Splice variants of CK1a and CK1a-like: Comparative analysis of subcellular localization, kinase activity, and function in the Wnt signaling pathway

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F24%3A00603489" target="_blank" >RIV/68081707:_____/24:00603489 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0021925824019082?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0021925824019082?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jbc.2024.107407" target="_blank" >10.1016/j.jbc.2024.107407</a>

Result language

angličtina

Original language name

Splice variants of CK1a and CK1a-like: Comparative analysis of subcellular localization, kinase activity, and function in the Wnt signaling pathway

Original language description

Members of the casein kinase 1 (CK1) family are important regulators of multiple signaling pathways. CK1a is a wellknown negative regulator of the Wnt/b-catenin pathway, which promotes the degradation of b-catenin via its phosphorylation of Ser45. In contrast, the closest paralog of CK1a, CK1a-like, is a poorly characterized kinase of unknown function. In this study, we show that the deletion of CK1a, but not CK1a-like, resulted in a strong activation of the Wnt/b-catenin pathway. Wnt-3a treatment further enhanced the activation, which suggests there are at least two modes, a CK1a-dependent and Wnt-dependent, of b-catenin regulation. Rescue experiments showed that only two out of ten naturally occurring splice CK1a/a-like variants were able to rescue the augmented Wnt/b-catenin signaling caused by CK1a deficiency in cells. Importantly, the ability to phosphorylate b-catenin on Ser45 in the in vitro kinase assay was required but not sufficient for such rescue. Our compound CK1a and GSK3a/b KO models suggest that the additional nonredundant function of CK1a in the Wnt pathway beyond Ser45-b-catenin phosphorylation includes Axin phosphorylation. Finally, we established NanoBRET assays for the three most common CK1a splice variants as well as CK1a-like. Target engagement data revealed comparable potency of known CK1a inhibitors for all CK1a variants but not for CK1a-like. In summary, our work brings important novel insights into the biology of CK1a, including evidence for the lack of redundancy with other CK1 kinases in the negative regulation of the Wnt/b-catenin pathway at the level of b- catenin and Axin.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Biological Chemistry

ISSN

0021-9258

e-ISSN

1083-351X

Volume of the periodical

300

Issue of the periodical within the volume

7

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

22

Pages from-to

107407

UT code for WoS article

001364964200001

EID of the result in the Scopus database

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