title: Cadherin cytoplasmic domains inhibit the cell surface localization of endogenous E-cadherin, blocking desmosome and tight junction formation and inducing cell dissociation.
abstract: The downregulation of E-cadherin function has fundamental consequences with respect to cancer progression, and occurs as part of the epithelial-mesenchymal transition (EMT). In this study, we show that the expression of the Discosoma sp. red fluorescent protein (DsRed)-tagged cadherin cytoplasmic domain in cells inhibited the cell surface localization of endogenous E-cadherin, leading to morphological changes, the inhibition of junctional assembly and cell dissociation. These changes were associated with increased cell migration, but were not accompanied by the down-regulation of epithelial markers and up-regulation of mesenchymal markers. Thus, these changes cannot be classified as EMT. The cadherin cytoplasmic domain interacted with β-catenin or plakoglobin, reducing the levels of β-catenin or plakoglobin associated with E-cadherin, and raising the possibility that β-catenin and plakoglobin sequestration by these constructs induced E-cadherin intracellular localization. Accordingly, a cytoplasmic domain construct bearing mutations that weakened the interactions with β-catenin or plakoglobin did not impair junction formation and adhesion, indicating that the interaction with β-catenin or plakoglobin was essential to the potential of the constructs. E-cadherin-α-catenin chimeras that did not require β-catenin or plakoglobin for their cell surface transport restored cell-cell adhesion and junction formation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ozawa
authors.affiliation: Department of Biochemistry and Molecular Biology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002450:Cell Communication / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D021381:Protein Transport; D019108:Tight Junctions / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D051185:gamma Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; D051176:beta Catenin; D051185:gamma Catenin