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Margaret J. Wheelock - One of the best experts on this subject based on the ideXlab platform.
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Cadherins as modulators of cellular phenotype
Annual Review of Cell and Developmental Biology, 2003Co-Authors: Margaret J. Wheelock, Keith R JohnsonAbstract:Cadherins are transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion. The cadherin family is large and diverse, and proteins are considered to be members of this family if they have one or more cadherin repeats in their extracellular domain. Cadherin family members are the transmembrane components of a number of cellular junctions, including adherens junctions, desmosomes, cardiac junctions, endothelial junctions, and synaptic junctions. Cadherin function is critical in normal development, and alterations in cadherin function have been implicated in tumorigenesis. The strength of cadherin interactions can be regulated by a number of proteins, including the catenins, which serve to link the cadherin to the cytoskeleton. Cadherins have been implicated in a number of signaling pathways that regulate cellular behavior, and it is becoming increasingly clear that integration of information received from cell-cell signaling, cell-matrix signaling, and growth factor signaling determines ultimate cellular phenotype and behavior.
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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.
William I Weis - One of the best experts on this subject based on the ideXlab platform.
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e cadherin is under constitutive actomyosin generated tension that is increased at cell cell contacts upon externally applied stretch
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Nicolas Borghi, James W Nelson, William I Weis, Maria Sorokina, Olga G Shcherbakova, Beth L Pruitt, Alexander R DunnAbstract:Classical Cadherins are transmembrane proteins at the core of intercellular adhesion complexes in cohesive metazoan tissues. The extracellular domain of classical Cadherins forms intercellular bonds with Cadherins on neighboring cells, whereas the cytoplasmic domain recruits catenins, which in turn associate with additional cytoskeleton binding and regulatory proteins. Cadherin/catenin complexes are hypothesized to play a role in the transduction of mechanical forces that shape cells and tissues during development, regeneration, and disease. Whether mechanical forces are transduced directly through Cadherins is unknown. To address this question, we used a Forster resonance energy transfer (FRET)-based molecular tension sensor to test the origin and magnitude of tensile forces transmitted through the cytoplasmic domain of E-cadherin in epithelial cells. We show that the actomyosin cytoskeleton exerts pN-tensile force on E-cadherin, and that this tension requires the catenin-binding domain of E-cadherin and αE-catenin. Surprisingly, the actomyosin cytoskeleton constitutively exerts tension on E-cadherin at the plasma membrane regardless of whether or not E-cadherin is recruited to cell–cell contacts, although tension is further increased at cell–cell contacts when adhering cells are stretched. Our findings thus point to a constitutive role of E-cadherin in transducing mechanical forces between the actomyosin cytoskeleton and the plasma membrane, not only at cell–cell junctions but throughout the cell surface.
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interactions of plakoglobin and beta catenin with desmosomal Cadherins basis of selective exclusion of alpha and beta catenin from desmosomes
Journal of Biological Chemistry, 2009Co-Authors: Heejung Choi, Julia Christina Gross, Sabine Pokutta, William I WeisAbstract:Plakoglobin and beta-catenin are homologous armadillo repeat proteins found in adherens junctions, where they interact with the cytoplasmic domain of classical Cadherins and with alpha-catenin. Plakoglobin, but normally not beta-catenin, is also a structural constituent of desmosomes, where it binds to the cytoplasmic domains of the desmosomal Cadherins, desmogleins and desmocollins. Here, we report structural, biophysical, and biochemical studies aimed at understanding the molecular basis of selective exclusion of beta-catenin and alpha-catenin from desmosomes. The crystal structure of the plakoglobin armadillo domain bound to phosphorylated E-cadherin shows virtually identical interactions to those observed between beta-catenin and E-cadherin. Trypsin sensitivity experiments indicate that the plakoglobin arm domain by itself is more flexible than that of beta-catenin. Binding of plakoglobin and beta-catenin to the intracellular regions of E-cadherin, desmoglein1, and desmocollin1 was measured by isothermal titration calorimetry. Plakoglobin and beta-catenin bind strongly and with similar thermodynamic parameters to E-cadherin. In contrast, beta-catenin binds to desmoglein-1 more weakly than does plakoglobin. beta-Catenin and plakoglobin bind with similar weak affinities to desmocollin-1. Full affinity binding of desmoglein-1 requires sequences C-terminal to the region homologous to the catenin-binding domain of classical Cadherins. Although pulldown assays suggest that the presence of N- and C-terminal beta-catenin "tails" that flank the armadillo repeat region reduces the affinity for desmosomal Cadherins, calorimetric measurements show no significant effects of the tails on binding to the Cadherins. Using purified proteins, we show that desmosomal Cadherins and alpha-catenin compete directly for binding to plakoglobin, consistent with the absence of alpha-catenin in desmosomes.
