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Wahl, J. K., P. A. Sacco, T. M. McGranahan-Sadler, L. M. Sauppe, M. J. Wheelock, and K. R. Johnson. "Plakoglobin domains that define its association with the desmosomal cadherins and the classical cadherins: identification of unique and shared domains." Journal of Cell Science 109, no. 5 (May 1, 1996): 1143–54. http://dx.doi.org/10.1242/jcs.109.5.1143.
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Two cell-cell junctions, the adherens junction and the desmosome, are prominent in epithelial cells. These junctions are composed of transmembrane cadherins which interact with cytoplasmic proteins that serve to link the cadherin to the cytoskeleton. One component of both adherens junctions and desmosomes is plakoglobin. In the adherens junction plakoglobin interacts with both the classical cadherin and with alpha-catenin. Alpha-catenin in turn interacts with microfilaments. The role plakoglobin plays in the desmosome is not well understood. Plakoglobin interacts with the desmosomal cadherins, but how and if this mediates interactions with the intermediate filament cytoskeleton is not known. Here we compare the domains of plakoglobin that allow it to associate with the desmosomal cadherins with those involved in interactions with the classical cadherins. We show that three sites on plakoglobin are involved in associations with the desmosomal cadherins. A domain near the N terminus is unique to the desmosomal cadherins and overlaps with the site that interacts with alpha-catenin, suggesting that there may be competition between alpha-catenin and the desmosomal cadherins for interactions with plakoglobin. In addition, a central domain is shared with regions used by plakoglobin to associate with the classical cadherins. Finally, a domain near the C terminus is shown to strongly modulate the interactions with the desmosomal cadherins. This latter domain also contributes to the association of plakoglobin with the classical cadherins.
21
Aladin, Darwesh Mohideen Kaderbatcha, Yeh Shiu Chu, Shuo Shen, Robert Charles Robinson, Sylvie Dufour, Virgile Viasnoff, Nicolas Borghi, and Jean Paul Thiery. "Extracellular domains of E-cadherin determine key mechanical phenotypes of an epithelium through cell- and non-cell-autonomous outside-in signaling." PLOS ONE 16, no. 12 (December 22, 2021): e0260593. http://dx.doi.org/10.1371/journal.pone.0260593.
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Cadherins control intercellular adhesion in most metazoans. In vertebrates, intercellular adhesion differs considerably between cadherins of type-I and type-II, predominantly due to their different extracellular regions. Yet, intercellular adhesion critically depends on actomyosin contractility, in which the role of the cadherin extracellular region is unclear. Here, we dissect the roles of the Extracellular Cadherin (EC) Ig-like domains by expressing chimeric E-cadherin with E-cadherin and cadherin-7 Ig-like domains in cells naturally devoid of cadherins. Using cell-cell separation, cortical tension measurement, tissue stretching and migration assays, we show that distinct EC repeats in the extracellular region of cadherins differentially modulate epithelial sheet integrity, cell-cell separation forces, and cell cortical tension with the Cdc42 pathway, which further differentially regulate epithelial tensile strength, ductility, and ultimately collective migration. Interestingly, dissipative processes rather than static adhesion energy mostly dominate cell-cell separation forces. We provide a framework for the emergence of epithelial phenotypes from cell mechanical properties dependent on EC outside-in signaling.
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Ito, Masayuki, Takuma Maruyama, Naotoshi Saito, Satoru Koganei, Kazuo Yamamoto, and Naoki Matsumoto. "Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity." Journal of Experimental Medicine 203, no. 2 (February 6, 2006): 289–95. http://dx.doi.org/10.1084/jem.20051986.
Full textAbstract:
Killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor expressed on subsets of natural killer (NK) cells and T cells, for which no endogenous ligands are known. Here, we show that KLRG1 binds three of the classical cadherins (E-, N-, and R-), which are ubiquitously expressed in vertebrates and mediate cell–cell adhesion by homotypic or heterotypic interactions. By expression cloning using the mouse KLRG1 tetramer as a probe, we identified human E-cadherin as a xenogeneic ligand. We also identified a syngeneic interaction between mouse KLRG1 and mouse E-cadherin. Furthermore, we show that KLRG1 binds N- and R-cadherins. Finally, we demonstrate that E-cadherin binding of KLRG1 prevents the lysis of E-cadherin–expressing targets by KLRG1+ NK cells. These results suggest that KLRG1 ligation by E-, N-, or R-cadherins may regulate the cytotoxicity of killer cells to prevent damage to tissues expressing the cadherins.
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Tinkle, Christopher L., H. Amalia Pasolli, Nicole Stokes, and Elaine Fuchs. "New insights into cadherin function in epidermal sheet formation and maintenance of tissue integrity." Proceedings of the National Academy of Sciences 105, no. 40 (September 22, 2008): 15405–10. http://dx.doi.org/10.1073/pnas.0807374105.
Full textAbstract:
Co-expression and gene linkage have hampered elucidating the physiological relevance of cadherins in mammalian tissues. Here, we combine conditional gene ablation and transgenic RNA interference to uncover new roles for E- and P-cadherins in epidermal sheet formation in vitro and maintenance of epidermal integrity in vivo. By devising skin-specific RNAi technology, we demonstrate that cadherin inhibition in vivo impairs junction formation and intercellular adhesion and increases apoptosis. These defects compromise epidermal barrier function and tissue integrity. In vitro, with only E-cadherin missing, epidermal sheet formation is delayed, but when both cadherins are suppressed, defects extend to adherens junctions, desmosomes, tight junctions and cortical actin dynamics. Using different rescue strategies, we show that cadherin level rather than subtype is critical. Finally, by comparing conditional loss-of-function studies of epidermal catenins and cadherins, we dissect cadherin-dependent and independent roles of adherens junction components in tissue physiology.
