Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a serine/threonine kinase that belongs to the DYRK family of proteins, a subgroup of the evolutionarily conserved CMGC protein kinase superfamily. Due to its localization on chromosome 21, the biological significance of DYRK1A was initially characterized in the pathogenesis of Down syndrome (DS) and related neurodegenerative diseases. However, increasing evidence has demonstrated a prominent role in cancer through its ability to regulate biologic processes including cell cycle progression, DNA damage repair, transcription, ubiquitination, tyrosine kinase activity, and cancer stem cell maintenance. DYRK1A has been identified as both an oncogene and tumor suppressor in different models, underscoring the importance of cellular context in its function. Here, we review mechanistic contributions of DYRK1A to cancer biology and its role as a potential therapeutic target.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Domain composition of the DYRK proteins.
Fig. 2: Known DYRK1A substrates.

Similar content being viewed by others

References

  1. Song WJ, Sternberg LR, Kasten-Sportès C, Keuren ML, Chung SH, Slack AC, et al. Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome “critical region”. Genomics. 1996;38:331–9.

    Article  CAS  PubMed  Google Scholar 

  2. Delabar JM, Theophile D, Rahmani Z, Chettouh Z, Blouin JL, Prieur M, et al. Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur J Hum Genet. 1993;1:114–24.

    Article  CAS  PubMed  Google Scholar 

  3. Tejedor F, Zhu XR, Kaltenbach E, Ackermann A, Baumann A, Canal I, et al. minibrain: a new protein kinase family involved in postembryonic neurogenesis in Drosophila. Neuron. 1995;14:287–301.

    Article  CAS  PubMed  Google Scholar 

  4. Altafaj X, Dierssen M, Baamonde C, Marti E, Visa J, Guimera J, et al. Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down’s syndrome. Hum Mol Genet. 2001;10:1915–23.

    Article  CAS  PubMed  Google Scholar 

  5. Ji J, Lee H, Argiropoulos B, Dorrani N, Mann J, Martinez-Agosto JA, et al. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur J Hum Genet. 2015;23:1473–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Feki A, Hibaoui Y. DYRK1A Protein, A Promising Therapeutic Target to improve cognitive deficits in down syndrome. Brain Sci. 2018;8:187.

    Article  CAS  PubMed Central  Google Scholar 

  7. Becker W, Joost HG. Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity. Prog Nucleic Acid Res Mol Biol. 1999;62:1–17.

    CAS  PubMed  Google Scholar 

  8. Himpel S, Panzer P, Eirmbter K, Czajkowska H, Sayed M, Packman LC, et al. Identification of the autophosphorylation sites and characterization of their effects in the protein kinase DYRK1A. Biochem J. 2001;359:497–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV, et al. Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure. 2013;21:986–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Galceran J, de Graaf K, Tejedor FJ, Becker W. The MNB/DYRK1A protein kinase: genetic and biochemical properties. J Neural Transm Suppl. 2003;67:139–48.

    Article  CAS  Google Scholar 

  11. Miyata Y, Nishida E. DYRK1A binds to an evolutionarily conserved WD40-repeat protein WDR68 and induces its nuclear translocation. Biochim Biophys Acta. 2011;1813:1728–39.

    Article  CAS  PubMed  Google Scholar 

  12. Yousefelahiyeh M, Xu J, Alvarado E, Yu Y, Salven D, Nissen RM. DCAF7/WDR68 is required for normal levels of DYRK1A and DYRK1B. PLoS ONE. 2018;13:e0207779.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K. ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem. 2010;285:4909–19.

    Article  CAS  PubMed  Google Scholar 

  14. Papadopoulos C, Arato K, Lilienthal E, Zerweck J, Schutkowski M, Chatain N, et al. Splice variants of the dual specificity tyrosine phosphorylation-regulated kinase 4 (DYRK4) differ in their subcellular localization and catalytic activity. J Biol Chem. 2011;286:5494–505.

