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.
Highlights
Cadherins comprise a large family of Ca2+-dependent cell–cell adhesion molecules
Cells expressing the control Discosoma sp. red fluorescent protein (DsRed) grew in monolayer cultures as epithelial clusters with a typical cobblestone morphology, whereas the expression of the DECT protein resulted in the loss of cell–cell contacts and in cell scattering (Fig. 1B)
DsRed cells migrated as cell sheets, DECT+ cells migrated as single cells, raising the possibility that DECT+ cells had lost the integrity of the epithelial sheets
Summary
E-Cadherin, a prototypical member of this family, is a transmembrane protein that forms the adherens junction between epithelial cells. ACatenin interacts with the cadherins indirectly via interactions with b-catenin or plakoglobin, and links the cadherin–catenin complex to the actin cytoskeleton through interactions with aactinin, vinculin, formin, EPLIN (epithelial protein lost in neoplasm), and actin filaments [1]. P120 can interact with cadherins and regulates the steady-state levels and endocytosis of cadherins in cells [2,3]. The loss of E-cadherin is accompanied by the upregulation of mesenchymal markers, such as N-cadherin, fibronectin, and vimentin. Concomitant with these molecular changes, cells acquire a spindle-shaped mesenchymal morphology, and display enhanced migration and invasive properties [5]
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