TY - JOUR T1 - <em>β</em>-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis JF - Gut JO - Gut SP - 1204 LP - 1212 DO - 10.1136/gut.2010.233460 VL - 60 IS - 9 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 Y1 - 2011/09/01 UR - http://gut.bmj.com/content/60/9/1204.abstract N2 - 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. ER -