Display options
Cite
Recasens A, Humphrey SJ, Ellis M, et al. Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells. Cell Death Discov. 2021;7(1):81doi: 10.1038/s41420-021-00456-6.
Recasens, A., Humphrey, S. J., Ellis, M., Hoque, M., Abbassi, R. H., Chen, B., Longworth, M., Needham, E. J., James, D. E., Johns, T. G., Day, B. W., Kassiou, M., Yang, P., & Munoz, L. (2021). Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells. Cell death discovery, 7(1), 81. https://doi.org/10.1038/s41420-021-00456-6
Recasens, Ariadna, et al. "Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells." Cell death discovery vol. 7,1 (2021): 81. doi: https://doi.org/10.1038/s41420-021-00456-6
Recasens A, Humphrey SJ, Ellis M, Hoque M, Abbassi RH, Chen B, Longworth M, Needham EJ, James DE, Johns TG, Day BW, Kassiou M, Yang P, Munoz L. Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells. Cell Death Discov. 2021 Apr 16;7(1):81. doi: 10.1038/s41420-021-00456-6. PMID: 33863878; PMCID: PMC8052442.
Copy Download .nbib Format: NLM
Share it on

Cell Death Discov. 2021 Apr 16;7(1):81. doi: 10.1038/s41420-021-00456-6.

Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells.

Cell death discovery

Ariadna Recasens, Sean J Humphrey, Michael Ellis, Monira Hoque, Ramzi H Abbassi, Brianna Chen, Mitchell Longworth, Elise J Needham, David E James, Terrance G Johns, Bryan W Day, Michael Kassiou, Pengyi Yang, Lenka Munoz

Affiliations

  1. Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia. [email protected].
  2. Charles Perkins Centre and School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Camperdown, NSW, 2006, Australia.
  3. Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.
  4. School of Chemistry, Faculty of Science, The University of Sydney, Camperdown, NSW, 2006, Australia.
  5. Oncogenic Signalling Laboratory, Telethon Kids Institute, Perth Children's Hospital, 15 Hospital Avenue, Nedlands, WA, 6009, Australia.
  6. QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
  7. Charles Perkins Centre and School of Mathematics and Statistics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia.
  8. Computational Systems Biology Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW, 2145, Australia.
  9. Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia. [email protected].

PMID: 33863878 PMCID: PMC8052442 DOI: 10.1038/s41420-021-00456-6

Abstract

Both tumour suppressive and oncogenic functions have been reported for dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Herein, we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma. Our phosphoproteomic and mechanistic studies show that DYRK1A induces degradation of cyclin B by phosphorylating CDC23, which is necessary for the function of the anaphase-promoting complex, a ubiquitin ligase that degrades mitotic proteins. DYRK1A inhibition leads to the accumulation of cyclin B and activation of CDK1. Importantly, we established that the phenotypic response of glioblastoma cells to DYRK1A inhibition depends on both retinoblastoma (RB) expression and the degree of residual DYRK1A activity. Moderate DYRK1A inhibition leads to moderate cyclin B accumulation, CDK1 activation and increased proliferation in RB-deficient cells. In RB-proficient cells, cyclin B/CDK1 activation in response to DYRK1A inhibition is neutralized by the RB pathway, resulting in an unchanged proliferation rate. In contrast, complete DYRK1A inhibition with high doses of inhibitors results in massive cyclin B accumulation, saturation of CDK1 activity and cell cycle arrest, regardless of RB status. These findings provide new insights into the complexity of context-dependent DYRK1A signalling in cancer cells.