    Article  CAS  PubMed  Google Scholar 

  15. Kinstrie R, Luebbering N, Miranda-Saavedra D, Sibbet G, Han J, Lochhead PA, et al. Characterization of a domain that transiently converts class 2 DYRKs into intramolecular tyrosine kinases. Sci Signal. 2010;3:ra16.

    Article  PubMed  CAS  Google Scholar 

  16. Kentrup H, Becker W, Heukelbach J, Wilmes A, Schurmann A, Huppertz C, et al. Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII. J Biol Chem. 1996;271:3488–95.

    Article  CAS  PubMed  Google Scholar 

  17. Alvarez M, Estivill X, de la Luna S. DYRK1A accumulates in splicing speckles through a novel targeting signal and induces speckle disassembly. J Cell Sci. 2003;116:3099–107.

    Article  CAS  PubMed  Google Scholar 

  18. Jin N, Yin X, Gu J, Zhang X, Shi J, Qian W, et al. Truncation and activation of dual specificity tyrosine phosphorylation-regulated kinase 1A by Calpain I: A molecular mechanism linked to tau pathology in alzheimer diSEASE. J Biol Chem. 2015;290:15219–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Negrini S, Prada I, D’Alessandro R, Meldolesi J. REST: an oncogene or a tumor suppressor? Trends Cell Biol. 2013;23:289–95.

    Article  CAS  PubMed  Google Scholar 

  20. Lu M, Zheng L, Han B, Wang L, Wang P, Liu H, et al. REST regulates DYRK1A transcription in a negative feedback loop. J Biol Chem. 2011;286:10755–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lepagnol-Bestel A-M, Zvara A, Maussion G, Quignon F, Ngimbous B, Ramoz N, et al. DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome. Hum Mol Genet. 2009;18:1405–14.

    Article  CAS  PubMed  Google Scholar 

  22. Canzonetta C, Mulligan C, Deutsch S, Ruf S, O’Doherty A, Lyle R, et al. DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. Am J Hum Genet. 2008;83:388–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu N, Nelson BR, Bezprozvannaya S, Shelton JM, Richardson JA, Bassel-Duby R, et al. Requirement of MEF2A, C, and D for skeletal muscle regeneration. Proc Natl Acad Sci. 2014;111:4109–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li M, Linseman DA, Allen MP, Meintzer MK, Wang X, Laessig T, et al. Myocyte enhancer factor 2A and 2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons. J Neurosci: Off J Soc Neurosci. 2001;21:6544–52.

    Article  CAS  Google Scholar 

  25. Wang P, Wang L, Chen L, Sun X. Dual-specificity tyrosine-phosphorylation regulated kinase 1A Gene Transcription is regulated by Myocyte Enhancer Factor 2D. Sci Rep. 2017;7:7240.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Wang P, Zhao J, Sun X. DYRK1A phosphorylates MEF2D and decreases its transcriptional activity. J Cell Mol Med. 2021;25:6082–93.

    Article  CAS  PubMed Central  Google Scholar 

  27. Hurtz C, Carroll MP, Tasian SK, Wertheim G, Bhansali RS, Lee SJ, et al. DYRK1A is required to alleviate replication stress in KMT2A-rearranged acute lymphoblastic leukemia. Blood. 2020;136:39–40.

    Article  Google Scholar 

  28. Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, et al. SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature. 2008;452:370–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu Q, Tang Y, Chen L, Liu N, Lang F, Liu H, et al. E3 Ligase SCFbetaTrCP-induced DYRK1A protein degradation is essential for cell cycle progression in HEK293 cells. J Biol Chem. 2016;291:26399–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Senft D, Qi J, Ronai ZA. Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer. 2018;18:69–88.