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interactions of plakoglobin and β catenin with desmosomal Cadherins basis of selective exclusion of α and β catenin from desmosomes
Journal of Biological Chemistry, 2009Co-Authors: Heejung Choi, Julia Christina Gross, Sabine Pokutta, William I WeisAbstract:Plakoglobin and beta-catenin are homologous armadillo repeat proteins found in adherens junctions, where they interact with the cytoplasmic domain of classical Cadherins and with alpha-catenin. Plakoglobin, but normally not beta-catenin, is also a structural constituent of desmosomes, where it binds to the cytoplasmic domains of the desmosomal Cadherins, desmogleins and desmocollins. Here, we report structural, biophysical, and biochemical studies aimed at understanding the molecular basis of selective exclusion of beta-catenin and alpha-catenin from desmosomes. The crystal structure of the plakoglobin armadillo domain bound to phosphorylated E-cadherin shows virtually identical interactions to those observed between beta-catenin and E-cadherin. Trypsin sensitivity experiments indicate that the plakoglobin arm domain by itself is more flexible than that of beta-catenin. Binding of plakoglobin and beta-catenin to the intracellular regions of E-cadherin, desmoglein1, and desmocollin1 was measured by isothermal titration calorimetry. Plakoglobin and beta-catenin bind strongly and with similar thermodynamic parameters to E-cadherin. In contrast, beta-catenin binds to desmoglein-1 more weakly than does plakoglobin. beta-Catenin and plakoglobin bind with similar weak affinities to desmocollin-1. Full affinity binding of desmoglein-1 requires sequences C-terminal to the region homologous to the catenin-binding domain of classical Cadherins. Although pulldown assays suggest that the presence of N- and C-terminal beta-catenin "tails" that flank the armadillo repeat region reduces the affinity for desmosomal Cadherins, calorimetric measurements show no significant effects of the tails on binding to the Cadherins. Using purified proteins, we show that desmosomal Cadherins and alpha-catenin compete directly for binding to plakoglobin, consistent with the absence of alpha-catenin in desmosomes.
