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Margaret J. Wheelock - One of the best experts on this subject based on the ideXlab platform.
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upregulation of p Cadherin expression in the lesional skin of pemphigus hailey hailey disease and darier s disease
Journal of Cutaneous Pathology, 2001Co-Authors: Megumi Hakuno, Margaret J. Wheelock, Masashi Akiyama, Hiroshi Shimizu, Takeji NishikawaAbstract:Background: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal Cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darier’s disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-Cadherin is one of the major Cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of Cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these atuoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-Cadherin expression is present in these diseases. Method: Distribution patterns of P-Cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-Cadherin antibodies, 6A9 and NCC-CAD-299. Results: In normal control skin, P-Cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-Cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases. Conclusions: The present results clearly demonstrated that upregulation of P-Cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-Cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.
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mechanism of extracellular domain deleted dominant negative Cadherins
Journal of Cell Science, 1999Co-Authors: Marvin T Nieman, Jae Beom Kim, Keith R Johnson, Margaret J. WheelockAbstract:The Cadherin/catenin complex mediates Ca2+-dependent cell-cell interactions that are essential for normal developmental processes. It has been proposed that sorting of cells during embryonic development is due, at least in part, to expression of different Cadherin family members or to expression of differing levels of a single family member. Expression of dominant-negative Cadherins has been used experimentally to decrease cell-cell interactions in whole organisms and in cultured cells. In this study, we elucidated the mechanism of action of extracellular domain-deleted dominant-negative Cadherin, showing that it is not Cadherin isotype-specific, and that it must be membrane-associated but the orientation within the membrane does not matter. In addition, membrane-targeted cytoplasmic domain Cadherin with the catenin-binding domain deleted does not function as a dominant-negative Cadherin. Expression of extracellular domain-deleted dominant-negative Cadherin results in down-regulation of endogenous Cadherins which presumably contributes to the non-adhesive phenotype.
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e Cadherin and p Cadherin have partially redundant roles in human epidermal stratification
Cell and Tissue Research, 1997Co-Authors: Pamela J Jensen, Brett Telegan, Robert M Lavker, Margaret J. WheelockAbstract:Classical Cadherins are Ca2+-dependent homotypic intercellular adhesion molecules that play major regulatory roles in tissue morphogenesis. Human epidermis, which expresses two classical Cadherins (E- and P-Cadherins), undergoes continual differentiation and morphogenesis, not just during embryonic development, but throughout life. The relative roles of E- and P-Cadherin in epidermal morphogenesis have been studied in human epidermal keratinocytes in culture. In these cultures, tissue morphogenesis can be initiated simply by elevation of the extracellular Ca2+ concentration, which activates the Cadherins, initiates desmosome organization, and then induces reorganization of the culture from a monolayer into a multilayered, more differentiated, epithelial-like structure. By examination of cultures after several days in high Ca2+, previous data have shown that concurrent inhibition of both E- and P-Cadherins nearly abrogates the Ca2+-induced stratification response; however, it has not been possible to discern from these studies whether the two Cadherins have unique or redundant regulatory properties. The present study has demonstrated, via electron-microscopic analysis of cultures at an early stage in stratification, that inhibition of either of the Cadherins alone does not affect the initiation of stratification, i.e. the formation of up to 2–3 cell layers. Thus, E-Cadherin and P-Cadherin may have similar regulatory functions with respect to the initiation of stratification. However, if stratification is to continue further to produce a tissue-like structure of 5–7 cell layers, then E-Cadherin is required and P-Cadherin cannot act as a substitute, presumably because of the distinct localizations of E- and P-Cadherins; E-Cadherin is found in all cell layers of the stratified epithelium, whereas P-Cadherin is lost after the basal keratinocytes become detached from the basement membrane and assume a suprabasal position. Therefore, basal cells, which have two Cadherins, can utilize either Cadherin to initiate stratification, whereas superficial cells, which have only E-Cadherin, are dependent on this Cadherin for further stratification.
