E-Cadherin Couples Death Receptors to the Cytoskeleton to Regulate Apoptosis

•EMT or loss of E-cadherin attenuates apoptotic signaling via DR4 and DR5•E-cadherin engagement augments apoptosis activation via DR4 and DR5•E-cadherin directly interacts with ligated DR4 or DR5 to enhance caspase-8 activation•E-cadherin augments signaling by coupling DR4 or DR5 to the actin cytoskeleton

SummaryEpithelial-to-mesenchymal transition (EMT) is a cellular process essential to the development and maintenance of solid tissues. In cancer, EMT suppresses apoptosis, but the mechanisms remain unclear. EMT selectively attenuated apoptosis signaling via the death receptors DR4 and DR5. Loss of the epithelial cell adhesion protein E-cadherin recapitulated this outcome, whereas homotypic E-cadherin engagement promoted apoptotic signaling via DR4/DR5, but not Fas. Depletion of α-catenin, which couples E-cadherin to the actin cytoskeleton, or actin polymerization inhibitors similarly attenuated DR4/DR5-induced apoptosis. E-cadherin bound specifically to ligated DR4/DR5, requiring extracellular cadherin domain 1 and calcium. E-cadherin augmented DR4/DR5 clustering and assembly of the death-inducing signaling complex (DISC), increasing caspase-8 activation in high molecular weight cell fractions. Conversely, EMT attenuated DR4/DR5-mediated DISC formation and caspase-8 stimulation. Consistent with these findings, epithelial cancer cell lines expressing higher E-cadherin levels displayed greater sensitivity to DR4/DR5-mediated apoptosis. These results have potential implications for tissue homeostasis as well as cancer therapy.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (288 K)Download as PowerPoint slide