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)http://hdl.handle.net/1765/22857enjournalArticle0017-5749Objective: 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.2011-02-09 0017-5749 urn:NBN:nl:ui:15-1765/22857