Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry
|Corresponding Author||Tian，Ruijun; Xiao，Junyu; Lei，Xiaoguang|
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.
Cited Times [WOS]:2
|Document Type||Journal Article|
|Department||Academy for Advanced Interdisciplinary Studies|
1.The State Key Laboratory of Protein and Plant Gene Research,School of Life Sciences,Peking University,Beijing,China
2.Peking-Tsinghua Center for Life Sciences,Peking University,Beijing,100871,China
3.Academy for Advanced Interdisciplinary Studies,Peking University,Beijing,100871,China
4.Beijing National Laboratory for Molecular Sciences,Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,College of Chemistry and Molecular Engineering,Peking University,Beijing,100871,China
5.SUSTech Academy for Advanced Interdisciplinary Studies,Southern University of Science and Technology,Shenzhen,518055,China
6.Beijing Key Laboratory of Gene Resource and Molecular Development,Key Laboratory of Cell Proliferation and Regulation Biology,Ministry of Education,College of Life Sciences,Beijing Normal University,Beijing,100875,China
7.Department of Chemistry,Southern University of Science and Technology,Shenzhen,518055,China
8.Institute of Molecular Medicine,Peking University,Beijing,100871,China
9.Peking University Institute of Hematology,People’s Hospital,Beijing,100044,China
10.Collaborative Innovation Center of Hematology,Suzhou,215006,China
11.Life Sciences Institute,Zhejiang University,Hangzhou,310058,China
12.Beijing Advanced Innovation Center for Genomics (ICG),Peking University,Beijing,100871,China
13.Institute for Cancer Research,Shenzhen Bay Laboratory,Shenzhen,518107,China
|Corresponding Author Affilication||Academy for Advanced Interdisciplinary Studies|
Wei，Tiantian,Wang，Jue,Liang，Ruqi,et al. Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry[J]. eLife,2022,11:e77696.
Wei，Tiantian.,Wang，Jue.,Liang，Ruqi.,Chen，Wendong.,Chen，Yilan.,...&Lei，Xiaoguang.(2022).Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry.eLife,11,e77696.
Wei，Tiantian,et al."Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry".eLife 11(2022):e77696.
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