Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry
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 struct...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-04-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/77696 |
| _version_ | 1818025840434216960 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Tiantian Wei |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T04:22:30Z |
| format | Article |
| id | doaj.art-d371ca8cabea45129010611a2413de8e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:22:30Z |
| publishDate | 2022-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d371ca8cabea45129010611a2413de8e2022-12-22T02:02:23ZengeLife Sciences Publications LtdeLife2050-084X2022-04-011110.7554/eLife.77696Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entryTiantian Wei0https://orcid.org/0000-0001-8964-8839Jue Wang1Ruqi Liang2Wendong Chen3Yilan Chen4Mingzhe Ma5An He6Yifei Du7Wenjing Zhou8Zhiying Zhang9Xin Zeng10Chu Wang11Jin Lu12Xing Guo13Xiao-Wei Chen14https://orcid.org/0000-0003-4564-5120Youjun Wang15https://orcid.org/0000-0003-0961-1716Ruijun Tian16Junyu Xiao17https://orcid.org/0000-0003-1822-1701Xiaoguang Lei18https://orcid.org/0000-0002-0380-8035The State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, ChinaBeijing 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, ChinaThe State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; 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, ChinaSUSTech Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, ChinaBeijing 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, ChinaBeijing 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, ChinaDepartment of Chemistry, Southern University of Science and Technology, Shenzhen, ChinaBeijing 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, ChinaInstitute of Molecular Medicine, Peking University, Beijing, ChinaThe State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, ChinaThe State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; 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, ChinaThe State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; 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, ChinaPeking University Institute of Hematology, People’s Hospital, Beijing, China; Collaborative Innovation Center of Hematology, Suzhou, ChinaLife Sciences Institute, Zhejiang University, Hangzhou, ChinaThe State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Institute of Molecular Medicine, Peking University, Beijing, ChinaBeijing 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, ChinaSUSTech Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, China; 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, ChinaThe State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, ChinaThe State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; 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, China; Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, ChinaThe 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.https://elifesciences.org/articles/77696chemical biologykinasecancerprotein synthesis |
| spellingShingle | 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 Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry eLife chemical biology kinase cancer protein synthesis |
| title | Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry |
| title_full | Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry |
| title_fullStr | Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry |
| title_full_unstemmed | Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry |
| title_short | Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry |
| title_sort | selective inhibition reveals the regulatory function of dyrk2 in protein synthesis and calcium entry |
| topic | chemical biology kinase cancer protein synthesis |
| url | https://elifesciences.org/articles/77696 |
| work_keys_str_mv | AT tiantianwei selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT juewang selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT ruqiliang selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT wendongchen selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT yilanchen selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT mingzhema selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT anhe selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT yifeidu selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT wenjingzhou selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT zhiyingzhang selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT xinzeng selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT chuwang selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT jinlu selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT xingguo selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT xiaoweichen selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT youjunwang selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT ruijuntian selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT junyuxiao selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry AT xiaoguanglei selectiveinhibitionrevealstheregulatoryfunctionofdyrk2inproteinsynthesisandcalciumentry |