| First Author | van Veelen W | Year | 2011 |
| Journal | Gut | Volume | 60 |
| Issue | 9 | Pages | 1204-12 |
| PubMed ID | 21307168 | Mgi Jnum | J:185942 |
| Mgi Id | MGI:5430596 | Doi | 10.1136/gut.2010.233460 |
| Citation | van Veelen W, et al. (2011) beta-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis. Gut 60(9):1204-12 |
| abstractText | Objective Deregulation of the Wnt signalling pathway by mutations in the Apc or beta-catenin genes underlies colorectal carcinogenesis. As a result, beta-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear beta-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 beta-catenin at tyrosine residues, which is thought to increase beta-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of beta-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 beta-catenin gene was introduced. Results This study provided in vivo evidence that beta-catenin(E654) 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 beta-catenin(E654) 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 betacatenin. Surprisingly, the expression of beta-catenin(E654) did not affect histological grade or induce tumour invasiveness. Conclusions A thus far unknown mechanism was uncovered in which Y654 phosphorylation of beta-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that beta-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling. |