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interactions of plakoglobin and beta catenin with desmosomal Cadherins basis of selective exclusion of alpha and beta catenin from desmosomes
Journal of Biological Chemistry, 2009Co-Authors: Heejung Choi, Julia Christina Gross, Sabine Pokutta, William I WeisAbstract:Plakoglobin and β-catenin are homologous armadillo repeat proteins found in adherens junctions, where they interact with the cytoplasmic domain of classical Cadherins and with α-catenin. Plakoglobin, but normally not β-catenin, is also a structural constituent of desmosomes, where it binds to the cytoplasmic domains of the desmosomal Cadherins, desmogleins and desmocollins. Here, we report structural, biophysical, and biochemical studies aimed at understanding the molecular basis of selective exclusion of β-catenin and α-catenin from desmosomes. The crystal structure of the plakoglobin armadillo domain bound to phosphorylated E-cadherin shows virtually identical interactions to those observed between β-catenin and E-cadherin. Trypsin sensitivity experiments indicate that the plakoglobin arm domain by itself is more flexible than that of β-catenin. Binding of plakoglobin and β-catenin to the intracellular regions of E-cadherin, desmoglein1, and desmocollin1 was measured by isothermal titration calorimetry. Plakoglobin and β-catenin bind strongly and with similar thermodynamic parameters to E-cadherin. In contrast, β-catenin binds to desmoglein-1 more weakly than does plakoglobin. β-Catenin and plakoglobin bind with similar weak affinities to desmocollin-1. Full affinity binding of desmoglein-1 requires sequences C-terminal to the region homologous to the catenin-binding domain of classical Cadherins. Although pulldown assays suggest that the presence of N- and C-terminal β-catenin “tails” that flank the armadillo repeat region reduces the affinity for desmosomal Cadherins, calorimetric measurements show no significant effects of the tails on binding to the Cadherins. Using purified proteins, we show that desmosomal Cadherins and α-catenin compete directly for binding to plakoglobin, consistent with the absence of α-catenin in desmosomes.
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structure and biochemistry of Cadherins and catenins
Cold Spring Harbor Perspectives in Biology, 2009Co-Authors: Lawrence Shapiro, William I WeisAbstract:Classical Cadherins mediate specific adhesion at intercellular adherens junctions. Interactions between cadherin ectodomains from apposed cells mediate cell-cell contact, whereas the intracellular region functionally links Cadherins to the underlying cytoskeleton. Structural, biophysical, and biochemical studies have provided important insights into the mechanism and specificity of cell-cell adhesion by classical Cadherins and their interplay with the cytoskeleton. Adhesive binding arises through exchange of beta strands between the first extracellular cadherin domains (EC1) of partner Cadherins from adjacent cells. This "strand-swap" binding mode is common to classical and desmosomal Cadherins, but sequence alignments suggest that other Cadherins will bind differently. The intracellular region of classical Cadherins binds to p120 and beta-catenin, and beta-catenin binds to the F-actin binding protein alpha-catenin. Rather than stably bridging beta-catenin to actin, it appears that alpha-catenin actively regulates the actin cytoskeleton at cadherin-based cell-cell contacts.
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.
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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a cadherin switch marks germ layer formation in the diploblastic sea anemone nematostella vectensis
Development, 2019Co-Authors: Ekaterina Pukhlyakova, Yulia Kraus, Bob Zimmermann, Anastasia Kirillova, 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 of 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 function of two paralogous classical Cadherins, Cadherin 1 and Cadherin 3, in a diploblastic animal, the sea anemone Nematostella vectensis We show that a cadherin switch accompanies 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 epithelial-to-mesenchymal transition of endodermal cells is marked by stepwise downregulation of Cadherin 3 and upregulation of Cadherin 1. 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.
Barry Honig - One of the best experts on this subject based on the ideXlab platform.
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thinking outside the cell how Cadherins drive adhesion
Trends in Cell Biology, 2012Co-Authors: Julia Brasch, O J Harrison, Barry Honig, Lawrence ShapiroAbstract:Cadherins are a superfamily of cell surface glycoproteins whose ectodomains contain multiple repeats of β-sandwich extracellular cadherin (EC) domains that adopt a similar fold to immunoglobulin domains. The best characterized Cadherins are the vertebrate ‘classical' Cadherins, which mediate adhesion via trans homodimerization between their membrane-distal EC1 domains that extend from apposed cells, and assemble intercellular adherens junctions through cis clustering. To form mature trans adhesive dimers, cadherin domains from apposed cells dimerize in a ‘strand-swapped' conformation. This occurs in a two-step binding process involving a fast-binding intermediate called the ‘X-dimer'. Trans dimers are less flexible than cadherin monomers, a factor that drives junction assembly following cell–cell contact by reducing the entropic cost associated with the formation of lateral cis oligomers. Cadherins outside the classical subfamily appear to have evolved distinct adhesive mechanisms that are only now beginning to be understood.
