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Splice variants of CK1α and CK1α-like: Comparative analysis of subcellular localization, kinase activity, and function in the Wnt signaling pathway

T. Gybeľ, Š. Čada, D. Klementová, MP. Schwalm, BT. Berger, M. Šebesta, S. Knapp, V. Bryja

. 2024 ; 300 (7) : 107407. [pub] 20240523

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, srovnávací studie

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019900

Members of the casein kinase 1 (CK1) family are important regulators of multiple signaling pathways. CK1α is a well-known negative regulator of the Wnt/β-catenin pathway, which promotes the degradation of β-catenin via its phosphorylation of Ser45. In contrast, the closest paralog of CK1α, CK1α-like, is a poorly characterized kinase of unknown function. In this study, we show that the deletion of CK1α, but not CK1α-like, resulted in a strong activation of the Wnt/β-catenin pathway. Wnt-3a treatment further enhanced the activation, which suggests there are at least two modes, a CK1α-dependent and Wnt-dependent, of β-catenin regulation. Rescue experiments showed that only two out of ten naturally occurring splice CK1α/α-like variants were able to rescue the augmented Wnt/β-catenin signaling caused by CK1α deficiency in cells. Importantly, the ability to phosphorylate β-catenin on Ser45 in the in vitro kinase assay was required but not sufficient for such rescue. Our compound CK1α and GSK3α/β KO models suggest that the additional nonredundant function of CK1α in the Wnt pathway beyond Ser45-β-catenin phosphorylation includes Axin phosphorylation. Finally, we established NanoBRET assays for the three most common CK1α splice variants as well as CK1α-like. Target engagement data revealed comparable potency of known CK1α inhibitors for all CK1α variants but not for CK1α-like. In summary, our work brings important novel insights into the biology of CK1α, including evidence for the lack of redundancy with other CK1 kinases in the negative regulation of the Wnt/β-catenin pathway at the level of β-catenin and Axin.

Citace poskytuje Crossref.org

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$a Čada, Štěpán $u Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
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$a Klementová, Darja $u Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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$a Schwalm, Martin P $u Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany; Structural Genomics Consortium, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany; German Cancer Consortium (DKTK)/German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, Heidelberg, Germany
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$a Berger, Benedict-Tilman $u Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany; Structural Genomics Consortium, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
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$a Šebesta, Marek $u CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic
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$a Knapp, Stefan $u Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany; Structural Genomics Consortium, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany; German Cancer Consortium (DKTK)/German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, Heidelberg, Germany
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