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Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling

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A Corrigendum to this article was published on 03 April 2017

Abstract

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.

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Acknowledgements

We thank Drs González-Sancho, C Niehrs, A Bigas and A Kikuchi for providing reagents and N Ontiveros for excellent technical assistance. 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. MV was a recipient of a predoctoral fellowship from FPI.

Author contributions

MD and AGdeH conceived the study. MV, BDV-P, JC, MP and AV performed the experiments. MV and BDV-P prepared the figures. MD and AGdeH designed the experiments and wrote the manuscript with inputs from MV and BDV-P and JY. All authors contributed to the interpretation and the discussion of the results.

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Author notes

  1. M Vinyoles and B Del Valle-Pérez: These authors contributed equally to this work.

Authors and Affiliations

  1. Department de Bioquímica i Biologia Molecular, CEB, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain

    M Vinyoles, B Del Valle-Pérez, J Curto, M Padilla, A Villarroel & M Duñach

  2. Programa de Recerca en Càncer, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain

    M Vinyoles & A G de Herreros

  3. Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Urbana, IL, USA

    J Yang

  4. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    A G de Herreros

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  1. M Vinyoles
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Correspondence to A G de Herreros or M Duñach.

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Vinyoles, M., Del Valle-Pérez, B., Curto, J. et al. Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling. Oncogene 36, 429–438 (2017). https://doi.org/10.1038/onc.2016.209

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