PT  - JOURNAL ARTICLE
AU  - Wendy van Veelen
AU  - Ngoc H Le
AU  - Werner Helvensteijn
AU  - Lau Blonden
AU  - Myrte Theeuwes
AU  - Elvira R M Bakker
AU  - Patrick F Franken
AU  - Léon van Gurp
AU  - Frits Meijlink
AU  - Martin A van der Valk
AU  - Ernst J Kuipers
AU  - Riccardo Fodde
AU  - Ron Smits
TI  - <em>β</em>-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis
AID  - 10.1136/gut.2010.233460
DP  - 2011 Sep 01
TA  - Gut
PG  - 1204--1212
VI  - 60
IP  - 9
4099  - http://gut.bmj.com/content/60/9/1204.short
4100  - http://gut.bmj.com/content/60/9/1204.full
SO  - Gut2011 Sep 01; 60
AB  - 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.