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interaction of alpha actinin with the Cadherin catenin cell cell adhesion complex via alpha catenin
Journal of Cell Biology, 1995Co-Authors: K A Knudsen, Alejandro Peralta Soler, K R Johnson, Margaret J. WheelockAbstract: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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p and e Cadherin are in separate complexes in cells expressing both Cadherins
Experimental Cell Research, 1993Co-Authors: Jani E Lewis, Alejandro Peralta Soler, James K Wahl, Dong Li, Margaret J. WheelockAbstract:Abstract E- and P-Cadherin are members of a family of calcium-dependent, cell surface glycoproteins involved in cell-cell adhesion. Extracellularly, the transmembrane Cadherins self-associate, while intracellularly, they interact with the actin-based cytoskeleton. Several intracellular proteins, collectively termed catenins, are tightly associated with E- and P-Cadherin. These proteins appear to link the Cadherin to the cytoskeleton and have been proposed to be involved in concentrating Cadherins at cell-cell adherens junctions. In this paper we report the production of monoclonal antibodies against both α- and β-catenin and use these antibodies to show that in cells simultaneously expressing two different Cadherins, E-Cadherin and P-Cadherin, each Cadherin appears to be present in a separate Cadherin/catenin complex.
Ulrich Technau - One of the best experts on this subject based on the ideXlab platform.
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A Cadherin switch marks germ layer formation in the diploblastic sea anemone Nematostella vectensis.
Development, 2019Co-Authors: Ekaterina Pukhlyakova, A. O. Kirillova, Yulia Kraus, Bob Zimmermann, Ulrich TechnauAbstract:Morphogenesis is a shape-building process during development of multicellular organisms. During this process the establishment and modulation of cell-cell contacts play an important role. Cadherins, the major cell adhesion molecules, form adherens junctions connecting epithelial cells. Numerous studies in Bilateria have shown that Cadherins are associated with the regulation of cell differentiation, cell shape changes, cell migration and tissue morphogenesis. To date, the role of Cadherins in non-bilaterians is unknown. Here, we study the expression and the function of two paralogous classical Cadherins, Cadherin1 and Cadherin3, in the diploblastic animal, the sea anemone Nematostella vectensis. We show that a Cadherin switch is accompanying the formation of germ layers. Using specific antibodies, we show that both Cadherins are localized to adherens junctions at apical and basal positions in ectoderm and endoderm. During gastrulation, partial EMT of endodermal cells is marked by a step-wise down-regulation of Cadherin3 and up-regulation of Cadherin1. Knockdown experiments show that both Cadherins are required for maintenance of tissue integrity and tissue morphogenesis. Thus, both sea anemones and bilaterians use independently duplicated Cadherins combinatorially for tissue morphogenesis and germ layer differentiation.
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Cadherin switch marks germ layer formation in the diploblastic sea anemone nematostella vectensis
bioRxiv, 2018Co-Authors: Ekaterina Pukhlyakova, A. O. Kirillova, Yulia Kraus, Ulrich TechnauAbstract:Morphogenesis is a shape-building process during development of multicellular organisms. During this process the establishment and modulation of cell-cell contacts play an important role. Cadherins, the major cell adhesion molecules, form adherens junctions connecting epithelial cells. Numerous studies in Bilateria have shown that Cadherins are associated with the regulation of cell differentiation, cell shape changes, cell migration and tissue morphogenesis. To date, the role of Cadherins in non-bilaterians is unknown. Here, we study the expression and the function of two paralogous classical Cadherins, Cadherin1 and Cadherin3, in the diploblastic animal, the sea anemone Nematostella vectensis. We show that a Cadherin switch is accompanying the formation of germ layers. Using specific antibodies, we show that both Cadherins are localized to adherens junctions at apical and basal positions in ectoderm and endoderm. During gastrulation, partial EMT of endodermal cells is marked by a step-wise downregulation of Cadherin3 and upregulation of Cadherin1. Knockdown experiments show that both Cadherins are required for maintenance of tissue integrity and tissue morphogenesis. This demonstrates that cnidarians convergently use Cadherins to differentially control morphogenetic events during development.
Frans Van Roy - One of the best experts on this subject based on the ideXlab platform.