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Nakagawa, S., and M. Takeichi. "Neural crest emigration from the neural tube depends on regulated cadherin expression." Development 125, no. 15 (August 1, 1998): 2963–71. http://dx.doi.org/10.1242/dev.125.15.2963.
Full textAbstract:
During the emergence of neural crest cells from the neural tube, the expression of cadherins dynamically changes. In the chicken embryo, the early neural tube expresses two cadherins, N-cadherin and cadherin-6B (cad6B), in the dorsal-most region where neural crest cells are generated. The expression of these two cadherins is, however, downregulated in the neural crest cells migrating from the neural tube; they instead begin expressing cadherin-7 (cad7). As an attempt to investigate the role of these changes in cadherin expression, we overexpressed various cadherin constructs, including N-cadherin, cad7, and a dominant negative N-cadherin (cN390), in neural crest-generating cells. This was achieved by injecting adenoviral expression vectors encoding these molecules into the lumen of the closing neural tube of chicken embryos at stage 14. In neural tubes injected with the viruses, efficient infection was observed at the neural crest-forming area, resulting in the ectopic cadherin expression also in migrating neural crest cells. Notably, the distribution of neural crest cells with the ectopic cadherins changed depending on which constructs were expressed. Many crest cells failed to escape from the neural tube when N-cadherin or cad7 was overexpressed. Moreover, none of the cells with these ectopic cadherins migrated along the dorsolateral (melanocyte) pathway. When these samples were stained for Mitf, an early melanocyte marker, positive cells were found accumulated within the neural tube, suggesting that the failure of their migration was not due to differentiation defects. In contrast to these phenomena, cells expressing non-functional cadherins exhibited a normal migration pattern. Thus, the overexpression of a neuroepithelial cadherin (N-cadherin) and a crest cadherin (cad7) resulted in the same blocking effect on neural crest segregation from neuroepithelial cells, especially for melanocyte precursors. These findings suggest that the regulation of cadherin expression or its activity at the neural crest-forming area plays a critical role in neural crest emigration from the neural tube.
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Katsunuma, Sayaka, Hisao Honda, Tomoyasu Shinoda, Yukitaka Ishimoto, Takaki Miyata, Hiroshi Kiyonari, Takaya Abe, Ken-ichi Nibu, Yoshimi Takai, and Hideru Togashi. "Synergistic action of nectins and cadherins generates the mosaic cellular pattern of the olfactory epithelium." Journal of Cell Biology 212, no. 5 (February 29, 2016): 561–75. http://dx.doi.org/10.1083/jcb.201509020.
Full textAbstract:
In the olfactory epithelium (OE), olfactory cells (OCs) and supporting cells (SCs), which express different cadherins, are arranged in a characteristic mosaic pattern in which OCs are enclosed by SCs. However, the mechanism underlying this cellular patterning is unclear. Here, we show that the cellular pattern of the OE is established by cellular rearrangements during development. In the OE, OCs express nectin-2 and N-cadherin, and SCs express nectin-2, nectin-3, E-cadherin, and N-cadherin. Heterophilic trans-interaction between nectin-2 on OCs and nectin-3 on SCs preferentially recruits cadherin via α-catenin to heterotypic junctions, and the differential distributions of cadherins between junctions promote cellular intercalations, resulting in the formation of the mosaic pattern. These observations are confirmed by model cell systems, and various cellular patterns are generated by the combinatorial expression of nectins and cadherins. Collectively, the synergistic action of nectins and cadherins generates mosaic pattern, which cannot be achieved by a single mechanism.
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Fagotto, F., N. Funayama, U. Gluck, and B. M. Gumbiner. "Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus." Journal of Cell Biology 132, no. 6 (March 15, 1996): 1105–14. http://dx.doi.org/10.1083/jcb.132.6.1105.
Full textAbstract:
beta-Catenin, a cytoplasmic protein known for its association with cadherin cell adhesion molecules, is also part of a signaling cascade involved in embryonic patterning processes such as the determination of the dorsoventral axis in Xenopus and determination of segment polarity in Drosophila. Previous studies suggest that increased cytoplasmic levels of beta-catenin correlate with signaling, raising questions about the need for in- teraction with cadherins in this process. We have tested the role of the beta-catenin-cadherin interaction in axis formation. Using beta-catenin deletion mutants, we demonstrate that significant binding to cadherins can be eliminated without affecting the signaling activity. Also, depletion of the soluble, cytosolic pool of beta-catenin by binding to overexpressed C-cadherin completely inhibited beta-catenin-inducing activity. We conclude that binding to cadherins is not required for beta-catenin signaling, and therefore the signaling function of beta-catenin is independent of its role in cell adhesion. Moreover, because beta-catenin signaling is antagonized by binding to cadherins, we suggest that cadherins can act as regulators of the intracellular beta-catenin signaling pathway.
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Angst, B. D., C. Marcozzi, and A. I. Magee. "The cadherin superfamily: diversity in form and function." Journal of Cell Science 114, no. 4 (February 15, 2001): 629–41. http://dx.doi.org/10.1242/jcs.114.4.629.
Full textAbstract:
Over recent years cadherins have emerged as a growing superfamily of molecules, and a complex picture of their structure and their biological functions is becoming apparent. Variation in their extracellular region leads to the large potential for recognition properties of this superfamily. This is demonstrated strikingly by the recently discovered FYN-binding CNR-protocadherins; these exhibit alternative expression of the extracellular portion, which could lead to distinct cell recognition in different neuronal populations, whereas their cytoplasmic part, and therefore intracellular interactions, is constant. Diversity in the cytoplasmic moiety of the cadherins imparts specificity to their interactions with cytoplasmic components; for example, classical cadherins interact with catenins and the actin filament network, desmosomal cadherins interact with catenins and the intermediate filament system and CNR-cadherins interact with the SRC-family kinase FYN. Recent evidence suggests that CNR-cadherins, 7TM-cadherins and T-cadherin, which is tethered to the membrane by a GPI anchor, all localise to lipid rafts, specialised cell membrane domains rich in signalling molecules. Originally thought of as cell adhesion molecules, cadherin superfamily molecules are now known to be involved in many biological processes, such as cell recognition, cell signalling, cell communication, morphogenesis, angiogenesis and possibly even neurotransmission.
