Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry
Abstract The dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a key regulator of cellular processes such as proteasome-mediated protein degradation. To gain further insights into its function, we took a chemical biology approach and developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by a number of 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. Collectively, these studies further expand our understanding of DYRK2 and provide a valuable tool to further pinpoint its biological function..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
bioRxiv.org - (2022) vom: 25. Mai Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wei, Tiantian [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/2021.02.12.430909 |
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| PPN (Katalog-ID): |
XBI019934009 |
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| 520 | |a Abstract The dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a key regulator of cellular processes such as proteasome-mediated protein degradation. To gain further insights into its function, we took a chemical biology approach and developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by a number of 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. Collectively, these studies further expand our understanding of DYRK2 and provide a valuable tool to further pinpoint its biological function. | ||
| 700 | 1 | |a Wang, Jue |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Ruqi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Wendong |e verfasserin |4 aut | |
| 700 | 1 | |a He, An |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Yifei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Wenjing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhiying |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Mingzhe |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xiaowei |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Ruijun |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Junyu |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Xiaoguang |e verfasserin |4 aut | |
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