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: Julia Matheson, Claudia Bühnemann, Emma J Carter, David Barnes, Hans-Jürgen Hoppe, Jennifer Hughes, Stephen Cobbold, James Harper, Hans Morreau, Mirvat Surakhy, A Bassim Hassan
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 43 Pg. 69883-69902 (Oct 25 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27566565 (Publication Type: Journal Article)

Chemical References

• APC protein, human
• Adenomatous Polyposis Coli Protein
• Antigens, CD
• CDH1 protein, human
• CTNNB1 protein, human
• Cadherins
• beta Catenin
• Tamoxifen

Topics

• Adenoma (etiology)
• Adenomatous Polyposis Coli Protein (physiology)
• Animals
• Antigens, CD
• Cadherins (chemistry, physiology)
• Cell Nucleus (metabolism)
• Embryonic Development
• Epithelial-Mesenchymal Transition
• Humans
• Intestinal Neoplasms (etiology)
• MCF-7 Cells
• Mice
• Organoids
• Protein Domains
• Recombination, Genetic
• Tamoxifen (pharmacology)
• beta Catenin (metabolism)