eLife (Apr 2022)

Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry

  • 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

DOI
https://doi.org/10.7554/eLife.77696
Journal volume & issue
Vol. 11

Abstract

Read online

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.

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