Splice variants of CK1α and CK1α-like: Comparative analysis of subcellular localization, kinase activity, and function in the Wnt signaling pathway
| Autoři | |
|---|---|
| Rok publikování | 2024 |
| Druh | Článek v odborném periodiku |
| Časopis / Zdroj | International Journal of Biological Chemistry |
| Fakulta / Pracoviště MU | |
| Citace | |
| www | https://www.sciencedirect.com/science/article/pii/S0021925824019082 |
| Doi | http://dx.doi.org/10.1016/j.jbc.2024.107407 |
| Klíčová slova | casein kinase 1 alpha (CK1?); casein kinase 1 alpha-like (CK1?-like); Wnt pathway; ß-catenin; Axin; phosphorylation; alternative splicing; gene knockout; NanoBRET; inhibitor |
| Přiložené soubory | |
| Popis | Members of the casein kinase 1 (CK1) family are important regulators of multiple signaling pathways. CK1? is a well-known negative regulator of the Wnt/ß-catenin pathway, which promotes the degradation of ß-catenin via its phosphorylation of Ser45. In contrast, the closest paralog of CK1?, CK1?-like, is a poorly characterized kinase of unknown function. In this study, we show that the deletion of CK1?, but not CK1?-like, resulted in a strong activation of the Wnt/ß-catenin pathway. Wnt-3a treatment further enhanced the activation, which suggests there are at least two modes, a CK1?-dependent and Wnt-dependent, of ß-catenin regulation. Rescue experiments showed that only two out of ten naturally occurring splice CK1?/?-like variants were able to rescue the augmented Wnt/ß-catenin signaling caused by CK1? deficiency in cells. Importantly, the ability to phosphorylate ß-catenin on Ser45 in the in vitro kinase assay was required but not sufficient for such rescue. Our compound CK1? and GSK3?/ß KO models suggest that the additional nonredundant function of CK1? in the Wnt pathway beyond Ser45-ß-catenin phosphorylation includes Axin phosphorylation. Finally, we established NanoBRET assays for the three most common CK1? splice variants as well as CK1?-like. Target engagement data revealed comparable potency of known CK1? inhibitors for all CK1? variants but not for CK1?-like. In summary, our work brings important novel insights into the biology of CK1?, including evidence for the lack of redundancy with other CK1 kinases in the negative regulation of the Wnt/ß-catenin pathway at the level of ß-catenin and Axin. |
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