    Article  CAS  PubMed  Google Scholar 

  31. Jin J, Xiao Y, Hu H, Zou Q, Li Y, Gao Y, et al. Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages. Nat Commun. 2015;6:5930.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang P, Zhang Z, Fu Y, Zhang Y, Washburn MP, Florens L, et al. K63-linked ubiquitination of DYRK1A by TRAF2 alleviates Sprouty 2-mediated degradation of EGFR. Cell Death Dis. 2021;12:608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xu X, Liu Q, Zhang C, Ren S, Xu L, Zhao Z, et al. Inhibition of DYRK1A-EGFR axis by p53-MDM2 cascade mediates the induction of cellular senescence. Cell Death Dis. 2019;10:282.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Park J, Oh Y, Yoo L, Jung MS, Song WJ, Lee SH, et al. Dyrk1A phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. J Biol Chem. 2010;285:31895–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Iness AN, Litovchick L. MuvB: A key to cell cycle control in ovarian cancer. Front Oncol. 2018;8:223.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 2011;25:801–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. MacDonald J, Ramos-Valdes Y, Perampalam P, Litovchick L, DiMattia GE, Dick FA. A systematic analysis of negative growth control implicates the DREAM complex in cancer cell dormancy. Mol Cancer Res. 2017;15:371–81.

    Article  CAS  PubMed  Google Scholar 

  38. Chen JY, Lin JR, Tsai FC, Meyer T. Dosage of Dyrk1a shifts cells within a p21-cyclin D1 signaling map to control the decision to enter the cell cycle. Mol Cell. 2013;52:87–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Soppa U, Schumacher J, Florencio Ortiz V, Pasqualon T, Tejedor FJ, Becker W. The Down syndrome-related protein kinase DYRK1A phosphorylates p27(Kip1) and Cyclin D1 and induces cell cycle exit and neuronal differentiation. Cell Cycle. 2014;13:2084–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thompson BJ, Bhansali R, Diebold L, Cook DE, Stolzenburg L, Casagrande AS, et al. DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3. J Exp Med. 2015;212:953–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Recasens A, Humphrey SJ, Ellis M, Hoque M, Abbassi RH, Chen B, et al. Global phosphoproteomics reveals DYRK1A regulates CDK1 activity in glioblastoma cells. Cell Death Discov. 2021;7:81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jiramongkol Y, Lam EWF. FOXO transcription factor family in cancer and metastasis. Cancer Metastasis Rev. 2020;39:681–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N. FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem. 2002;277:26729–32.

    Article  CAS  PubMed  Google Scholar 

  44. Bhansali RS, Rammohan M, Lee P, Laurent AP, Wen Q, Suraneni P, et al. DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3. J Clin Invest. 2021;131:e135937.

    Article  PubMed Central  Google Scholar 

  45. Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S, et al. The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J. 2001;355:597–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Roewenstrunk J, Di Vona C, Chen J, Borras E, Dong C, Arato K, et al. A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response. Sci Rep. 2019;9:6014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Guard SE, Poss ZC, Ebmeier CC, Pagratis M, Simpson H, Taatjes DJ, et al. The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair. Sci Rep. 2019;9:6539.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Menon VR, Ananthapadmanabhan V, Swanson S, Saini S, Sesay F, Yakovlev V, et al. DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169. Cell Cycle. 2019;18:531–51.

    Article  PubMed  CAS  Google Scholar 

  49. An L, Dong C, Li J, Chen J, Yuan J, Huang J, et al. RNF169 limits 53BP1 deposition at DSBs to stimulate single-strand annealing repair. Proc Natl Acad Sci USA. 2018;115:E8286–E95.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Guo X, Williams JG, Schug TT, Li X. DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1. J Biol Chem. 2010;285:13223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Di Vona C, Bezdan D, Islam AB, Salichs E, Lopez-Bigas N, Ossowski S, et al. Chromatin-wide profiling of DYRK1A reveals a role as a gene-specific RNA polymerase II CTD kinase. Mol Cell. 2015;57:506–20.

    Article  PubMed  CAS  Google Scholar 

  52. Lu H, Yu D, Hansen AS, Ganguly S, Liu R, Heckert A, et al. Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II. Nature. 2018;558:318–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yu D, Cattoglio C, Xue Y, Zhou Q. A complex between DYRK1A and DCAF7 phosphorylates the C-terminal domain of RNA polymerase II to promote myogenesis. Nucleic Acids Res. 2019;47:4462–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Leontovich AA, Jalalirad M, Salisbury JL, Mills L, Haddox C, Schroeder M, et al. NOTCH3 expression is linked to breast cancer seeding and distant metastasis. Breast Cancer Res. 2018;20:105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005;5:472–84.