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Wang, Bowen, Zengqi Tan, and Feng Guan. "Tumor-Derived Exosomes Mediate the Instability of Cadherins and Promote Tumor Progression." International Journal of Molecular Sciences 20, no. 15 (July 26, 2019): 3652. http://dx.doi.org/10.3390/ijms20153652.
Full textAbstract:
Cadherins, including E-cadherin, N-cadherin, VE-cadherin, etc., are important adhesion molecules mediating intercellular junctions. The abnormal expression of cadherins is often associated with tumor development and progression. Epithelial–mesenchymal transition (EMT) is the most important step in the metastasis cascade and is accompanied by altered expression of cadherins. Recent studies reveal that as a cargo for intercellular communication, exosomes—one type of extracellular vesicles that can be secreted by tumor cells—are involved in a variety of physiological and pathological processes, especially in tumor metastasis. Tumor-derived exosomes play a crucial role in mediating the cadherin instability in recipient cells by transferring bioactive molecules (oncogenic microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), EMT-related proteins, and others), modulating their local and distant microenvironment, and facilitating cancer metastasis. In turn, aberrant expression of cadherins in carcinoma cells can also affect the biogenesis and release of exosomes. Therefore, we summarize the current research on the crosstalk between tumor-derived exosomes and aberrant cadherin signals to reveal the unique role of exosomes in cancer progression.
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Niessen, Carien M., and Barry M. Gumbiner. "Cadherin-mediated cell sorting not determined by binding or adhesion specificity." Journal of Cell Biology 156, no. 2 (January 14, 2002): 389–400. http://dx.doi.org/10.1083/jcb.200108040.
Full textAbstract:
Cadherin adhesion molecules play important roles in the establishment of tissue boundaries. Cells expressing different cadherins sort out from each other in cell aggregation assays. To determine the contribution of cadherin binding and adhesion specificity to the sorting process, we examined the adhesion of cells to different purified cadherin proteins. Chinese hamster ovary cell lines expressing one of four different cadherins were allowed to bind to the purified cadherin extracellular domains of either human E-cadherin or Xenopus C-cadherin, and the specificity of adhesion was compared with cell-sorting assays. None of the different cadherin-expressing cells exhibited any adhesive specificity toward either of the two purified cadherin substrates, even though these cadherins differ considerably in their primary sequence. In addition, all cells exhibited similar strengthening of adhesion on both substrates. However, this lack of adhesive specificity did not determine whether different cadherin-expressing cells would sort from each other, and the tendency to sort was not predictable by the extent of sequence diversity in their extracellular domains. These results show that cadherins are far more promiscuous in their adhesive-binding capacity than had been expected and that the ability to sort out must be determined by mechanisms other than simple adhesive-binding specificity.
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Gorski, Jessica A., Lisa L. Gomez, John D. Scott, and Mark L. Dell'Acqua. "Association of an A-Kinase-anchoring Protein Signaling Scaffold with Cadherin Adhesion Molecules in Neurons and Epithelial Cells." Molecular Biology of the Cell 16, no. 8 (August 2005): 3574–90. http://dx.doi.org/10.1091/mbc.e05-02-0134.
Full textAbstract:
A-kinase-anchoring protein (AKAP) 79/150 organizes a scaffold of cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and protein phosphatase 2B/calcineurin that regulates phosphorylation pathways underlying neuronal long-term potentiation and long-term depression (LTD) synaptic plasticity. AKAP79/150 postsynaptic targeting requires three N-terminal basic domains that bind F-actin and acidic phospholipids. Here, we report a novel interaction of these domains with cadherin adhesion molecules that are linked to actin through β-catenin (β-cat) at neuronal synapses and epithelial adherens junctions. Mapping the AKAP binding site in cadherins identified overlap with β-cat binding; however, no competition between AKAP and β-cat binding to cadherins was detected in vitro. Accordingly, AKAP79/150 exhibited polarized localization with β-cat and cadherins in epithelial cell lateral membranes, and β-cat was present in AKAP–cadherin complexes isolated from epithelial cells, cultured neurons, and rat brain synaptic membranes. Inhibition of epithelial cell cadherin adhesion and actin polymerization redistributed intact AKAP–cadherin complexes from lateral membranes to intracellular compartments. In contrast, stimulation of neuronal pathways implicated in LTD that depolymerize postsynaptic F-actin disrupted AKAP–cadherin interactions and resulted in loss of the AKAP, but not cadherins, from synapses. This neuronal regulation of AKAP79/150 targeting to cadherins may be important in functional and structural synaptic modifications underlying plasticity.
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Noe, V., J. Willems, J. Vandekerckhove, F. V. Roy, E. Bruyneel, and M. Mareel. "Inhibition of adhesion and induction of epithelial cell invasion by HAV-containing E-cadherin-specific peptides." Journal of Cell Science 112, no. 1 (January 1, 1999): 127–35. http://dx.doi.org/10.1242/jcs.112.1.127.
Full textAbstract:
The E-cadherin/catenin complex, an organizer of epithelial structure and function, is disturbed in invasive cancer. The HAV (histidine alanine valine) sequence in the first extracellular domain of E-cadherin is crucial for homophilic interactions between cadherins. We report that specific peptides containing an HAV sequence interfere with the functions of the E-cadherin/catenin complex. Cells either expressing specific cadherins or not were challenged with both cadherin and noncadherin peptides comprising a central HAV sequence. Specific E-cadherin peptides inhibited cell aggregation, disturbed the epithelial morphotype and were able to stimulate invasion of cells expressing E-cadherins. Conditioned medium, containing E-cadherin fragments, also stimulated invasion in contrast to conditioned medium from which the E-cadherin fragments were removed. Our studies show that E-cadherin functions are inhibited by homologous proteolytic HAV-containing fragments that are released in an autocrine manner and subsequently inhibit the E-cadherin/catenin complex. In this way such cadherin fragments may induce and support cancer invasion.
