title: Epithelial-mesenchymal transition and nuclear β-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 β-catenin. Here, we evaluate whether E-cadherin binding can inhibit β-catenin when there is loss of Adenomatous polyposis coli (APC) from the β-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 β-catenin localization, suggesting that E-cadherin inhibits β-catenin. Combination with an intestinal stem cell Cre (Lgr5CreERT2) resulted in ApcΔ/Δ recombination and adenoma, but intact Cdh1fl/fl alleles. Cultured ApcΔ/ΔCdh1fl/fl adenoma cells infected with adenovirus-Cre induced Cdh1fl/fl recombination (Cdh1Δ/Δ), disruption of organoid morphology, nuclear β-catenin localization, and cells with an epithelial-mesenchymal phenotype. Complementation with adenovirus expressing wild-type Cdh1 (Cdh1-WT) rescued adhesion and β-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 β-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.
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: Julia
authors: J
authors: Matheson
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: Claudia
authors: C
authors: Bühnemann
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: Emma J
authors: EJ
authors: Carter
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: David
authors: D
authors: Barnes
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: Hans-Jürgen
authors: HJ
authors: Hoppe
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: Jennifer
authors: J
authors: Hughes
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: Stephen
authors: S
authors: Cobbold
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: James
authors: J
authors: Harper
authors: Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Hans
authors: H
authors: Morreau
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: Mirvat
authors: M
authors: Surakhy
authors: Tumour Growth Group, Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors: A Bassim
authors: AB
authors: Hassan
mesh_terms: D000236:Adenoma / Q000209:etiology; D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000737:chemistry / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D047108:Embryonic Development; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007414:Intestinal Neoplasms / Q000209:etiology; D061986:MCF-7 Cells; D051379:Mice; D009940:Organoids; D000072417:Protein Domains; D011995:Recombination, Genetic; D013629:Tamoxifen / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin; D013629:Tamoxifen
keywords: Apc; E-cadherin; adhesion complex; intestine; β-catenin