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New insights into the evolution of metazoan Cadherins
2016Co-Authors: Paco Hulpiau, Frans Van RoyAbstract:Mining newly sequenced genomes of basal metazoan organisms reveals the evolutionary origin of modern protein families. Specific cell–cell adhesion and intracellular communication are key processes in multicellular animals, and members of the Cadherin superfamily are essential players in these processes. Mammalian genomes contain over 100 genes belonging to this superfamily. By a combination of tBLASTn and profile hidden Markov model analyses, we made an exhaustive search for Cadherins and compiled the Cadherin repertoires in key organisms, including Branchiostoma floridae (amphioxus), the sea anemone Nematostella vectensis, and the placozoan Trichoplax adhaerens. Comparative analyses of multiple protein domains within known and novel Cadherins enabled us to reconstruct the complex evolution in metazoa of this large superfamily. Five main Cadherin branches are represented in the primitive metazoan Trichoplax: classical (CDH), flamingo (CELSR), dachsous (DCHS), FAT, and FAT-like. Classical Cadherins, such as E-Cadherin, arose from an Urmetazoan Cadherin, which progressively lost N-terminal extracellular Cadherin repeats, whereas its cytoplasmic domain, which binds the armadillo proteins p120ctn and b-catenin, remained quite conserved from placozoa to man. The origin of protoCadherins predates the Bilateria and is likely rooted in an ancestral FAT Cadherin. Several but not all protostomians lost protoCadherins. The emergence of chordates coincided with a great expansion of the protoCadherin repertoire. The evolution of ancient metazoan Cadherins points to their unique and crucial roles in multicellular animal life
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Beyond E-Cadherin: roles of other Cadherin superfamily members in cancer
Nature reviews. Cancer, 2014Co-Authors: Frans Van RoyAbstract:Loss of Cadherin 1 (CDH1; also known as epithelial Cadherin (E-Cadherin)) is used for the diagnosis and prognosis of epithelial cancers. However, it should not be ignored that the superfamily of transmembrane Cadherin proteins encompasses more than 100 members in humans, including other classical Cadherins, numerous protoCadherins and Cadherin-related proteins. Elucidation of their roles in suppression versus initiation or progression of various tumour types is a young but fascinating field of molecular cancer research. These Cadherins are very diverse in both structure and function, and their mutual interactions seem to influence biological responses in complex and versatile ways.
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Involvement of Members of the Cadherin Superfamily in Cancer
Cold Spring Harbor perspectives in biology, 2009Co-Authors: Geert Berx, Frans Van RoyAbstract:We review the role of Cadherins and Cadherin-related proteins in human cancer. Cellular and animal models for human cancer are also dealt with whenever appropriate. E-Cadherin is the prototype of the large Cadherin superfamily and is renowned for its potent malignancy suppressing activity. Different mechanisms for inactivating E-Cadherin/CDH1 have been identified in human cancers: inherited and somatic mutations, aberrant protein processing, increased promoter methylation, and induction of transcriptional repressors such as Snail and ZEB family members. The latter induce epithelial mesenchymal transition, which is also associated with induction of "mesenchymal" Cadherins, a hallmark of tumor progression. VE-Cadherin/CDH5 plays a role in tumor-associated angiogenesis. The atypical T-Cadherin/CDH13 is often silenced in cancer cells but up-regulated in tumor vasculature. The review also covers the status of protoCadherins and several other Cadherin-related molecules in human cancer. Perspectives for emerging Cadherin-related anticancer therapies are given.
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phylogenetic analysis of the Cadherin superfamily allows identification of six major subfamilies besides several solitary members
Journal of Molecular Biology, 2000Co-Authors: Friedel Nollet, Patrick Kools, Frans Van RoyAbstract:Cadherins play an important role in specific cell-cell adhesion events. Their expression appears to be tightly regulated during development and each tissue or cell type shows a characteristic pattern of Cadherin molecules. Inappropriate regulation of their expression levels or functionality has been observed in human malignancies, in many cases leading to aggravated cancer cell invasion and metastasis. The Cadherins form a superfamily with at least six subfamilies, which can be distinguished on the basis of protein domain composition, genomic structure, and phylogenetic analysis of the protein sequences. These subfamilies comprise classical or type-I Cadherins, atypical or type-II Cadherins, desmocollins, desmogleins, protoCadherins and Flamingo Cadherins. In addition, several Cadherins clearly occupy isolated positions in the Cadherin superfamily (Cadherin-13, -15, -16, -17, Dachsous, RET, FAT, MEGF1 and most invertebrate Cadherins). We suggest a different evolutionary origin of the protoCadherin and Flamingo Cadherin genes versus the genes encoding desmogleins, desmocollins, classical Cadherins, and atypical Cadherins. The present phylogenetic analysis may accelerate the functional investigation of the whole Cadherin superfamily by allowing focused research of prototype Cadherins within each subfamily.