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Fujimori, T., and M. Takeichi. "Disruption of epithelial cell-cell adhesion by exogenous expression of a mutated nonfunctional N-cadherin." Molecular Biology of the Cell 4, no. 1 (January 1993): 37–47. http://dx.doi.org/10.1091/mbc.4.1.37.
Full textAbstract:
Cadherins, a family of transmembrane cell-cell adhesion receptors, require interactions with the cytoskeleton for normal function. To assess the mechanisms of these interactions, we studied the effect of exogenous expression of a mutant N-cadherin, cN390 delta; on epithelial cell-cell adhesion. The intracellular domain of cN390 delta was intact but its extracellular domain was largely deleted so that this molecule was not functional for cell adhesion. cDNA of cN390 delta was attached to the metallothionein promoter, and introduced into the keratinocyte line PAM212 expressing endogenous E- and P-cadherin. When the expression of cN390 delta was induced by Zn2+, cadherin-dependent adhesion of the transfected cells was inhibited, resulting in the dispersion of cell colonies, although their contacts were maintained under high cell density conditions. In these cultures, cN390 delta was expressed not only on the free surfaces of the cells but also at cell-cell junctions. The endogenous cadherins were concentrated at cell-cell junctions under normal conditions. As a result of cN390 delta expression, however, the endogenous cadherins localizing at the cell-cell junctions were largely diminished, suggesting that these molecules were replaced by the mutant molecules at these sites. As a control, we transfected the same cell line with cDNA of a truncated form of N-cadherin cadherin whose intracellular C terminus had been deleted leaving the extracellular domain intact. This molecule had no effect on cell-cell adhesion, nor did it localize to cell-cell contact sites. We also found that the association of the endogenous cadherins with alpha- and beta-catenins and plakoglobin was not affected by the expression of cN390 delta, which also formed a complex with these molecules, suggesting that no competition occurred between the endogenous and exogenous cadherins for these cytoplasmic proteins. These and other additional results suggest that the nonfunctional cadherins whose intracellular domain is intact occupy the sites where the endogenous cadherins should localize, through interactions with the cytoskeleton, and inhibit the cadherin adhesion system.
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Nose, A., and M. Takeichi. "A novel cadherin cell adhesion molecule: its expression patterns associated with implantation and organogenesis of mouse embryos." Journal of Cell Biology 103, no. 6 (December 1, 1986): 2649–58. http://dx.doi.org/10.1083/jcb.103.6.2649.
Full textAbstract:
The Ca2+-dependent cell adhesion molecules, termed cadherins, were previously divided into two subclasses, E- and N-types, with different adhesive specificity. In this study, we identified a novel class of cadherin, termed P-cadherin, using a visceral endoderm cell line PSA5-E. This cadherin was a 118,000-D glycoprotein and distinct from E- and N-cadherins in immunological specificity and molecular mass. In accord with these findings, cells with P-cadherin did not cross-adhere with cells with E-cadherin. P-Cadherin first appeared in developing mouse embryos in the extraembryonic ectoderm and the visceral endoderm at the egg cylinder stage and later was expressed in various tissues. The placenta and the uterine decidua most abundantly expressed this cadherin. The expression of P-cadherin was transient in many tissues, and its permanent expression was limited to certain tissues such as the epidermis, the mesothelium, and the corneal endothelium. When the tissue distribution of P-cadherin was compared with that of E-cadherin, we found that: each cadherin displayed a unique spatio-temporal pattern of expression; P-cadherin was co-expressed with E-cadherin in local regions of various tissues; and onset or termination of expression of P-cadherin was closely associated with connection or segregation of cell layers, as found with other cadherins. These results suggested that differential expression of multiple classes of cadherins play a role in implantation and morphogenesis of embryos by providing cells with heterogenous adhesive specificity.
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Viji Babu, Prem Kumar, Ursula Mirastschijski, Ganzanfer Belge, and Manfred Radmacher. "Homophilic and heterophilic cadherin bond rupture forces in homo- or hetero-cellular systems measured by AFM-based single-cell force spectroscopy." European Biophysics Journal 50, no. 3-4 (April 20, 2021): 543–59. http://dx.doi.org/10.1007/s00249-021-01536-2.
Full textAbstract:
AbstractCadherins enable intercellular adherens junctions to withstand tensile forces in tissues, e.g. generated by intracellular actomyosin contraction. In-vitro single molecule force spectroscopy experiments can reveal cadherin–cadherin extracellular region binding dynamics such as bond formation and strength. However, characterization of cadherin-presenting cell homophilic and heterophilic binding in the proteins’ native conformational and functional states in living cells has rarely been done. Here, we used atomic force microscopy (AFM) based single-cell force spectroscopy (SCFS) to measure rupture forces of homophilic and heterophilic bond formation of N- (neural), OB- (osteoblast) and E- (epithelial) cadherins in living fibroblast and epithelial cells in homo- and hetero-cellular arrangements, i.e., between cells and cadherins of the same and different types. In addition, we used indirect immunofluorescence labelling to study and correlate the expression of these cadherins in intercellular adherens junctions. We showed that N/N and E/E-cadherin homophilic binding events are stronger than N/OB heterophilic binding events. Disassembly of intracellular actin filaments affects the cadherin bond rupture forces suggesting a contribution of actin filaments in cadherin extracellular binding. Inactivation of myosin did not affect the cadherin rupture force in both homo- and hetero-cellular arrangements, but particularly strengthened the N/OB heterophilic bond and reinforced the other cadherins’ homophilic bonds.
