{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:08:23Z","timestamp":1783483703192,"version":"3.55.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010801","name":"Xunta de Galicia","doi-asserted-by":"publisher","award":["PID2020-115121GB-I00"],"award-info":[{"award-number":["PID2020-115121GB-I00"]}],"id":[{"id":"10.13039\/501100010801","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010801","name":"Xunta de Galicia","doi-asserted-by":"publisher","award":["ED 431C 2021\/18"],"award-info":[{"award-number":["ED 431C 2021\/18"]}],"id":[{"id":"10.13039\/501100010801","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Dual specificity tyrosine-phosphorylation-regulated kinases (DYRKs) are a group of conserved eukaryotic kinases phosphorylating tyrosine, serine, and threonine residues. The human DYRK family comprises 5 members (DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4). The different DYRKs have been implicated in neurological diseases, cancer, and virus infection. Specifically, DYRK2 has been mainly implicated in cancer progression. However, its role in healthy and pathological nervous system function has been overlooked. In this context, we review current available data on DYRK2 in the nervous system, where the available studies indicate that it has key roles in neuronal development and function. DYRK2 regulates neuronal morphogenesis (e.g., axon growth and branching) by phosphorylating cytoskeletal elements (e.g., doublecortin). Comparative data reveals that it is involved in the development of olfactory and visual systems, the spinal cord and possibly the cortex. DYRK2 also participates in processes such as olfaction, vision and, learning. However, DYRK2 could be involved in other brain functions since available expression data shows that it is expressed across the whole brain. High DYRK2 protein levels have been detected in basal ganglia and cerebellum. In adult nervous system, DYRK2 mRNA expression is highest in the cortex, hippocampus, and retina. Regarding nervous system disease, DYRK2 has been implicated in neuroblastoma, glioma, epilepsy, neuroinflammation, Alzheimer\u2019s disease, Parkinson\u2019s disease, spinal cord injury and virus infection. DYRK2 upregulation usually has a negative impact in cancer-related conditions and a positive impact in non-malignant conditions. Its role in axon growth makes DYRK2 as a promising target for spinal cord or brain injury and regeneration.<\/jats:p>","DOI":"10.3389\/fnins.2022.994256","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T05:33:50Z","timestamp":1662615230000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Roles of dual specificity tyrosine-phosphorylation-regulated kinase 2 in nervous system development and disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Gabriel Nicol\u00e1s","family":"Santos-Dur\u00e1n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f3n","family":"Barreiro-Iglesias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1126\/SCIENCE.1262110","article-title":"Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans.","volume":"348","author":"Ardlie","year":"2015","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0079-6603(08)60503-6","article-title":"Structural and functional characteristics of Dyrk, a novel subfamily of protein kinases with dual specificity.","volume":"62","author":"Becker","year":"1999","journal-title":"Prog. Nucleic Acid Res. Mol. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"25893","DOI":"10.1074\/jbc.273.40.25893","article-title":"Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases.","volume":"273","author":"Becker","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e24502","DOI":"10.7554\/eLife.24502","article-title":"Inhibition of DYRK1A disrupts neural lineage specificationin human pluripotent stem cells.","volume":"6","author":"Bellmaine","year":"2017","journal-title":"eLife"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1534\/g3.116.029884","article-title":"Copy number profiling of Brazilian astrocytomas.","volume":"6","author":"Bidinotto","year":"2016","journal-title":"G3"},{"key":"B6","doi-asserted-by":"publisher","first-page":"36665","DOI":"10.1074\/jbc.M807844200","article-title":"DYRK3 dual-specificity kinase attenuates erythropoiesis during anemia.","volume":"283","author":"Bogacheva","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"2106","DOI":"10.3390\/cancers12082106","article-title":"The DYRK family of kinases in cancer: Molecular functions and therapeutic opportunities.","volume":"12","author":"Boni","year":"2020","journal-title":"Cancers"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.3389\/fnins.2019.01453","article-title":"Physical activity induces nucleus accumbens genes expression changes preventing chronic pain susceptibility promoted by high-fat diet and sedentary behavior in mice.","volume":"13","author":"Brand\u00e3o","year":"2020","journal-title":"Front. