Disparate effects of different mutations in plakoglobin on cell mechanical behavior

Abstract

Mutations in genes encoding desmosomal proteins have been implicated in the pathogenesis of heart and skin diseases. This has led to the hypothesis that defective cell-cell adhesion is the underlying cause of injury in tissues that repeatedly bear high mechanical loads. In this study, we examined the effects of two different mutations in plakoglobin on cell migration, stiffness, and adhesion. One is a C-terminal mutation causing Naxos disease, a recessive syndrome of arrhythmogenic right ventricular cardiomyopathy (ARVC) and abnormal skin and hair. The other is an N-terminal mutation causing dominant inheritance of ARVC without cutaneous abnormalities. To assess the effects of plakoglobin mutations on a broad range of cell mechanical behavior, we characterized a model system consisting of stably transfected HEK cells which are particularly well suited for analyses of cell migration and adhesion. Both mutations increased the speed of wound healing which appeared to be related to increased cell motility rather than increased cell proliferation. However, the C-terminal mutation led to dramatically decreased cell-cell adhesion, whereas the N-terminal mutation caused a decrease in cell stiffness. These results indicate that different mutations in plakoglobin have markedly disparate effects on cell mechanical behavior, suggesting complex biomechanical roles for this protein.

High Motility of Triple-negative Breast Cancer Cells Is Due to Repression of Plakoglobin Gene by Metastasis Modulator Protein SLUG

“…Tissues-As mentioned above, the armadillo motif-containing protein plakoglobin is known to negatively regulate the motility of epithelial cells (17)(18)(19)(20)(21)(22)(23). Because SLUG in the breast cancer cells regulates the motility of these cells, we hypothesized that SLUG represses plakoglobin gene in these cells to increase their motility.…”

“…Recent report indicates that plakoglobin not only inhibits motility of keratinocytes in contact but also inhibits Src-dependent single cell motility (17). These results indicate that plakoglobin is capable of regulating single cell motility through matrix deposition in concert with Rho GTPases independently of its role as a cell-cell adhesion molecule (17,18).…”

“…Out of several epithelial cell molecules implicated in the direct or indirect regulation of cellular motility, the catenin molecule plakoglobin stands out as a major player in negatively regulating the motility of these cells (17)(18)(19)(20)(21)(22)(23). Plakoglobin (also known as junction plakoglobin (JUP)) is a member of the armadillo family of proteins and a close relative of ␤-catenin (24).…”

“…Plakoglobin (also known as junction plakoglobin (JUP)) is a member of the armadillo family of proteins and a close relative of ␤-catenin (24). Plakoglobin comprises 12 central armadillo repeats, which are flanked by N-and C-terminal domains (17)(18)(19). By interacting with both the desmosomal cadherins and the N terminus of desmoplakin, plakoglobin is positioned to play a role in linking intermediate filaments to the desmosomal plaque (17)(18)(19).…”

“…Plakoglobin comprises 12 central armadillo repeats, which are flanked by N-and C-terminal domains (17)(18)(19). By interacting with both the desmosomal cadherins and the N terminus of desmoplakin, plakoglobin is positioned to play a role in linking intermediate filaments to the desmosomal plaque (17)(18)(19). Recent report indicates that plakoglobin not only inhibits motility of keratinocytes in contact but also inhibits Src-dependent single cell motility (17).…”