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Hirano, S., A. Nose, K. Hatta, A. Kawakami, and M. Takeichi. "Calcium-dependent cell-cell adhesion molecules (cadherins): subclass specificities and possible involvement of actin bundles." Journal of Cell Biology 105, no. 6 (December 1, 1987): 2501–10. http://dx.doi.org/10.1083/jcb.105.6.2501.
Full textAbstract:
Cadherins are a family of cell-cell adhesion molecules and are divided into subclasses with distinct adhesive specificities and tissue distribution. Here we examined the distribution of cadherins at contact sites between cells expressing the same or different cadherin subclasses. Each cadherin was concentrated at the boundary between cells expressing an identical cadherin subclass, irrespective of the cell types connected. However, such localization decreased or disappeared at the boundary between cells containing different cadherin subclasses. We also found that the localization of cadherins precisely coincided with that of actin bundles; both were detected at the apical region of cell sheets. This co-localization was retained even after cells were either treated with cytochalasin D or extracted with the detergent NP40. These results suggest that each cadherin subclass preferentially interacts with its own molecular type at intercellular boundaries, and that cadherin molecules may be associated with actin-based cytoskeletal elements.
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Nanes, Benjamin A., Christine Chiasson-MacKenzie, Anthony M. Lowery, Noboru Ishiyama, Victor Faundez, Mitsuhiko Ikura, Peter A. Vincent, and Andrew P. Kowalczyk. "p120-catenin binding masks an endocytic signal conserved in classical cadherins." Journal of Cell Biology 199, no. 2 (October 15, 2012): 365–80. http://dx.doi.org/10.1083/jcb.201205029.
Full textAbstract:
p120-catenin (p120) binds to the cytoplasmic tails of classical cadherins and inhibits cadherin endocytosis. Although p120 regulation of cadherin internalization is thought to be important for adhesive junction dynamics, the mechanism by which p120 modulates cadherin endocytosis is unknown. In this paper, we identify a dual-function motif in classical cadherins consisting of three highly conserved acidic residues that alternately serve as a p120-binding interface and an endocytic signal. Mutation of this motif resulted in a cadherin variant that was both p120 uncoupled and resistant to endocytosis. In endothelial cells, in which dynamic changes in adhesion are important components of angiogenesis and inflammation, a vascular endothelial cadherin (VE-cadherin) mutant defective in endocytosis assembled normally into cell–cell junctions but potently suppressed cell migration in response to vascular endothelial growth factor. These results reveal the mechanistic basis by which p120 stabilizes cadherins and demonstrate that VE-cadherin endocytosis is crucial for endothelial cell migration in response to an angiogenic growth factor.
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Piprek, Rafał P., Malgorzata Kloc, Paulina Mizia, and Jacek Z. Kubiak. "The Central Role of Cadherins in Gonad Development, Reproduction, and Fertility." International Journal of Molecular Sciences 21, no. 21 (November 4, 2020): 8264. http://dx.doi.org/10.3390/ijms21218264.
Full textAbstract:
Cadherins are a group of membrane proteins responsible for cell adhesion. They are crucial for cell sorting and recognition during the morphogenesis, but they also play many other roles such as assuring tissue integrity and resistance to stretching, mechanotransduction, cell signaling, regulation of cell proliferation, apoptosis, survival, carcinogenesis, etc. Within the cadherin superfamily, E- and N-cadherin have been especially well studied. They are involved in many aspects of sexual development and reproduction, such as germline development and gametogenesis, gonad development and functioning, and fertilization. E-cadherin is expressed in the primordial germ cells (PGCs) and also participates in PGC migration to the developing gonads where they become enclosed by the N-cadherin-expressing somatic cells. The differential expression of cadherins is also responsible for the establishment of the testis or ovary structure. In the adult testes, N-cadherin is responsible for the integrity of the seminiferous epithelium, regulation of sperm production, and the establishment of the blood–testis barrier. Sex hormones regulate the expression and turnover of N-cadherin influencing the course of spermatogenesis. In the adult ovaries, E- and N-cadherin assure the integrity of ovarian follicles and the formation of corpora lutea. Cadherins are expressed in the mature gametes and facilitate the capacitation of sperm in the female reproductive tract and gamete contact during fertilization. The germ cells and accompanying somatic cells express a series of different cadherins; however, their role in gonads and reproduction is still unknown. In this review, we show what is known and unknown about the role of cadherins in the germline and gonad development, and we suggest topics for future research.
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Kaszak, Ilona, Olga Witkowska-Piłaszewicz, Zuzanna Niewiadomska, Bożena Dworecka-Kaszak, Felix Ngosa Toka, and Piotr Jurka. "Role of Cadherins in Cancer—A Review." International Journal of Molecular Sciences 21, no. 20 (October 15, 2020): 7624. http://dx.doi.org/10.3390/ijms21207624.
Full textAbstract:
Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.
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Huber, Andrew H., Daniel B. Stewart, Douglas V. Laurents, W. James Nelson, and William I. Weis. "The Cadherin Cytoplasmic Domain Is Unstructured in the Absence of β-Catenin." Journal of Biological Chemistry 276, no. 15 (December 19, 2000): 12301–9. http://dx.doi.org/10.1074/jbc.m010377200.
Full textAbstract:
Cadherins are single pass transmembrane proteins that mediate Ca2+-dependent homophilic cell-cell adhesion by linking the cytoskeletons of adjacent cells. In adherens junctions, the cytoplasmic domain of cadherins bind to β-catenin, which in turn binds to the actin-associated protein α-catenin. The physical properties of the E-cadherin cytoplasmic domain and its interactions with β-catenin have been investigated. Proteolytic sensitivity, tryptophan fluorescence, circular dichroism, and1H NMR measurements indicate that murine E-cadherin cytoplasmic domain is unstructured. Upon binding to β-catenin, the domain becomes resistant to proteolysis, suggesting that it structures upon binding. Cadherin-β-catenin complex stability is modestly dependent on ionic strength, indicating that, contrary to previous proposals, the interaction is not dominated by electrostatics. Comparison of 18 cadherin sequences indicates that their cytoplasmic domains are unlikely to be structured in isolation. This analysis also reveals the presence of PEST sequences, motifs associated with ubiquitin/proteosome degradation, that overlap the previously identified β-catenin-binding site. It is proposed that binding of cadherins to β-catenin prevents recognition of degradation signals that are exposed in the unstructured cadherin cytoplasmic domain, favoring a cell surface population of catenin-bound cadherins capable of participating in cell adhesion.
