Epithelial-Mesenchymal Transition And Nuclear Beta-Catenin Induced By Conditional Intestinal Disruption Of Cdh1 With Apc Is E-Cadherin Ec1 Domain Dependent

Two important protein-protein interactions establish E-cadherin (Cdh1) in the adhesion complex; homophilic binding via the extra-cellular (EC1) domain and cytoplasmic tail binding to beta-catenin. Here, we evaluate whether E-cadherin binding can inhibit beta-catenin when there is loss of Adenomatous polyposis coli (APC) from the beta-catenin destruction complex. Combined conditional loss of Cdh1 and Apc were generated in the intestine, intestinal adenoma and adenoma organoids. Combined intestinal disruption (Cdh1(fl/fl)Apc(fl/fl)Vil-CreERT2) resulted in lethality, breakdown of the intestinal barrier, increased Wnt target gene expression and increased nuclear beta-catenin localization, suggesting that E-cadherin inhibits beta-catenin. Combination with an intestinal stem cell Cre (Lgr5CreERT2) resulted in Apc(Delta/Delta) recombination and adenoma, but intact Cdh1(fl/fl) alleles. Cultured Apc(Delta/Delta)Cdh1(fl/fl) adenoma cells infected with adenovirus-Cre induced Cdh1(fl/fl) recombination (Cdh1(Delta/Delta)), disruption of organoid morphology, nuclear beta-catenin localization, and cells with an epithelial-mesenchymal phenotype. Complementation with adenovirus expressing wild-type Cdh1 (Cdh1-WT) rescued adhesion and beta-catenin membrane localization, yet an EC1 specific double mutant defective in homophilic adhesion (Cdh1-Mut(W2A,S78W)) did not. These data suggest that E-cadherin inhibits beta-catenin in the context of disruption of the APC-destruction complex, and that this function is also EC1 domain dependent. Both binding functions of E-cadherin may be required for its tumour suppressor activity.