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E‐cadherin can limit the transforming properties of activating β‐catenin mutations
Author(s) -
Huels David J,
Ridgway Rachel A,
Radulescu Sorina,
Leushacke Marc,
Campbell Andrew D,
Biswas Sujata,
Leedham Simon,
Serra Stefano,
Chetty Runjan,
Moreaux Guenievre,
Parry Lee,
Matthews James,
Song Fei,
Hedley Ann,
Kalna Gabriela,
Ceteci Fatih,
Reed Karen R,
Meniel Valerie S,
Maguire Aoife,
Doyle Brendan,
Söderberg Ola,
Barker Nick,
Watson Alastair,
Larue Lionel,
Clarke Alan R,
Sansom Owen J
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201591739
Subject(s) - wnt signaling pathway , catenin , cancer research , mutation , cadherin , phenotype , colorectal cancer , frameshift mutation , biology , progenitor cell , beta catenin , gene silencing , cancer , microbiology and biotechnology , cell , genetics , signal transduction , stem cell , gene
Wnt pathway deregulation is a common characteristic of many cancers. Only colorectal cancer predominantly harbours mutations in APC , whereas other cancer types (hepatocellular carcinoma, solid pseudopapillary tumours of the pancreas) have activating mutations in β‐catenin ( CTNNB 1) . 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 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 higher expression of E‐cadherin and a higher number of E‐cadherin:β‐catenin complexes at the membrane. Reduction in E‐cadherin synergised with an activating mutation of β‐catenin resulting in a rapid CPC phenotype within the SI and colon. Thus, there is a threshold of β‐catenin that is required to drive transformation, and E‐cadherin can act as a buffer to sequester mutated β‐catenin.