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Barami, Kaveh, Laura Lewis-Tuffin, and Panos Z. Anastasiadis. "The role of cadherins and catenins in gliomagenesis." Neurosurgical Focus 21, no. 4 (October 2006): 1–4. http://dx.doi.org/10.3171/foc.2006.21.4.14.
Full textAbstract:
✓Cell–cell adhesion is a crucial process occurring during normal tissue development. Cadherins are calcium-dependent cell-surface adhesion molecules involved in cell–cell adhesion. They reorganize the actin cytoskeleton via interaction with the catenins. Modulation of the cadherin/catenin system plays a role in cell motility. Dysregulation of the cadherin/catenin assembly has been implicated in various cancers. In this review, the authors summarize all studies focusing on the role of cadherins and catenins in glioma formation. With the emergence of recent data regarding gliomas' putative cell of origin, elucidation of the role of cadherins/catenins in gliomagenesis will become important in devising new therapeutic approaches against such deadly cancers.
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Manibog, Kristine, Kannan Sankar, Sun-Ae Kim, Yunxiang Zhang, Robert L. Jernigan, and Sanjeevi Sivasankar. "Molecular determinants of cadherin ideal bond formation: Conformation-dependent unbinding on a multidimensional landscape." Proceedings of the National Academy of Sciences 113, no. 39 (September 12, 2016): E5711—E5720. http://dx.doi.org/10.1073/pnas.1604012113.
Full textAbstract:
Classical cadherin cell–cell adhesion proteins are essential for the formation and maintenance of tissue structures; their primary function is to physically couple neighboring cells and withstand mechanical force. Cadherins from opposing cells bind in two distinct trans conformations: strand-swap dimers and X-dimers. As cadherins convert between these conformations, they form ideal bonds (i.e., adhesive interactions that are insensitive to force). However, the biophysical mechanism for ideal bond formation is unknown. Here, we integrate single-molecule force measurements with coarse-grained and atomistic simulations to resolve the mechanistic basis for cadherin ideal bond formation. Using simulations, we predict the energy landscape for cadherin adhesion, the transition pathways for interconversion between X-dimers and strand-swap dimers, and the cadherin structures that form ideal bonds. Based on these predictions, we engineer cadherin mutants that promote or inhibit ideal bond formation and measure their force-dependent kinetics using single-molecule force-clamp measurements with an atomic force microscope. Our data establish that cadherins adopt an intermediate conformation as they shuttle between X-dimers and strand-swap dimers; pulling on this conformation induces a torsional motion perpendicular to the pulling direction that unbinds the proteins and forms force-independent ideal bonds. Torsional motion is blocked when cadherins associate laterally in a cis orientation, suggesting that ideal bonds may play a role in mechanically regulating cadherin clustering on cell surfaces.
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Geiger, B., T. Volberg, D. Ginsberg, S. Bitzur, I. Sabanay, and R. O. Hynes. "Broad spectrum pan-cadherin antibodies, reactive with the C-terminal 24 amino acid residues of N-cadherin." Journal of Cell Science 97, no. 4 (December 1, 1990): 607–14. http://dx.doi.org/10.1242/jcs.97.4.607.
Full textAbstract:
We describe here the preparation and application of antibodies directed against a synthetic, 24 amino acid long, peptide corresponding to the conserved cytoplasmic C terminus of N-cadherin. We demonstrate here that the antibodies to the synthetic peptide react extensively with all known members of the cadherin family and, in addition, recognize novel cadherins in a variety of cells and tissues, suggesting that these antibodies indeed exhibit pan-cadherin reactivity. By Western blot screening of chicken tissues at least 4 different immunoreactive bands were resolved, commonly disclosing 2–3 distinct bands within the same tissue. The pan-cadherin antibodies also displayed a broad interspecies cross reactivity, recognizing cadherins in man, bovine, canine, avian, amphibian and teleost cells. This property renders these antibodies excellent reagents for the cloning and identification of novel cadherins. Immunocytochemical labelling with the pan-cadherin antibodies, at the light- and electron-microscope levels, revealed an extensive reactivity with intercellular adherens junctions in cardiac muscle and in various epithelia. We thus propose that the pan-cadherin antibodies may be used as ubiquitous cadherin probes and serve as markers for adherens junctions.
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Zarka, T. A., A. C. Han, M. I. Edelson, and N. G. Rosenblum. "Expression of cadherins, p53, and BCL2 in small cell carcinomas of the cervix: Potential tumor suppressor role for N-cadherin." International Journal of Gynecologic Cancer 13, no. 2 (February 2003): 240–43. http://dx.doi.org/10.1136/ijgc-00009577-200303000-00024.
