E-cadherin can limit the transforming properties of activating {beta}-catenin mutations
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 (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 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.
Source: EMBO Journal - Category: Molecular Biology Authors: Huels, D. J., Ridgway, R. A., Radulescu, S., Leushacke, M., Campbell, A. D., Biswas, S., Leedham, S., Serra, S., Chetty, R., Moreaux, G., Parry, L., Matthews, J., Song, F., Hedley, A., Kalna, G., Ceteci, F., Reed, K. R., Meniel, V. S., Maguire, A., Doyle, Tags: Cancer, Cell Adhesion, Polarity & Cytoskeleton Articles Source Type: research
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