    Article  CAS  PubMed  Google Scholar 

  56. Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature.2006;441:595–600.

    Article  CAS  PubMed  Google Scholar 

  57. Jauliac S, Lopez-Rodriguez C, Shaw LM, Brown LF, Rao A, Toker A. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol. 2002;4:540–4.

    Article  CAS  PubMed  Google Scholar 

  58. Quang CT, Leboucher S, Passaro D, Fuhrmann L, Nourieh M, Vincent-Salomon A, et al. The calcineurin/NFAT pathway is activated in diagnostic breast cancer cases and is essential to survival and metastasis of mammary cancer cells. Cell Death Dis. 2015;6:e1658.

    Article  CAS  PubMed  Google Scholar 

  59. Malinge S, Bliss-Moreau M, Kirsammer G, Diebold L, Chlon T, Gurbuxani S, et al. Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome. J Clin Invest. 2012;122:948–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 2014;1845:136–54.

    CAS  PubMed  Google Scholar 

  61. Yin W, Cheepala S, Roberts JN, Syson-Chan K, DiGiovanni J, Clifford JL. Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions. Mol Cancer. 2006;5:15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Wu P, Wu D, Zhao L, Huang L, Shen G, Huang J, et al. Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis. Oncotarget.2016;7:19863–83.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Okada Y, Watanabe T, Shoji T, Taguchi K, Ogo N, Asai A. Visualization and quantification of dynamic STAT3 homodimerization in living cells using homoFluoppi. Sci Rep. 2018;8:2385.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264:95–8.

    Article  CAS  PubMed  Google Scholar 

  65. Li D, Jackson RA, Yusoff P, Guy GR. Direct association of Sprouty-related protein with an EVH1 domain (SPRED) 1 or SPRED2 with DYRK1A modifies substrate/kinase interactions. J Biol Chem. 2010;285:35374–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kurabayashi N, Nguyen MD, Sanada K. DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model. EMBO Rep. 2015;16:1548–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aznar S, Valeron PF, del Rincon SV, Perez LF, Perona R, Lacal JC. Simultaneous tyrosine and serine phosphorylation of STAT3 transcription factor is involved in Rho A GTPase oncogenic transformation. Mol Biol Cell. 2001;12:3282–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sakaguchi M, Oka M, Iwasaki T, Fukami Y, Nishigori C. Role and regulation of STAT3 phosphorylation at Ser727 in melanocytes and melanoma cells. J Invest Dermatol. 2012;132:1877–85.

    Article  CAS  PubMed  Google Scholar 

  69. Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82:241–50.

    Article  CAS  PubMed  Google Scholar 

  70. Chan KS, Sano S, Kataoka K, Abel E, Carbajal S, Beltran L, et al. Forced expression of a constitutively active form of Stat3 in mouse epidermis enhances malignant progression of skin tumors induced by two-stage carcinogenesis. Oncogene. 2008;27:1087–94.

    Article  CAS  PubMed  Google Scholar 

  71. Johnston PA, Grandis JR. STAT3 signaling: anticancer strategies and challenges. Mol Inter. 2011;11:18–26.

    Article  CAS  Google Scholar 

  72. Li YL, Ding K, Hu X, Wu LW, Zhou DM, Rao MJ, et al. DYRK1A inhibition suppresses STAT3/EGFR/Met signalling and sensitizes EGFR wild-type NSCLC cells to AZD9291. J Cell Mol Med. 2019;23:7427–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li Y, Xie X, Jie Z, Zhu L, Yang J-Y, Ko C-J, et al. DYRK1a mediates BAFF-induced noncanonical NF-kB activation to promote autoimmunity and B cell leukemogenesis. Blood. 2021;138:2360–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Baek KH, Zaslavsky A, Lynch RC, Britt C, Okada Y, Siarey RJ, et al. Down’s syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature. 2009;459:1126–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rozen EJ, Roewenstrunk J, Barallobre MJ, Di Vona C, Jung C, Figueiredo AF, et al. DYRK1A kinase positively regulates angiogenic responses in endothelial cells. Cell Rep. 2018;23:1867–78.

