title: Wnt controls the transcriptional activity of Kaiso through CK1ε-dependent phosphorylation of p120-catenin.
abstract: p120-catenin is an E-cadherin-associated protein that modulates E-cadherin function and stability. In response to Wnt3a, p120-catenin is phosphorylated at Ser268 and Ser269, disrupting its interaction with E-cadherin. Here, we describe that Wnt-induced p120-catenin phosphorylation at Ser268 and Ser269 also enhances its binding to the transcriptional factor Kaiso, preventing Kaiso-mediated inhibition of the β-catenin-Tcf-4 transcriptional complex. Kaiso-mediated repression of this complex is due to its association not only with Tcf-4 but also with β-catenin. Disruption of Tcf-4-Kaiso and β-catenin-Kaiso interactions by p120-catenin not only releases Tcf-4 and β-catenin enabling its mutual association and the formation of the transcriptional complex but also permits Kaiso binding to methylated CpG islands, an interaction that is weakly inhibited by p120-catenin. Consequently, Wnt stimulates Kaiso association to the CDKN2A promoter, which contains CpG sequences, in cells where these sequences are extensively methylated, such as HT-29 M6, an effect accompanied by decreased expression of its gene product. These results indicate that, when released from E-cadherin by Wnt3a-stimulated phosphorylation, p120-catenin controls the activity of the Kaiso transcriptional factor, enhancing its binding to repressed promoters and relieving its inhibition of the β-catenin-Tcf-4 transcriptional complex.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra E-08193, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Del Valle-Pérez
authors.forename: David
authors.initials: D
authors.lastname: Casagolda
authors.forename: Ero
authors.initials: E
authors.lastname: Lugilde
authors.forename: Gabriela
authors.initials: G
authors.lastname: Valls
authors.forename: Montserrat
authors.initials: M
authors.lastname: Codina
authors.forename: Natàlia
authors.initials: N
authors.lastname: Dave
authors.forename: Antonio García
authors.initials: AG
authors.lastname: de Herreros
authors.forename: Mireia
authors.initials: M
authors.lastname: Duñach
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D051177:Catenins / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019942:Genes, p16; D006801:Humans; D008745:Methylation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D000095002:Delta Catenin
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; D051177:Catenins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C492254:ZBTB33 protein, human; D051176:beta Catenin; D000095002:Delta Catenin; C000722347:CTNND1 protein, human