Fernando Schmitt - One of the best experts on this subject based on the ideXlab platform.
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co expression of e and p Cadherin in breast cancer role as an invasion suppressor or as an invasion promoter
BMC Proceedings, 2010Co-Authors: Ana Sofia Ribeiro, Laura Carreto, Andre Albergaria, Barbara Sousa, Fernanda Milanezi, Raquel Seruca, Fernando Schmitt, Sara Ricardo, Manuel A S SantosAbstract:Cadherins are cell-cell adhesion molecules. During tumor progression, their expression and/or function are frequently altered. E-Cadherin down-regulation is often associated with tumor initiation and progression in breast cancer [1], whereas P-Cadherin overexpression is associated with a worse patient survival [2] and with invasive breast cancer cells [3]. In this study, we aimed to understand if P-Cadherin overexpression could interfere with E-Cadherin invasion suppressor role in breast cancer. Therefore, E- and P-Cadherin expression was evaluated in a series of invasive breast carcinomas. P-Cadherin overexpressing tumors often do not loose E-Cadherin and tumors co-expressing both Cadherins showed a more aggressive behavior and were related with the worst patient survival. Further, we performed in vitro studies by silencing both Cadherins in BT-20 breast cancer cells. E- and P-Cadherin co-expressing breast cancer cells showed increased cell invasion and migration capacities, when compared with the ones expressing only one Cadherin. P-Cadherin silencing led to increased levels of cell death, demonstrating it as a cancer cell survival signal. Also, microarrays of BT-20 cells, after E- and/or P-Cadherin silencing, showed that the role of each Cadherin alone is distinct from when these are co-expressed in the same cell, conferring different transcriptional programs. We can conclude that E- and P-Cadherin co-expression has an invasion promoter role in breast cancer cells and is a poor patient prognostic biomarker.
Malcolm S Steinberg - One of the best experts on this subject based on the ideXlab platform.
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measurement of tumor cell cohesion and suppression of invasion by e or p Cadherin
Cancer Research, 1997Co-Authors: Ramsey A. Foty, Malcolm S SteinbergAbstract:Invasiveness of carcinomas was connected early to decreased cohesiveness and has more recently been associated with loss or decreased activity of E-Cadherin. In the first thermodynamic measurements of cohesive intensities among malignant cells, we here find the cohesive intensities of Lewis lung carcinoma cells to fall within the range measured previously for cells from a series of noninvasive embryonic tissues. Thus, too-low cohesiveness is itself an insufficient explanation for invasiveness. Nevertheless, transfection-mediated Cadherin expression sufficient to increase cohesiveness by as little as 26% suffices to greatly reduce invasion of aggregates of Lewis lung carcinoma cells into Matrigel. This property is not restricted to E-Cadherin but is shared by P-Cadherin. The same Cadherin-transfected cells do not display this invasion suppression when plated sparsely, indicating that invasion-suppression activity of Cadherins requires cell-cell contact. These facts are consistent with the invasion-suppression activity of Cadherins resulting either from the physical restraint of increased cohesion per se or from another Cadherin activity mediated through cell-cell contact.
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measurement of tumor cell cohesion and suppression of invasion by e or p Cadherin
Cancer Research, 1997Co-Authors: Ramsey A. Foty, Malcolm S SteinbergAbstract:Invasiveness of carcinomas was connected early to decreased cohesiveness and has more recently been associated with loss or decreased activity of E-Cadherin. In the first thermodynamic measurements of cohesive intensities among malignant cells, we here find the cohesive intensities of Lewis lung carcinoma cells to fall within the range measured previously for cells from a series of noninvasive embryonic tissues. Thus, too-low cohesiveness is itself an insufficient explanation for invasiveness. Nevertheless, transfection-mediated Cadherin expression sufficient to increase cohesiveness by as little as 26% suffices to greatly reduce invasion of aggregates of Lewis lung carcinoma cells into Matrigel. This property is not restricted to E-Cadherin but is shared by P-Cadherin. The same Cadherin-transfected cells do not display this invasion suppression when plated sparsely, indicating that invasion-suppression activity of Cadherins requires cell-cell contact. These facts are consistent with the invasion-suppression activity of Cadherins resulting either from the physical restraint of increased cohesion per se or from another Cadherin activity mediated through cell-cell contact.
