Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling.
Canonical Wnt signaling induces the stabilization of β-catenin, its translocation to the nucleus and the activation of target promoters. This pathway is initiated by the binding of Wnt ligands to the Frizzled receptor, the association of the LRP5/6 co-receptor and the formation of a complex comprising Dvl-2, Axin and protein kinases CK1α, ɛ, γ and GSK3. Among these, activation of CK1ɛ, constitutively bound to LRP5/6 through p120-catenin, is required for the association of the rest of the components. We describe here that CK1ɛ is activated by the PP2A/PR61ɛ phosphatase. Binding of Wnt ligands promotes the interaction of LRP5/6-associated CK1ɛ with Frizzled-bound PR61ɛ regulatory subunit, facilitating the access of PP2A catalytic subunit to CK1ɛ and its activation, what enables the recruitment of Dvl-2 to the receptor complex and the initiation of the Wnt pathway. Our results uncover the mechanism of activation of the canonical Wnt pathway by its ligands.
Department de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.
M
M
Vinyoles
Department de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
B
B
Del Valle-Pérez
Department de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
J
J
Curto
Department de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
M
M
Padilla
Department de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
A
A
Villarroel
Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Urbana, IL, USA.
J
J
Yang
Programa de Recerca en Càncer, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain.|Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
A G
AG
de Herreros
Department de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
M
M
Duñach
D048148:Casein Kinase Idelta / Q000378:metabolism*; D051157:Frizzled Receptors / Q000378:metabolism; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D060449:Wnt Signaling Pathway
D051157:Frizzled Receptors; C525690:PPP2R5A protein, human; D048148:Casein Kinase Idelta; D054648:Protein Phosphatase 2