| Structural highlights
Function
DYRK2_HUMAN Serine/threonine-protein kinase involved in the regulation of the mitotic cell cycle, cell proliferation, apoptosis, organization of the cytoskeleton and neurite outgrowth. Functions in part via its role in ubiquitin-dependent proteasomal protein degradation. Functions downstream of ATM and phosphorylates p53/TP53 at 'Ser-46', and thereby contributes to the induction of apoptosis in response to DNA damage. Phosphorylates NFATC1, and thereby inhibits its accumulation in the nucleus and its transcription factor activity. Phosphorylates EIF2B5 at 'Ser-544', enabling its subsequent phosphorylation and inhibition by GSK3B. Likewise, phosphorylation of NFATC1, CRMP2/DPYSL2 and CRMP4/DPYSL3 promotes their subsequent phosphorylation by GSK3B. May play a general role in the priming of GSK3 substrates. Inactivates GYS1 by phosphorylation at 'Ser-641', and potentially also a second phosphorylation site, thus regulating glycogen synthesis. Mediates EDVP E3 ligase complex formation and is required for the phosphorylation and subsequent degradation of KATNA1. Phosphorylates SIAH2, and thereby increases its ubiquitin ligase activity. Promotes the proteasomal degradation of MYC and JUN, and thereby regulates progress through the mitotic cell cycle and cell proliferation. Promotes proteasomal degradation of GLI2 and GLI3, and thereby plays a role in smoothened and sonic hedgehog signaling. Plays a role in cytoskeleton organization and neurite outgrowth via its phosphorylation of DCX and DPYSL2. Phosphorylates CRMP2/DPYSL2, CRMP4/DPYSL3, DCX, EIF2B5, EIF4EBP1, GLI2, GLI3, GYS1, JUN, MDM2, MYC, NFATC1, p53/TP53, TAU/MAPT and KATNA1. Can phosphorylate histone H1, histone H3 and histone H2B (in vitro). Can phosphorylate CARHSP1 (in vitro).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
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.
Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry.,Wei T, Wang J, Liang R, Chen W, Chen Y, Ma M, He A, Du Y, Zhou W, Zhang Z, Zeng X, Wang C, Lu J, Guo X, Chen XW, Wang Y, Tian R, Xiao J, Lei X Elife. 2022 Apr 19;11. pii: 77696. doi: 10.7554/eLife.77696. PMID:35439114[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, Joost HG. Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. J Biol Chem. 1998 Oct 2;273(40):25893-902. PMID:9748265
- ↑ Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG. The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem J. 2001 May 1;355(Pt 3):609-15. PMID:11311121
- ↑ Wang X, Li W, Parra JL, Beugnet A, Proud CG. The C terminus of initiation factor 4E-binding protein 1 contains multiple regulatory features that influence its function and phosphorylation. Mol Cell Biol. 2003 Mar;23(5):1546-57. PMID:12588975
- ↑ Skurat AV, Dietrich AD. Phosphorylation of Ser640 in muscle glycogen synthase by DYRK family protein kinases. J Biol Chem. 2004 Jan 23;279(4):2490-8. Epub 2003 Oct 30. PMID:14593110 doi:10.1074/jbc.M301769200
- ↑ Auld GC, Campbell DG, Morrice N, Cohen P. Identification of calcium-regulated heat-stable protein of 24 kDa (CRHSP24) as a physiological substrate for PKB and RSK using KESTREL. Biochem J. 2005 Aug 1;389(Pt 3):775-83. PMID:15910284 doi:10.1042/BJ20050733
- ↑ Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, Hernandez F, Eickholt BJ, Nikolic M, Sutherland C. Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem. 2006 Jun 16;281(24):16591-8. Epub 2006 Apr 12. PMID:16611631 doi:10.1074/jbc.M513344200
- ↑ Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H, Bolton D, Feske S, Hogan PG, Rao A. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature. 2006 Jun 1;441(7093):646-50. Epub 2006 Mar 1. PMID:16511445 doi:10.1038/nature04631
- ↑ Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K. DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol Cell. 2007 Mar 9;25(5):725-38. PMID:17349958 doi:10.1016/j.molcel.2007.02.007
- ↑ Yoshida K. Role for DYRK family kinases on regulation of apoptosis. Biochem Pharmacol. 2008 Dec 1;76(11):1389-94. doi: 10.1016/j.bcp.2008.05.021., Epub 2008 Jul 2. PMID:18599021 doi:10.1016/j.bcp.2008.05.021
- ↑ Varjosalo M, Bjorklund M, Cheng F, Syvanen H, Kivioja T, Kilpinen S, Sun Z, Kallioniemi O, Stunnenberg HG, He WW, Ojala P, Taipale J. Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell. 2008 May 2;133(3):537-48. doi: 10.1016/j.cell.2008.02.047. PMID:18455992 doi:10.1016/j.cell.2008.02.047
- ↑ Maddika S, Chen J. Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol. 2009 Apr;11(4):409-19. doi: 10.1038/ncb1848. Epub 2009 Mar 15. PMID:19287380 doi:10.1038/ncb1848
- ↑ Taira N, Mimoto R, Kurata M, Yamaguchi T, Kitagawa M, Miki Y, Yoshida K. DYRK2 priming phosphorylation of c-Jun and c-Myc modulates cell cycle progression in human cancer cells. J Clin Invest. 2012 Mar 1;122(3):859-72. doi: 10.1172/JCI60818. Epub 2012 Feb 6. PMID:22307329 doi:10.1172/JCI60818
- ↑ Perez M, Garcia-Limones C, Zapico I, Marina A, Schmitz ML, Munoz E, Calzado MA. Mutual regulation between SIAH2 and DYRK2 controls hypoxic and genotoxic signaling pathways. J Mol Cell Biol. 2012 Oct;4(5):316-30. doi: 10.1093/jmcb/mjs047. Epub 2012 Aug 9. PMID:22878263 doi:10.1093/jmcb/mjs047
- ↑ Wei T, Wang J, Liang R, Chen W, Chen Y, Ma M, He A, Du Y, Zhou W, Zhang Z, Zeng X, Wang C, Lu J, Guo X, Chen XW, Wang Y, Tian R, Xiao J, Lei X. Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry. Elife. 2022 Apr 19;11. pii: 77696. doi: 10.7554/eLife.77696. PMID:35439114 doi:https://dx.doi.org/10.7554/eLife.77696
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