title: E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis.
abstract: Epithelial-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.
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Ye
authors.affiliation: Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.affiliation: Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors.forename: Lino
authors.initials: L
authors.lastname: Gonzalez
authors.affiliation: Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: aa@gene.com.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D015703:Antigens, CD; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D003599:Cytoskeleton; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051178:alpha Catenin / Q000235:genetics
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C513384:CDH1 protein, human; D015820:Cadherins; D053200:Fas-Associated Death Domain Protein; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D016212:Transforming Growth Factor beta; D051178:alpha Catenin; D053181:Caspase 8; D002118:Calcium