title: β-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis.
abstract: 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-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 β-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 βcatenin. Surprisingly, the expression of β-catenin(E654) 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.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, room L-63, 's Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. w.vanveelen@erasmusmc.nl
authors.forename: Wendy
authors.initials: W
authors.lastname: van Veelen
authors.forename: Ngoc H
authors.initials: NH
authors.lastname: Le
authors.forename: Werner
authors.initials: W
authors.lastname: Helvensteijn
authors.forename: Lau
authors.initials: L
authors.lastname: Blonden
authors.forename: Myrte
authors.initials: M
authors.lastname: Theeuwes
authors.forename: Elvira R M
authors.initials: ER
authors.lastname: Bakker
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Franken
authors.forename: Léon
authors.initials: L
authors.lastname: van Gurp
authors.forename: Frits
authors.initials: F
authors.lastname: Meijlink
authors.forename: Martin A
authors.initials: MA
authors.lastname: van der Valk
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D020964:Embryo Loss / Q000235:genetics; D055879:Gene Knock-In Techniques; D017491:Genes, APC; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051153:Wnt Proteins; D051176:beta Catenin; D017868:Cyclic AMP-Dependent Protein Kinases