E-cadherin can limit the transforming properties of activating β-catenin mutations

Huels, David, Ridgeway, Rachel, Radulescu, Sorina, Leushacke, Marc, Campbell, Andrew, Biswas, Sujata, Leedham, Simon, Serra, Stefano, Chetty, Runjan, Moreaux, Guenieve, Parry, Lee, Matthews, James, Song, Fei, Hedley, Ann, Kalna, Gabriela, Ceteci, Fatih, Reed, Karen R, Meniel, Valerie S, Maguire, Aoife, Soderberg, Ola, Barker, Nicholas, Watson, Alastair, Larue, Lionel and Sansom, Owen (2015) E-cadherin can limit the transforming properties of activating β-catenin mutations. The EMBO Journal, 34 (18). pp. 2321-2333. ISSN 0261-4189

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    Abstract

    Wnt pathway deregulation is a common characteristic of many cancers. But only Colorectal Cancer predominantly harbours mutations in APC, whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of pancreas) have activating mutations in β-catenin (CTNNB1). We have compared the dynamics and the potency of β-catenin mutations in vivo. Within the murine small intestine (SI), an activating mutation of β-catenin took much longer to achieve a Wnt deregulation and acquire a crypt-progenitor-cell (CPC) phenotype than Apc or Gsk3 loss. Within the colon, a single activating mutation of β-catenin was unable to drive Wnt deregulation or induce the CPC phenotype. This ability of β-catenin mutation to differentially transform the SI versus the colon correlated with significantly higher expression of the β-catenin binding partner E-cadherin. This increased expression is associated with a higher number of E-cadherin:β-catenin complexes at the membrane. Reduction of E-cadherin synergised with an activating mutation of β-catenin so there was now a rapid CPC phenotype within the colon and SI. Thus there is a threshold of β-catenin that is required to drive transformation and E-cadherin can act as a buffer to prevent β-catenin accumulation.

    Item Type: Article
    Additional Information: © 2015 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
    Uncontrolled Keywords: apc,b-catenin,colorectal cancer,e-cadherin
    Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
    University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
    Depositing User: Pure Connector
    Date Deposited: 13 Nov 2015 13:00
    Last Modified: 28 Aug 2018 14:32
    URI: https://ueaeprints.uea.ac.uk/id/eprint/55189
    DOI: 10.15252/embj.201591739

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