Activation of CK1ϵ by PP2A/PR61ϵ 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, ϵ, γ and GSK3. Among these, activation of CK1ϵ, constitutively bound to LRP5/6 through p120-catenin, is required for the association of the rest of the components. We describe here that CK1ϵ is activated by the PP2A/PR61ϵ phosphatase. Binding of Wnt ligands promotes the interaction of LRP5/6-associated CK1ϵ with Frizzled-bound PR61ϵ regulatory subunit, facilitating the access of PP2A catalytic subunit to CK1ϵ 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.