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structure and binding mechanism of vascular endothelial cadherin a divergent classical cadherin
Journal of Molecular Biology, 2011Co-Authors: Julia Brasch, O J Harrison, Goran Ahlsen, Stewart M Carnally, Barry Honig, Robert M Henderson, Lawrence ShapiroAbstract:Vascular endothelial cadherin (VE-cadherin), a divergent member of the type II classical cadherin family of cell adhesion proteins, mediates homophilic adhesion in the vascular endothelium. Previous investigations with a bacterially produced protein suggested that VE-cadherin forms cell surface trimers that bind between apposed cells to form hexamers. Here we report studies of mammalian-produced VE-cadherin ectodomains suggesting that, like other classical Cadherins, VE-cadherin forms adhesive trans dimers between monomers located on opposing cell surfaces. Trimerization of the bacterially produced protein appears to be an artifact that arises from a lack of glycosylation. We also present the 2.1-A-resolution crystal structure of the VE-cadherin EC1-2 adhesive region, which reveals homodimerization via the strand-swap mechanism common to classical Cadherins. In common with type II Cadherins, strand-swap binding involves two tryptophan anchor residues, but the adhesive interface resembles type I Cadherins in that VE-cadherin does not form a large nonswapped hydrophobic surface. Thus, VE-cadherin is an outlier among classical Cadherins, with characteristics of both type I and type II subfamilies.
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sequence and structural determinants of strand swapping in cadherin domains do all Cadherins bind through the same adhesive interface
Journal of Molecular Biology, 2008Co-Authors: Lawrence Shapiro, Shoshana Posy, Barry HonigAbstract:Cadherins are cell surface adhesion proteins important for tissue development and integrity. Type I and type II, or “classical”, Cadherins form adhesive dimers via an interface formed through the exchange, or “swapping”, of the N-terminal β-strands from their membrane-distal EC1 domains. Here we ask which sequence and structural features in EC1 domains are responsible for β-strand swapping and whether members of other cadherin families also form similar strand-swapped binding interfaces. We first create a comprehensive database consisting of multiple alignments of each type of cadherin domain. We use the known three-dimensional structures of classical Cadherins to identify conserved positions in multiple sequence alignments that appear to be crucial determinants of the cadherin domain structure. We further identify features that are unique to EC1 domains. On the basis of our analysis we conclude that all cadherin domains have very similar overall folds but, with the exception of classical and desmosomal cadherin EC1 domains, most of them do not appear to bind through a strand swapping mechanism. Thus, non-classical Cadherins that function in adhesion are likely to use different protein-protein interaction interfaces. Our results have implications for the evolution of molecular mechanisms of cadherin-mediated adhesion in vertebrates.
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type ii cadherin ectodomain structures implications for classical cadherin specificity
Cell, 2006Co-Authors: Saurabh D Patel, Carlo Ciatto, Chien Peter Chen, Fabiana Bahna, Manisha Rajebhosale, Natalie Arkus, Ira Schieren, Thomas M Jessell, Barry HonigAbstract:Type I and II classical Cadherins help to determine the adhesive specificities of animal cells. Crystal-structure determination of ectodomain regions from three type II Cadherins reveals adhesive dimers formed by exchange of N-terminal β strands between partner extracellular cadherin-1 (EC1) domains. These interfaces have two conserved tryptophan side chains that anchor each swapped strand, compared with one in type I Cadherins, and include large hydrophobic regions unique to type II interfaces. The EC1 domains of type I and type II Cadherins appear to encode cell adhesive specificity in vitro. Moreover, perturbation of motor neuron segregation with chimeric Cadherins depends on EC1 domain identity, suggesting that this region, which includes the structurally defined adhesive interface, encodes type II cadherin functional specificity in vivo.