    Article  CAS  PubMed  Google Scholar 

  76. Cho HJ, Lee JG, Kim JH, Kim SY, Huh YH, Kim HJ, et al. Vascular defects of DYRK1A knockouts are ameliorated by modulating calcium signaling in zebrafish. Dis Model Mech. 2019;12:dmm037044.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Luna J, Boni J, Cuatrecasas M, Bofill-De Ros X, Nunez-Manchon E, Gironella M, et al. DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth. Gut. 2019;68:1465–76.

    Article  CAS  PubMed  Google Scholar 

  78. Ferron SR, Pozo N, Laguna A, Aranda S, Porlan E, Moreno M, et al. Regulated segregation of kinase Dyrk1A during asymmetric neural stem cell division is critical for EGFR-mediated biased signaling. Cell Stem Cell. 2010;7:367–79.

    Article  CAS  PubMed  Google Scholar 

  79. Pozo N, Zahonero C, Fernandez P, Linares JM, Ayuso A, Hagiwara M, et al. Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth. J Clin Invest. 2013;123:2475–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell. 2012;22:318–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34.

    Article  CAS  PubMed  Google Scholar 

  82. Lee SB, Frattini V, Bansal M, Castano AM, Sherman D, Hutchinson K, et al. An ID2-dependent mechanism for VHL inactivation in cancer. Nature. 2016;529:172–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Chen B, McCuaig-Walton D, Tan S, Montgomery AP, Day BW, Kassiou M, et al. DYRK1A Negatively Regulates CDK5-SOX2 pathway and self-renewal of glioblastoma stem cells. Int J Mol Sci. 2021;22:4011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kamal MM, Sathyan P, Singh SK, Zinn PO, Marisetty AL, Liang S, et al. REST regulates oncogenic properties of glioblastoma stem cells. Stem Cells (Dayt, Ohio). 2012;30:405–14.

    Article  CAS  Google Scholar 

  85. Martin CE, Nguyen A, Kang MK, Kim RH, Park N-H, Shin K-H. DYRK1A is required for maintenance of cancer stemness, contributing to tumorigenic potential in oral/oropharyngeal squamous cell carcinoma. Exp Cell Res. 2021;405:112656.

    Article  CAS  PubMed  Google Scholar 

  86. Wegiel J, Kaczmarski W, Barua M, Kuchna I, Nowicki K, Wang KC, et al. Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome. J Neuropathol Exp Neurol. 2011;70:36–50.

    Article  CAS  PubMed  Google Scholar 

  87. Qian W, Liang H, Shi J, Jin N, Grundke-Iqbal I, Iqbal K, et al. Regulation of the alternative splicing of tau exon 10 by SC35 and Dyrk1A. Nucleic Acids Res. 2011;39:6161–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. de Graaf K, Czajkowska H, Rottmann S, Packman LC, Lilischkis R, Lüscher B, et al. The protein kinase DYRK1A phosphorylates the splicing factor SF3b1/SAP155 at Thr434, a novel in vivo phosphorylation site. BMC Biochem. 2006;7:7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Ding S, Shi J, Qian W, Iqbal K, Grundke-Iqbal I, Gong C-X, et al. Regulation of alternative splicing of tau exon 10 by 9G8 and Dyrk1A. Neurobiol Aging. 2012;33:1389–99.

    Article  CAS  PubMed  Google Scholar 

  90. Yin X, Jin N, Gu J, Shi J, Zhou J, Gong CX, et al. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10 inclusion. J Biol Chem. 2012;287:30497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shi J, Zhang T, Zhou C, Chohan MO, Gu X, Wegiel J, et al. Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome. J Biol Chem. 2008;283:28660–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wang E, Bello Pineda JM, Bourcier J, Stahl M, Penson AV, Wakiro I, et al. Modulation of RNA splicing enhances response to BCL2 inhibition in acute myeloid leukemia. Blood.2021;138:507.

