| Title | β-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis |
|---|---|
| Published in | Gut (English Edition): an international journal of gastroenterology & hepatology. ISSN 0017-5749. |
| Author | Veelen, van W. (Wendy); Le, N.H. (Ngoc); Helvensteijn, W. (Werner); Blonden, L. (Lau); Theeuwes, J.J.M. (Myrte); Bakker, E. (Elvira); Franken, P.F. (Patrick); Gurp, van L. (Léon); Meijlink, F. (Frits); Valk, van der M.A. (Martin); Kuipers, E.J. (Ernst); Fodde, R. (Riccardo); Smits, R. (Ron) |
| Date | 2011-02-09 |
| Language | English |
| Type | article |
| Abstract | Objective: Deregulation of the Wnt signalling pathway by mutations in the Apc or β-catenin genes underlies colorectal carcinogenesis. As a result, β-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear β-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate β-catenin at tyrosine residues, which is thought to increase β-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of β-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design: A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous β-catenin gene was introduced. Results: This study provided in vivo evidence that β-cateninE654 is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the β-cateninE654 targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of βcatenin. Surprisingly, the expression of β-cateninE654 did not affect histological grade or induce tumour invasiveness. Conclusions: A thus far unknown mechanism was uncovered in which Y654 phosphorylation of β-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that β-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling. |
| Publication | http://hdl.handle.net/1765/22857 |
| Persistent Identifier | urn:NBN:nl:ui:15-1765/22857 |
| Metadata | XML |
| Repository | Erasmus University Rotterdam |
Go to page top
Go back to contents
Go back to site navigation