References

  1. J Med Chem. 2017 Mar 9;60(5):2052-2070 - PubMed
  2. Mol Cell. 2019 Apr 18;74(2):378-392.e5 - PubMed
  3. Structure. 2013 Jun 4;21(6):986-96 - PubMed
  4. Nat Rev Drug Discov. 2017 Jun;16(6):424-440 - PubMed
  5. ACS Pharmacol Transl Sci. 2019 Jul 30;2(6):402-413 - PubMed
  6. Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18507-12 - PubMed
  7. Nat Biotechnol. 2015 Sep;33(9):990-5 - PubMed
  8. Nat Methods. 2009 Nov;6(11):786-7 - PubMed
  9. Pharmacol Ther. 2015 Jul;151:87-98 - PubMed
  10. PLoS Biol. 2007 May;5(5):e123 - PubMed
  11. Cell Cycle. 2007 Jun 15;6(12):1408-11 - PubMed
  12. Eur J Med Chem. 2019 Mar 15;166:304-317 - PubMed
  13. Genes Dev. 2011 Apr 15;25(8):801-13 - PubMed
  14. Pharmacol Ther. 2019 Feb;194:199-221 - PubMed
  15. IUBMB Life. 2019 Jun;71(6):738-748 - PubMed
  16. Nat Protoc. 2018 Sep;13(9):1897-1916 - PubMed
  17. Sci Rep. 2019 Apr 12;9(1):6014 - PubMed
  18. Mol Cell. 2010 Mar 26;37(6):753-67 - PubMed
  19. Nucleic Acids Res. 2015 Jan;43(Database issue):D512-20 - PubMed
  20. Trends Pharmacol Sci. 2019 Feb;40(2):128-141 - PubMed
  21. PLoS One. 2014 Jun 05;9(6):e98853 - PubMed
  22. Cancer Res. 2013 Aug 15;73(16):5120-9 - PubMed
  23. Mol Cancer Res. 2017 Apr;15(4):371-381 - PubMed
  24. Cell Cycle. 2019 Mar;18(5):531-551 - PubMed
  25. J Med Chem. 2011 Jun 23;54(12):4172-86 - PubMed
  26. Sci Rep. 2016 Oct 31;6:36132 - PubMed
  27. Nature. 2016 Jan 14;529(7585):172-7 - PubMed
  28. Nat Rev Mol Cell Biol. 2013 May;14(5):297-306 - PubMed
  29. J Cell Biol. 2009 Apr 20;185(2):193-202 - PubMed
  30. Methods Mol Med. 2002;69:259-74 - PubMed
  31. Nat Biotechnol. 2008 Dec;26(12):1367-72 - PubMed
  32. Cancer Res. 2016 Nov 1;76(21):6424-6435 - PubMed
  33. Proc Natl Acad Sci U S A. 2016 May 10;113(19):E2570-8 - PubMed
  34. J Med Chem. 2011 Jul 14;54(13):4474-89 - PubMed
  35. Nat Rev Mol Cell Biol. 2011 Jun 02;12(7):427-38 - PubMed
  36. Eur J Med Chem. 2018 Sep 5;157:1005-1016 - PubMed
  37. Sci Rep. 2019 Mar 20;9(1):4902 - PubMed
  38. J Med Chem. 2018 Sep 13;61(17):7687-7699 - PubMed
  39. JCI Insight. 2020 Jan 16;5(1): - PubMed
  40. Gut. 2019 Aug;68(8):1465-1476 - PubMed
  41. Endocrinology. 2018 Sep 1;159(9):3143-3157 - PubMed
  42. Nature. 2015 Jun 25;522(7557):450-454 - PubMed
  43. J Med Chem. 2013 Dec 12;56(23):9569-85 - PubMed
  44. Genes Dev. 2019 Jun 1;33(11-12):591-609 - PubMed
  45. Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10268-10273 - PubMed
  46. J Clin Invest. 2013 Jun;123(6):2475-87 - PubMed
  47. PLoS One. 2014 Nov 21;9(11):e113283 - PubMed
  48. Nat Methods. 2016 Sep;13(9):731-40 - PubMed
  49. Proteomics. 2016 Jul;16(13):1868-71 - PubMed
  50. Cell Syst. 2019 May 22;8(5):427-445.e10 - PubMed
  51. Cell Cycle. 2014;13(13):2084-100 - PubMed
  52. J Clin Invest. 2012 Mar;122(3):948-62 - PubMed
  53. Mol Cell Biol. 2010 Feb;30(3):640-56 - PubMed

Publication Types

Grant support