    Article  Google Scholar 

  93. Zhang Y, Qian J, Gu C, Yang Y. Alternative splicing and cancer: a systematic review. Signal Transduct Target Ther. 2021;6:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lamoral-Theys D, Pottier L, Dufrasne F, Neve J, Dubois J, Kornienko A, et al. Natural polyphenols that display anticancer properties through inhibition of kinase activity. Curr Med Chem. 2010;17:812–25.

    Article  CAS  PubMed  Google Scholar 

  95. Almatroodi SA, Almatroudi A, Khan AA, Alhumaydhi FA, Alsahli MA, Rahmani AH. Potential Therapeutic Targets of Epigallocatechin Gallate (EGCG), the most abundant catechin in green tea, and its role in the therapy of various types of cancer. Molecules. 2020;25:3146.

    Article  PubMed Central  CAS  Google Scholar 

  96. Djamshidian A, Bernschneider-Reif S, Poewe W, Lees AJ. Banisteriopsis caapi, a Forgotten Potential Therapy for Parkinson’s Disease? Mov Disord Clin Pr. 2016;3:19–26.

    Article  Google Scholar 

  97. Zhang L, Li D, Yu S. Pharmacological effects of harmine and its derivatives: a review. Arch Pharm Res. 2020;43:1259–75.

    Article  CAS  PubMed  Google Scholar 

  98. Kim H, Sablin SO, Ramsay RR. Inhibition of monoamine oxidase A by beta-carboline derivatives. Arch Biochem Biophys. 1997;337:137–42.

    Article  CAS  PubMed  Google Scholar 

  99. Balint B, Weber C, Cruzalegui F, Burbridge M, Kotschy A. Structure-based design and synthesis of harmine derivatives with different selectivity profiles in kinase versus monoamine oxidase inhibition. ChemMedChem.2017;12:932–9.

    Article  CAS  PubMed  Google Scholar 

  100. Wurzlbauer A, Rüben K, Gürdal E, Chaikuad A, Knapp S, Sippl W, et al. How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition-The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine. Molecules. 2020;25:5962.

    Article  PubMed Central  CAS  Google Scholar 

  101. Fruit C, Couly F, Bhansali R, Rammohan M, Lindberg MF, Crispino JD, et al. Biological Characterization of 8-Cyclopropyl-2-(pyridin-3-yl)thiazolo[5,4-f]quinazolin-9(8H)-one, a Promising Inhibitor of DYRK1A. Pharmaceuticals (Basel). 2019;12:185.

    Article  CAS  Google Scholar 

  102. Naert G, Ferre V, Meunier J, Keller E, Malmstrom S, Givalois L, et al. Leucettine L41, a DYRK1A-preferential DYRKs/CLKs inhibitor, prevents memory impairments and neurotoxicity induced by oligomeric Abeta25-35 peptide administration in mice. Eur Neuropsychopharmacol. 2015;25:2170–82.

    Article  CAS  PubMed  Google Scholar 

  103. Coutadeur S, Benyamine H, Delalonde L, de Oliveira C, Leblond B, Foucourt A, et al. A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer’s disease: effect on Tau and amyloid pathologies in vitro. J Neurochem. 2015;133:440–51.

    Article  CAS  PubMed  Google Scholar 

  104. Deng X, Friedman E. Mirk kinase inhibition blocks the in vivo growth of pancreatic cancer cells. Genes Cancer. 2014;5:337–47.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Couly F, Harari M, Dubouilh-Benard C, Bailly L, Petit E, Diharce J, et al. Development of Kinase Inhibitors via Metal-Catalyzed C-H Arylation of 8-Alkyl-thiazolo[5,4-f]-quinazolin-9-ones Designed by Fragment-Growing Studies. Molecules. 2018;23:2181.

