Dual specificity tyrosine-phosphorylation-regulated kinase

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Function

Dual specificity tyrosine-phosphorylation-regulated kinase (DYRK) is a member of a 5-member family of evolutionary conserved protein kinases. DYRK1A is associated with both neuropathological phenotypes and cancer susceptibility in patients with Down syndrome[1].

  • DYRK2 is a 26S proteasome-regulating kinase[2].
  • DYRK3 interacts with proteins associated with endoplasmic reticulum exit sites[3].

Relevance

DYRK1A protects against insulin resistance in the brain by elevating insulin receptor substrate 1 expression[4]. DYRK1A inhibitors attenuate cognitive dysfunction in animal models for Down syndrome and Alzheimer Disease. DYRK1A is a potential cancer therapeutic target because of its role in the regulation of cell cycle progression by affecting both tumor suppressors and oncogenes. Some DYRK1A inhibitors block the tau phosphorylation that is a hallmark of Alzheimer's disease[5]. DYRK2 is a therapeutic target for multiple myeloma and triple-negative breast cancer[6].

Structural highlights

The complex of human DYRK1A kinase domain with an inhibitor shows between the protein ATP pocket and the inhibitor including with the and the [7]. The gatekeeper Phe is a vital residue which is responsible for the selectivity of inhibitors[8].

3D structures of dual specificity tyrosine-phosphorylation-regulated kinase

Dual specificity tyrosine-phosphorylation-regulated kinase 3D structures


Human DYRK1A kinase domain containing a phosphorylated Tyr residue complex with inhibitor (PDB code 6eij)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Jarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS. Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics. J Med Chem. 2018 Nov 21;61(22):9791-9810. doi: 10.1021/acs.jmedchem.8b00185. Epub, 2018 Jul 20. PMID:29985601 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00185
  2. ↑ Guo X, Dixon JE. The 26S proteasome: A cell cycle regulator regulated by cell cycle. Cell Cycle. 2016;15(7):875-6. doi: 10.1080/15384101.2016.1151728. Epub 2016 Mar, 3. PMID:26940127 doi:http://dx.doi.org/10.1080/15384101.2016.1151728
  3. ↑ Gallo R, Rai AK, McIntyre ABR, Meyer K, Pelkmans L. DYRK3 enables secretory trafficking by maintaining the liquid-like state of ER exit sites. Dev Cell. 2023 Oct 9;58(19):1880-1897.e11. PMID:37643612 doi:10.1016/j.devcel.2023.08.005
  4. ↑ Tian S, Jia W, Lu M, Zhao J, Sun X. Dual-specificity tyrosine phosphorylation-regulated kinase 1A ameliorates insulin resistance in neurons by up-regulating IRS-1 expression. J Biol Chem. 2019 Dec 27;294(52):20164-20176. doi: 10.1074/jbc.RA119.010809. Epub, 2019 Nov 13. PMID:31723029 doi:http://dx.doi.org/10.1074/jbc.RA119.010809
  5. ↑ Czarna A, Wang J, Zelencova D, Liu Y, Deng X, Choi HG, Zhang T, Zhou W, Chang JW, Kildalsen H, Seternes OM, Gray NS, Engh RA, Rothweiler U. Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors. J Med Chem. 2018 Aug 23. doi: 10.1021/acs.jmedchem.7b01847. PMID:30095246 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01847
  6. ↑ Banerjee S, Wei T, Wang J, Lee JJ, Gutierrez HL, Chapman O, Wiley SE, Mayfield JE, Tandon V, Juarez EF, Chavez L, Liang R, Sah RL, Costello C, Mesirov JP, de la Vega L, Cooper KL, Dixon JE, Xiao J, Lei X. Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression. Proc Natl Acad Sci U S A. 2019 Nov 21. pii: 1912033116. doi:, 10.1073/pnas.1912033116. PMID:31754034 doi:http://dx.doi.org/10.1073/pnas.1912033116
  7. ↑ Czarna A, Wang J, Zelencova D, Liu Y, Deng X, Choi HG, Zhang T, Zhou W, Chang JW, Kildalsen H, Seternes OM, Gray NS, Engh RA, Rothweiler U. Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors. J Med Chem. 2018 Aug 23. doi: 10.1021/acs.jmedchem.7b01847. PMID:30095246 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01847
  8. ↑ Arbones ML, Thomazeau A, Nakano-Kobayashi A, Hagiwara M, Delabar JM. DYRK1A and cognition: A lifelong relationship. Pharmacol Ther. 2019 Feb;194:199-221. doi: 10.1016/j.pharmthera.2018.09.010. Epub, 2018 Sep 28. PMID:30268771 doi:http://dx.doi.org/10.1016/j.pharmthera.2018.09.010

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