Abstract
Yes-associated protein (YAP) regulates numerous cellular homeostasis processes and malignant transformation. We found that YAP influences ZO-1-mediated cell migration using E-cadherin-restored EC96 cells derived from gastric malignant AGS cells. Ectopic expression of E-cadherin enhanced straightforward migration of cells, in comparison to the meandering movement of parental AGS cells. In EC96 cells, YAP and ZO-1 expression increased but nuclear YAP levels and activity were reduced. Nuclear factor-κB (NF-κB) mediated the increase in ZO-1 expression, possibly stabilizing cytoplasmic YAP post-translationally. Downregulation of YAP expression using siYAP RNA or stable knock-down inhibited straightforward cell migration by fragmenting ZO-1 containing tight junctions (TJs) but not adherens junctions, implying involvement of YAP in ZO-1-mediated cell migration. The association of YAP with ZO-1 was mediated by angiomotin (AMOT) because downregulation of AMOT dissociated YAP from ZO-1 and reduced cell migration. E-cadherin restoration in malignant cancer cells induced NF-κB signaling to enhance ZO-1 expression and subsequently stabilize YAP. At high expression levels, YAP associates with ZO-1 via AMOT at TJs, influencing ZO-1-mediated cell migration and maintaining TJ integrity.
Highlights
The Hippo signaling pathway and its major effector protein, Yes-associated protein (YAP), are evolutionarily conserved regulators of cell growth, organ size, and tissue homeostasis in a variety of species from Drosophila to mammals [1,2]
To identify the underlying mechanism, we investigated the effect of YAP on ZO-1-mediated tight junctions (TJs) structures and cell migration
E-cadherin plays an important role in cell–cell adhesion and regulates cellular processes including migration [33]
Summary
The Hippo signaling pathway and its major effector protein, Yes-associated protein (YAP), are evolutionarily conserved regulators of cell growth, organ size, and tissue homeostasis in a variety of species from Drosophila to mammals [1,2]. Disruption of TJs or AJs in cultured mammalian cells induces YAP nuclear localization and target gene expression [12,14]. Β-catenin, a major effector of the Wnt signaling pathway and a component of AJs, binds with YAP directly and mediates cross-regulation between the. Several components of TJs regulate Hippo and YAP activities [12]. Angiomotin (AMOT) family proteins interact with YAP and multiple components of TJs and AJs, such as β-catenin and ZO-1 [24,25]. We observed that E-cadherin restoration elevated expression of ZO-1 and YAP, which was accompanied by increased cell migration in the context of reduced YAP nuclear accumulation and activity. To identify the underlying mechanism, we investigated the effect of YAP on ZO-1-mediated TJ structures and cell migration
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