Epithelial-mesenchymal transition and nuclear ?-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent.

ABSTRACT: 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 ?-catenin. Here, we evaluate whether E-cadherin binding can inhibit ?-catenin when there is loss of Adenomatous polyposis coli (APC) from the ?-catenin destruction complex. Combined conditional loss of Cdh1 and Apc were generated in the intestine, intestinal adenoma and adenoma organoids. Combined intestinal disruption (Cdh1fl/flApcfl/flVil-CreERT2) resulted in lethality, breakdown of the intestinal barrier, increased Wnt target gene expression and increased nuclear ?-catenin localization, suggesting that E-cadherin inhibits ?-catenin. Combination with an intestinal stem cell Cre (Lgr5CreERT2) resulted in Apc?/? recombination and adenoma, but intact Cdh1fl/fl alleles. Cultured Apc?/?Cdh1fl/fl adenoma cells infected with adenovirus-Cre induced Cdh1fl/fl recombination (Cdh1?/?), disruption of organoid morphology, nuclear ?-catenin localization, and cells with an epithelial-mesenchymal phenotype. Complementation with adenovirus expressing wild-type Cdh1 (Cdh1-WT) rescued adhesion and ?-catenin membrane localization, yet an EC1 specific double mutant defective in homophilic adhesion (Cdh1-MutW2A, S78W) did not. These data suggest that E-cadherin inhibits ?-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.

SUBMITTER: Matheson J 

PROVIDER: S-EPMC5342522 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature