beta-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis

W. van Veelen, N.H. Le, W. Helvensteijn, L. Blonden, M. Theeuwes, E.R. Bakker, P.F. Franken, L. van Gurp, F. Meijlink, M.A. van der Valk, E.J. Kuipers, R. Fodde, R.E.H.M. Smits

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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. [KEYWORDS: Adenoma/genetics/metabolism, Animals, COS Cells, Cadherins/metabolism, Cell Membrane/metabolism, Cell Transformation, Neoplastic/genetics/ metabolism, Cercopithecus aethiops, Colorectal Neoplasms/genetics/ metabolism, Cyclic AMP-Dependent Protein Kinases/pharmacology, Embryo Loss/genetics, Gene Knock-In Techniques, Genes, APC, Genotype, Heterozygote, Homozygote, Mice, Mice, Inbred C57BL, Phosphorylation/drug effects/physiology, Wnt Proteins/ physiology, beta Catenin/ metabolism]
Original languageEnglish
Pages (from-to)1204-1212
JournalGut
Volume60
Issue number9
DOIs
Publication statusPublished - 2011

Fingerprint

Dive into the research topics of 'beta-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis'. Together they form a unique fingerprint.

Cite this