E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis.

Epithelial-to-mesenchymal transition (EMT) is acellular process essential to the development andmaintenance of solid tissues. In cancer, EMT sup-presses apoptosis, but the mechanisms remain un-clear.EMTselectivelyattenuatedapoptosissignalingvia the death receptors DR4 and DR5. Loss of theepithelial cell adhesion protein E-cadherin recapitu-lated this outcome, whereas homotypic E-cadherinengagement promoted apoptotic signaling via DR4/DR5, but not Fas. Depletion of a-catenin, whichcouples E-cadherin to the actin cytoskeleton, oractin polymerization inhibitors similarly attenuatedDR4/DR5-induced apoptosis. E-cadherin boundspecifically to ligated DR4/DR5, requiring extracel-lular cadherin domain 1 and calcium. E-cadherinaugmented DR4/DR5 clustering and assembly of thedeath-inducing signaling complex (DISC), increasingcaspase-8 activation in high molecular weight cellfractions. Conversely, EMT attenuated DR4/DR5-mediatedDISCformationandcaspase-8stimulation.Consistent with these findings, epithelial cancer celllines expressing higher E-cadherin levels displayedgreater sensitivity to DR4/DR5-mediated apoptosis.These results have potential implications for tissuehomeostasis as well as cancer therapy.