Full textAbstract:
Cadherins are tissue-specific cell adhesion molecules that function as tumor suppressors. Analysis of cadherin expression is useful for differentiation of tumor histogenesis, and because they serve as markers of tumor behavior and prognosis. Since the pattern of cadherin expression is not well characterized for small cell carcinoma of the cervix, we examined cases of these tumors for expression of cadherins, and two other oncoproteins p53 and BCL2. Four cases of small cell neuroendocrine carcinomas were identified from the Gynecologic Oncology Service with diagnoses confirmed by immunohistochemistry for neuroendocrine markers. Archival paraffin blocks were studied by heat-enhanced immunohistochemistry using commercially available antibodies specific for E-cadherin, P-cadherin, and N-cadherin, p53, and BCL2. Sections were examined for specific membrane staining of cadherins, nuclear staining of p53, and cytoplasmic staining of BCL2. E-cadherin was expressed in three of four cases, P-cadherin in one of four, and N-cadherin in none of four cases. P53 was expressed in one of four cases and BCL2 in one of four cases. The four cases showed three different patterns of immunohistochemical staining for the five oncoproteins. Specifically, two cases expressed E-cadherin only; one case lacked all three cadherins, was negative for BCL2, and was only positive for p53; and one case expressed E- and P-cadherin and BCL2. Prior studies of other neuroendocrine and small cell tumors of other organs showed E-cadherin expressed in 98% (42 /43), N-cadherin in 65% (28/43), and P-cadherin in 40% (17/43) of cases. Additionally, one case of vaginal small cell carcinoma showed expression of all three cadherins. The only significant difference between cervical primaries and other primary sites is that N-cadherin was not detected in our four cases vs. 65% expression in other sites (P < 0.001). We conclude that cadherin and oncoprotein profiles in small cell carcinoma of the cervix are different in the four cases analyzed. Additional cases need to be studied to determine the specificity and frequency of these oncoprotein profiles for small cell carcinoma of the cervix. These may possibly represent different oncogenic pathways in development of small cell cancer of the cervix. Also, our results suggest that N-cadherin may be a tumor suppressor gene in these tumors.
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Teo, Jessica L., Robert G. Parton, and Alpha S. Yap. "The membrane environment of cadherin adhesion receptors: a working hypothesis." Biochemical Society Transactions 47, no. 4 (July 5, 2019): 985–95. http://dx.doi.org/10.1042/bst20180012.
Full textAbstract:
Abstract Classical cadherin cell adhesion receptors are integral membrane proteins that mediate cell–cell interactions, tissue integrity and morphogenesis. Cadherins are best understood to function as membrane-spanning molecular composites that couple adhesion to the cytoskeleton. On the other hand, the membrane lipid environment of the cadherins is an under-investigated aspect of their cell biology. In this review, we discuss two lines of research that show how the membrane can directly or indirectly contribute to cadherin function. Firstly, we consider how modification of its local lipid environment can potentially influence cadherin signalling, adhesion and dynamics, focusing on a role for phosphoinositide-4,5-bisphosphate. Secondly, we discuss how caveolae may indirectly regulate cadherins by modifying either the lipid composition and/or mechanical tension of the plasma membrane. Thus, we suggest that the membrane is a frontier of cadherin biology that is ripe for re-exploration.
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Krishna, K., and Christoph Redies. "Expression of Cadherin Superfamily Genes in Brain Vascular Development." Journal of Cerebral Blood Flow & Metabolism 29, no. 2 (October 22, 2008): 224–29. http://dx.doi.org/10.1038/jcbfm.2008.123.
Full textAbstract:
Cadherins are Ca2+-dependent cell adhesion molecules that are important in vertebrate nervous system development. We identified seven members of the cadherin superfamily (cadherin-4, cadherin-5, cadherin-6, cadherin-6, cadherin-11, protocadherin-1, and protocadherin-17) and an intracellular binding partner of δ-protocadherins, protein phosphatase 1α, as novel markers for developing blood vessels in the ferret brain. Some of the cadherin molecules are restricted to specific brain regions or a subset of blood vessels. The expression levels show a peak during perinatal vascular development. Our results suggest that multiple cadherins, which are also involved in neurogenesis, are regulators of angiogenesis in developing vertebrate brain.
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Knudsen, K. A., A. P. Soler, K. R. Johnson, and M. J. Wheelock. "Interaction of alpha-actinin with the cadherin/catenin cell-cell adhesion complex via alpha-catenin." Journal of Cell Biology 130, no. 1 (July 1, 1995): 67–77. http://dx.doi.org/10.1083/jcb.130.1.67.
Full textAbstract:
Cadherins are Ca(2+)-dependent, cell surface glycoproteins involved in cell-cell adhesion. Extracellularly, transmembrane cadherins such as E-, P-, and N-cadherin self-associate, while intracellularly they interact indirectly with the actin-based cytoskeleton. Several intracellular proteins termed catenins, including alpha-catenin, beta-catenin, and plakoglobin, are tightly associated with these cadherins and serve to link them to the cytoskeleton. Here, we present evidence that in fibroblasts alpha-actinin, but not vinculin, colocalizes extensively with the N-cadherin/catenin complex. This is in contrast to epithelial cells where both cytoskeletal proteins colocalize extensively with E-cadherin and catenins. We further show that alpha-actinin, but not vinculin, coimmunoprecipitates specifically with alpha- and beta-catenin from N- and E-cadherin-expressing cells, but only if alpha-catenin is present. Moreover, we show that alpha-actinin coimmunoprecipitates with the N-cadherin/catenin complex in an actin-independent manner. We therefore propose that cadherin/catenin complexes are linked to the actin cytoskeleton via a direct association between alpha-actinin and alpha-catenin.
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Han, Aaron C., Alejandro Peralta Soler, Chik-Kwun Tang, Karen A. Knudsen, and Hernando Salazar. "Nuclear Localization of E-Cadherin Expression in Merkel Cell Carcinoma." Archives of Pathology & Laboratory Medicine 124, no. 8 (August 1, 2000): 1147–51. http://dx.doi.org/10.5858/2000-124-1147-nloece.