    Article  PubMed Central  CAS  Google Scholar 

  106. Tazarki H, Zeinyeh W, Esvan YJ, Knapp S, Chatterjee D, Schröder M, et al. New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis. Eur J Medicinal Chem. 2019;166:304–17.

    Article  CAS  Google Scholar 

  107. Coombs TC, Tanega C, Shen M, Wang JL, Auld DS, Gerritz SW, et al. Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315. Bioorg Medicinal Chem Lett. 2013;23:3654–61.

    Article  CAS  Google Scholar 

  108. Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O’Brien SE, et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res. 2010;70:10288–98.

    Article  CAS  PubMed  Google Scholar 

  109. Quotti Tubi L, Gurrieri C, Brancalion A, Bonaldi L, Bertorelle R, Manni S, et al. Inhibition of protein kinase CK2 with the clinical-grade small ATP-competitive compound CX-4945 or by RNA interference unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and daunorubicin-induced cytotoxicity. J Hematol Oncol. 2013;6:78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Buontempo F, Orsini E, Martins LR, Antunes I, Lonetti A, Chiarini F, et al. Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling. Leukemia. 2014;28:543–53.

    Article  CAS  PubMed  Google Scholar 

  111. Martins LR, Lúcio P, Melão A, Antunes I, Cardoso BA, Stansfield R, et al. Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. Leukemia. 2014;28:179–82.

    Article  CAS  PubMed  Google Scholar 

  112. Prins RC, Burke RT, Tyner JW, Druker BJ, Loriaux MM, Spurgeon SE. CX-4945, a selective inhibitor of casein kinase-2 (CK2), exhibits anti-tumor activity in hematologic malignancies including enhanced activity in chronic lymphocytic leukemia when combined with fludarabine and inhibitors of the B-cell receptor pathway. Leukemia. 2013;27:2094–6.

    Article  CAS  PubMed  Google Scholar 

  113. Kim HM, Jeong I, Kim HJ, Kang SK, Kwon WS, Kim TS, et al. Casein Kinase 2 Inhibitor, CX-4945, as a potential targeted anticancer agent in gastric cancer. Anticancer Res. 2018;38:6171–80.

    Article  CAS  PubMed  Google Scholar 

  114. Borad MJ, Bai L-Y, Chen M-H, Hubbard JM, Mody K, Rha SY, et al. Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: a phase Ib/II study. J Clin Oncol. 2021;39:312.

    Article  Google Scholar 

  115. Weber C, Sipos M, Paczal A, Balint B, Kun V, Foloppe N, et al. Structure-guided discovery of potent and selective DYRK1A inhibitors. J Med Chem. 2021;64:6745–64.

    Article  CAS  PubMed  Google Scholar 

  116. Lee Walmsley D, Murray JB, Dokurno P, Massey AJ, Benwell K, Fiumana A, et al. Fragment-derived selective inhibitors of dual-specificity kinases DYRK1A and DYRK1B. J Medicinal Chem. 2021;64:8971–91.

    Article  CAS  Google Scholar 

  117. Henderson SH, Sorrell F, Bennett J, Fedorov O, Hanley MT, Godoi PH, et al. Discovery and characterization of selective and ligand-efficient DYRK inhibitors. J Med Chem. 2021;64:11709–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Henderson SH, Sorrell F, Bennett J, Hanley MT, Robinson S, Hopkins Navratilova I, et al. Mining public domain data to develop selective DYRK1A inhibitors. ACS Medicinal Chem Lett. 2020;11:1620–6.

    Article  CAS  Google Scholar 

  119. Yoon HR, Balupuri A, Choi K-E, Kang NS. Small molecule inhibitors of DYRK1A identified by computational and experimental approaches. Int J Mol Sci. 2020;21:6826.

    Article  CAS  PubMed Central  Google Scholar 

  120. Becker W. A wake-up call to quiescent cancer cells - potential use of DYRK1B inhibitors in cancer therapy. FEBS J. 2018;285:1203–11.

    Article  CAS  PubMed  Google Scholar 

  121. Liu Q, Liu N, Zang S, Liu H, Wang P, Ji C, et al. Tumor suppressor DYRK1A effects on proliferation and chemoresistance of AML cells by downregulating c-Myc. PLoS ONE. 2014;9:e98853.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Li Y, Zhou D, Xu S, Rao M, Zhang Z, Wu L, et al. DYRK1A suppression restrains Mcl-1 expression and sensitizes NSCLC cells to Bcl-2 inhibitors. Cancer Biol Med. 2020;17:387–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kottakis F, Polytarchou C, Foltopoulou P, Sanidas I, Kampranis SC, Tsichlis PN. FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol Cell. 2011;43:285–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Radhakrishnan A, Nanjappa V, Raja R, Sathe G, Puttamallesh VN, Jain AP, et al. A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma. Sci Rep. 2016;6:36132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhao C, Wang D, Gao Z, Kan H, Qiu F, Chen L, et al. Licocoumarone induces BxPC-3 pancreatic adenocarcinoma cell death by inhibiting DYRK1A. Chem Biol Interact. 2020;316:108913.

    Article  CAS  PubMed  Google Scholar 

  126. Shin CM, Lee DH, Seo AY, Lee HJ, Kim SB, Son WC, et al. Green tea extracts for the prevention of metachronous colorectal polyps among patients who underwent endoscopic removal of colorectal adenomas: a randomized clinical trial. Clin Nutr. 2018;37:452–8.

    Article  CAS  PubMed  Google Scholar 

  127. Kumar NB, Dickinson SI, Schell MJ, Manley BJ, Poch MA, Pow-Sang J. Green tea extract for prevention of prostate cancer progression in patients on active surveillance. Oncotarget. 2018;9:37798–806.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Fan H, Peng J, Hamann MT, Hu J-F. Lamellarins and related pyrrole-derived alkaloids from marine organisms. Chem Rev. 2008;108:264–87.

    Article  CAS  PubMed  Google Scholar 

  129. Quesada AR, García Grávalos MD, Fernández Puentes JL. Polyaromatic alkaloids from marine invertebrates as cytotoxic compounds and inhibitors of multidrug resistance caused by P-glycoprotein. Br J Cancer. 1996;74:677–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Jarry M, Lecointre C, Malleval C, Desrues L, Schouft MT, Lejoncour V, et al. Impact of meriolins, a new class of cyclin-dependent kinase inhibitors, on malignant glioma proliferation and neo-angiogenesis. Neuro Oncol. 2014;16:1484–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Park NS, Park YK, Ramalingam M, Yadav AK, Cho HR, Hong VS, et al. Meridianin C inhibits the growth of YD-10B human tongue cancer cells through macropinocytosis and the down-regulation of Dickkopf-related protein-3. J Cell Mol Med. 2018;22:5833–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Rossignol E, Debiton E, Fabbro D, Moreau P, Prudhomme M, Anizon F. In-vitro antiproliferative activities and kinase inhibitory potencies of meridianin derivatives. Anticancer Drugs. 2008;19:789–92.

    Article  CAS  PubMed  Google Scholar 

  133. Imperatore C, Aiello A, D'Aniello F, Senese M, Menna M. Alkaloids from marine invertebrates as important leads for anticancer drugs discovery and development. Molecules. 2014;19:20391–423.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Rüben K, Wurzlbauer A, Walte A, Sippl W, Bracher F, Becker W. Selectivity profiling and biological activity of novel β-carbolines as potent and selective DYRK1 kinase inhibitors. PLOS ONE. 2015;10:e0132453.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This review was supported in part by the NIH (R35 CA253096). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support was provided St. Jude/ALSAC. EH is supported by the American Society of Hematology’s Medical Student Physician-Scientist Award.

Author information

Authors and Affiliations

Authors

Contributions

MR, EH, RB, EZ, LSL, and JDC wrote the review.

Corresponding author

Correspondence to John D. Crispino.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rammohan, M., Harris, E., Bhansali, R.S. et al. The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target. Oncogene 41, 2003–2011 (2022). https://doi.org/10.1038/s41388-022-02245-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02245-6

This article is cited by

Search

Quick links