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.

This work was funded by grants from the Ministerio de Economía y Competitividad (BFU2012-31554 and BFU2015-65153-R, both MINECO/FEDER, to MD and SAF2013-48849-C2-R1 to AGH) and Fundació La Marató de TV3 (120130) to MD and AGH. Support from ICREA Academia, 2014SGR-32 from Generalitat de Catalunya and ISCIII/FEDER (RD12/0036/005) is also appreciated