title: Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6.
abstract: The Wnt canonical ligands elicit the activation of β-catenin transcriptional activity, a response dependent on, but not limited to, β-catenin stabilization through the inhibition of GSK3 activity. Two mechanisms have been proposed for this inhibition, one dependent on the binding and subsequent block of GSK3 to LRP5/6 Wnt coreceptor and another one on its sequestration into multivesicular bodies (MVBs). Here we report that internalization of the GSK3-containing Wnt-signalosome complex into MVBs is dependent on the dissociation of p120-catenin/cadherin from this complex. Disruption of cadherin-LRP5/6 interaction is controlled by cadherin phosphorylation and requires the previous separation of p120-catenin; thus, p120-catenin and cadherin mutants unable to dissociate from the complex block GSK3 sequestration into MVBs. These mutants substantially inhibit, but do not completely prevent, the β-catenin upregulation caused by Wnt3a. These results, besides elucidating how GSK3 is sequestered into MVBs, support this mechanism as cause of β-catenin stabilization by Wnt.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Vinyoles
authors.affiliation: Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Del Valle-Pérez
authors.affiliation: Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Josué
authors.initials: J
authors.lastname: Curto
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), E-08003 Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Viñas-Castells
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), E-08003 Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Alba-Castellón
authors.affiliation: Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), E-08003 Barcelona, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain. Electronic address: agarcia@imim.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: García de Herreros
authors.affiliation: Departament de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain. Electronic address: mireia.dunach@uab.es.
authors.forename: Mireia
authors.initials: M
authors.lastname: Duñach
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D051177:Catenins / Q000378:metabolism / Q000502:physiology*; D022461:Caveolins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000032:analysis / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D057146:Multivesicular Bodies / Q000378:metabolism*; D010766:Phosphorylation; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism / Q000502:physiology; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; D022461:Caveolins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D060509:Wnt3A Protein; D038362:Glycogen Synthase Kinase 3; D000095002:Delta Catenin