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

Gybeľ, Tomáš; Čada, Štěpán; Klementová, Darja; Schwalm, Martin P.; Berger, Benedict-Tilman; Šebesta, Marek; Knapp, Stefan; Bryja, Vítězslav

doi:10.1016/j.jbc.2024.107407

Journal of Biological Chemistry

2024

DOI: 10.1016/j.jbc.2024.107407

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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

Tomáš Gybeľ,

Štěpán Čada,

Darja Klementová

et al.

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Cited by 2 publications

References 103 publications

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Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Haag,

Němec,

Janovská

et al. 2024

J. Med. Chem.

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Members of the casein kinase 1 (CK1) family have emerged as key regulators of cellular signaling and as potential drug targets. Functional annotation of the 7 human isoforms would benefit from isoform-selective inhibitors, allowing studies on the role of these enzymes in normal physiology and disease pathogenesis. However, due to significant sequence homology within the catalytic domain, isoform selectivity is difficult to achieve with conventional small molecules. Here, we used a PROTAC (Proteolysis TArgeting Chimeras) approach to develop a highly selective degrader AH078 (37) targeting CK1δ and CK1ε with excellent selectivity over the highly related CK1α isoform. The developed PROTAC, AH078 (37) selectively degraded CK1δ and CK1ε with a DC 50 of 200 nM. Characterization of AH078 (37) revealed a VHL and Ubiquitindependent degradation mechanism. Thus, AH078 (37) represents a versatile chemical tool to study CK1δ and CK1ε function in cellular systems.

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Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Haag,

Němec,

Janovská

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

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Role of Wnt5a in modulation of osteoporotic adipose‐derived stem cells and osteogenesis

Liu,

Luo,

et al. 2024

Cell Proliferation

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Osteoporosis, a condition marked by the deterioration of bone microarchitecture and increased facture risk, arises from a disruption in bone metabolism, with osteoclasts surpassing osteoblasts in bone resorption versus formation. The Wnt signalling pathway, a key regulator of bone maintenance, remains partially understood in osteoporosis. Our research delves into the role of Wnt‐related molecules in this disease. In osteoporotic adipose‐derived stem cells (OP‐ASCs), we detected a significant decrease in Ctnnb1 and Frizzled‐6 (Fzd6), contrasted by an increase in Gsk‐3β and Wnt5a. Activation of the Wnt pathway by LiCl resulted in elevated Ctnnb1 and Fzd6, but decreased Gsk‐3β and Wnt5a levels, promoting OP‐ASCs' bone‐formation capacity. In contrast, inhibition of this pathway by DKK‐1 led to diminished Ctnnb1 and Fzd6, and increased Gsk‐3β and Wnt5a, adversely affecting osteogenesis. Furthermore, our findings show that overexpressing Wnt5a impedes, while silencing it enhances the bone‐forming capability of OP‐ASCs. In a cranial bone defect model, the implantation of Wnt5a‐silenced OP‐ASCs with biphasic calcium phosphate scaffolds significantly promoted new bone formation. These observations indicated a repression of the canonical Wnt pathway and a stimulation of the non‐canonical pathway in OP‐ASCs. Silencing Wnt5a increased the osteogenic and regenerative abilities of OP‐ASCs. Our study suggests targeting Wnt5a could be a promising strategy for enhancing bone regeneration in post‐menopausal osteoporosis.

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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

Cited by 2 publications

References 103 publications

Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Development and Discovery of a Selective Degrader of Casein Kinases 1 δ/ε

Role of Wnt5a in modulation of osteoporotic adipose‐derived stem cells and osteogenesis

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