Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry
Autor: | Tiantian Wei, Jue Wang, Ruqi Liang, Wendong Chen, Yilan Chen, Mingzhe Ma, An He, Yifei Du, Wenjing Zhou, Zhiying Zhang, Xin Zeng, Chu Wang, Jin Lu, Xing Guo, Xiao-Wei Chen, Youjun Wang, Ruijun Tian, Junyu Xiao, Xiaoguang Lei |
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Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: | |
Zdroj: | eLife, Vol 11 (2022) |
Druh dokumentu: | article |
ISSN: | 2050-084X 45129010 |
DOI: | 10.7554/eLife.77696 |
Popis: | The dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a critical regulator of cellular processes. We took a chemical biology approach to gain further insights into its function. We developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by several co-crystallized structures. C17 displayed an effect on DYRK2 at a single-digit nanomolar IC50 and showed outstanding selectivity for the human kinome containing 467 other human kinases. Using C17 as a chemical probe, we further performed quantitative phosphoproteomic assays and identified several novel DYRK2 targets, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and stromal interaction molecule 1 (STIM1). DYRK2 phosphorylated 4E-BP1 at multiple sites, and the combined treatment of C17 with AKT and MEK inhibitors showed synergistic 4E-BP1 phosphorylation suppression. The phosphorylation of STIM1 by DYRK2 substantially increased the interaction of STIM1 with the ORAI1 channel, and C17 impeded the store-operated calcium entry process. These studies collectively further expand our understanding of DYRK2 and provide a valuable tool to pinpoint its biological function. |
Databáze: | Directory of Open Access Journals |
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