Full textAbstract:
Abstract Context.—Cadherins are cell-cell adhesion proteins that act as tumor suppressor genes and have a critical role in cell sorting and tissue formation during organogenesis. The pattern of cadherin expression constitutes a useful diagnostic and prognostic tool in the evaluation of tumors and for determining the histogenesis of tumor cells. We have previously characterized the cell types of several tumors based on the expression of individual cadherins. Objective.—To investigate the expression of cadherins in Merkel cell carcinomas. Design.—Paraffin immunohistochemical analysis of the 3 best-studied cadherins was performed on 35 cases of Merkel cell carcinoma. Results.—E-cadherin was expressed in 34 (97%) of 35 Merkel cell carcinomas examined, N-cadherin was expressed in 22 (63%) of 35 cases, and P-cadherin was expressed in 15 (43%) of 35 cases. This frequency of cadherin expression was similar to a group of small cell and neuroendocrine tumors from other primary sites. Interestingly, the localization of E-cadherin expression was unique in Merkel cell carcinomas compared with other primary neuroendocrine tumors. Merkel cell carcinomas showed marked preference for nuclear versus membrane localization, whereas small cell tumors from other sites showed fewer cases of nuclear E-cadherin expression. The nuclear localization of E-cadherin did not correlate with cadherin-associated protein β-catenin nuclear expression. Conclusions.—Our findings show that E-cadherin is the most frequently expressed cadherin in Merkel cell carcinoma, followed in frequency by N-cadherin then P-cadherin. The pattern of nuclear E-cadherin expression is more frequent for Merkel cell carcinoma than small cell tumors of other primary sites. These observations suggest that E-cadherin expression and function are altered in Merkel cell carcinoma, and this finding has potential use in the differential diagnosis of these tumors.
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Napolitano, E. W., K. Venstrom, E. F. Wheeler, and L. F. Reichardt. "Molecular cloning and characterization of B-cadherin, a novel chick cadherin." Journal of Cell Biology 113, no. 4 (May 15, 1991): 893–905. http://dx.doi.org/10.1083/jcb.113.4.893.
Full textAbstract:
Calcium-dependent cell-cell adhesion is mediated in large part by a set of homologous integral membrane glycoproteins termed cadherins. In this report, antibodies to conserved domains in previously described cadherins have been used to isolate cDNAs encoding a novel chick cadherin. The deduced primary structure of this novel molecule, assigned the name B-cadherin, contains 726 amino acid residues which include five extracellular domains characteristic of this class of adhesion molecules, a single putative transmembrane spanning region, and a cytoplasmic tail. In each domain, B-cadherin shares extensive homologies with other cadherins, but is more closely related to E-cadherin, P-cadherin, and L-CAM than to N-cadherin. It is expressed in a wide variety of chick tissues at embryonic day 13. In particular, immunohistochemical staining and in situ hybridization localize B-cadherin protein and mRNA to the epithelial lining of the choroid plexus and to cells in specific layers of the optic tectum in chick brain. Levels of the protein and RNA transcript change dramatically as development proceeds in chick brain. These results suggest that B-cadherin has important functions in neurogenesis, in at least some epithelia, and in embryogenesis.
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Marcozzi, C., I. D. Burdett, R. S. Buxton, and A. I. Magee. "Coexpression of both types of desmosomal cadherin and plakoglobin confers strong intercellular adhesion." Journal of Cell Science 111, no. 4 (February 15, 1998): 495–509. http://dx.doi.org/10.1242/jcs.111.4.495.
Full textAbstract:
Desmosomes are unique intercellular junctions in that they invariably contain two types of transmembrane cadherin molecule, desmocollins and desmogleins. In addition they possess a distinct cytoplasmic plaque structure containing a few major proteins including desmoplakins and the armadillo family member plakoglobin. Desmosomal cadherins are putative cell-cell adhesion molecules and we have tested their adhesive capacity using a transfection approach in mouse L cells. We find that L cells expressing either one or both of the desmosomal cadherins desmocollin 2a or desmoglein 1 display weak cell-cell adhesion activity that is Ca2+-dependent. Both homophilic and heterophilic adhesion could be detected. However, co-expression of plakoglobin with both desmosomal cadherins, but not with desmoglein 1 alone, resulted in a dramatic potentiation of cell-cell aggregation and the accumulation of detergent-insoluble desmosomal proteins at points of cell-cell contact. The effect of plakoglobin seems to be due directly to its interaction with the desmosomal cadherins rather than to its signalling function. The data suggest that the desmosome may obligatorily contain two cadherins and is consistent with a model in which desmocollins and desmogleins may form side by side heterodimers in contrast to the classical cadherins that are homodimeric. Plakoglobin may function by potentiating dimer formation, accretion of dimers to cell-cell contact sites or desmosomal cadherin stability.
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Navarro, Pilar, Luigi Ruco, and Elisabetta Dejana. "Differential Localization of VE- and N-Cadherins in Human Endothelial Cells: VE-Cadherin Competes with N-Cadherin for Junctional Localization." Journal of Cell Biology 140, no. 6 (March 23, 1998): 1475–84. http://dx.doi.org/10.1083/jcb.140.6.1475.
Full textAbstract:
The two major cadherins of endothelial cells are neural (N)-cadherin and vascular endothelial (VE)- cadherin. 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. 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. Similar amounts of α- and β-catenins and plakoglobin were associated to VE- and N-cadherins, whereas p120 was higher in the VE-cadherin complex. The presence of VE-cadherin did not affect N-cadherin homotypic adhesive properties or its capacity to localize at junctions when cotransfectants were cocultured with cells transfected with N-cadherin only. To define the molecular domain responsible for the VE-cadherin–dominant activity we prepared a chimeric construct formed by VE-cadherin extracellular region linked to N-cadherin intracellular domain. The chimera lost the capacity to exclude N-cadherin from junctions indicating that the extracellular domain of VE-cadherin alone is not sufficient for the preferential localization of the molecule at the junctions. 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. This indicates that the Arg621–Pro702 sequence in the VE-cadherin cytoplasmic tail is required for N-cadherin exclusion from junctions. Competition between cadherins for their clustering at intercellular junctions in the same cell has never been described before. We speculate that, in the endothelium, VE- and N-cadherin play different roles; whereas VE-cadherin mostly promotes the homotypic interaction between endothelial cells, N-cadherin may be responsible for the anchorage of the endothelium to other surrounding cell types expressing N-cadherin such as vascular smooth muscle cells or pericytes.