Epithelial-mesenchymal transition and nuclear β-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 β-catenin. Here, we evaluate whether E-cadherin binding can inhibit β-catenin when there is loss of Adenomatous polyp...
| المؤلفون الرئيسيون: | , , , , , , , , , , |
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| التنسيق: | Journal article |
| اللغة: | English |
| منشور في: |
Impact Journal
2016
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| _version_ | 1826296654339244032 |
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| author | Matheson, J Bühnemann, C Carter, E Barnes, D Hoppe, H Hughes, J Cobbold, S Harper, J Morreau, H Surakhy, M Hassan, A |
| author_facet | Matheson, J Bühnemann, C Carter, E Barnes, D Hoppe, H Hughes, J Cobbold, S Harper, J Morreau, H Surakhy, M Hassan, A |
| author_sort | Matheson, J |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:19:40Z |
| format | Journal article |
| id | oxford-uuid:ca953b62-7592-4e09-b7f0-0cae0d0e55da |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:19:40Z |
| publishDate | 2016 |
| publisher | Impact Journal |
| record_format | dspace |
| spelling | oxford-uuid:ca953b62-7592-4e09-b7f0-0cae0d0e55da2022-03-27T07:08:32ZEpithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependentJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ca953b62-7592-4e09-b7f0-0cae0d0e55daEnglishSymplectic Elements at OxfordImpact Journal2016Matheson, JBühnemann, CCarter, EBarnes, DHoppe, HHughes, JCobbold, SHarper, JMorreau, HSurakhy, MHassan, ATwo 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. |
| spellingShingle | Matheson, J Bühnemann, C Carter, E Barnes, D Hoppe, H Hughes, J Cobbold, S Harper, J Morreau, H Surakhy, M Hassan, A Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent |
| title | Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent |
| title_full | Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent |
| title_fullStr | Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent |
| title_full_unstemmed | Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent |
| title_short | Epithelial-mesenchymal transition and nuclear β-catenin induced by conditional intestinal disruption of Cdh1 with Apc is E-cadherin EC1 domain dependent |
| title_sort | epithelial mesenchymal transition and nuclear β catenin induced by conditional intestinal disruption of cdh1 with apc is e cadherin ec1 domain dependent |
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