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"11986","DOI":"10.3390\/ijms222111986","article-title":"Establishment of human-induced pluripotent stem cell-derived neurons\u2014a promising in vitro model for a molecular study of rabies virus and host interaction.","volume":"22","author":"Chailangkarn","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"16591","DOI":"10.1074\/jbc.M513344200","article-title":"Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo.","volume":"281","author":"Cole","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4747","DOI":"10.1007\/s00018-020-03556-1","article-title":"Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): Molecular basis, functions and role in diseases.","volume":"77","author":"Correa-S\u00e1ez","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"9098","DOI":"10.3390\/ijms22169098","article-title":"Gsk-3\u03b2, fyn, and dyrk1a: Master regulators in neurodegenerative pathways.","volume":"22","author":"Demuro","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e1000582","DOI":"10.1371\/journal.pbio.1000582","article-title":"A high-resolution anatomical atlas of the transcriptome in the mouse embryo.","volume":"9","author":"Diez-Roux","year":"2011","journal-title":"PLoS Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"6636","DOI":"10.1128\/mcb.22.18.6636-6647.2002","article-title":"Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice.","volume":"22","author":"Fotaki","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e63731","DOI":"10.7554\/eLife.63731","article-title":"CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels.","volume":"10","author":"Gon\u00e7alves","year":"2021","journal-title":"eLife"},{"key":"B16","doi-asserted-by":"publisher","first-page":"e1005995","DOI":"10.1371\/journal.pgen.1005995","article-title":"shRNA-based screen identifies endocytic recycling pathway components that act as genetic modifiers of alpha-synuclein aggregation, secretion and toxicity.","volume":"12","author":"Gon\u00e7alves","year":"2016","journal-title":"PLoS Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1080\/21541248.2016.1199191","article-title":"Traffic jams and the complex role of \u03b1-Synuclein aggregation in Parkinson disease.","volume":"8","author":"Gon\u00e7alves","year":"2017","journal-title":"Small GTPases"},{"key":"B18","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1038\/nature04631","article-title":"A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.","volume":"441","author":"Gwack","year":"2006","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1021\/acschemneuro.6b00222","article-title":"MiRNA-187-3p-mediated regulation of the KCNK10\/TREK-2 potassium channel in a rat epilepsy model.","volume":"7","author":"Haenisch","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1096\/fasebj.9.8.7768349","article-title":"The eukaryotic protein kinase superfamily: Kinase (catalytic) domain structure and classification 1.","volume":"9","author":"Hanks","year":"1995","journal-title":"FASEB J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"109","DOI":"10.18632\/aging.203811","article-title":"Kampo formulas alleviate aging-related emotional disturbances and neuroinflammation in male senescence-accelerated mouse prone 8 mice.","volume":"14","author":"Ito","year":"2022","journal-title":"Aging"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1523\/JNEUROSCI.1557-20.2021","article-title":"Distinct transcriptomic profiles in the dorsal hippocampus and prelimbic cortex are transiently regulated following episodic learning.","volume":"41","author":"Katzman","year":"2021","journal-title":"J. Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"3488","DOI":"10.1074\/jbc.271.7.3488","article-title":"Dyrk, a dual specificity protein kinase with unique structural features whose activity is dependent on tyrosine residues between subdomains VII and VIII.","volume":"271","author":"Kentrup","year":"1996","journal-title":"J. Biol. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1093\/cercor\/bhl118","article-title":"Genetic analysis of anterior-posterior expression gradients in the developing mammalian forebrain.","volume":"17","author":"Kudo","year":"2007","journal-title":"Cereb. Cortex"},{"key":"B25","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/cbf.3582","article-title":"The role of Shh signalling pathway in central nervous system development and related diseases.","volume":"39","author":"Li","year":"2021","journal-title":"Cell Biochem. Funct."},{"key":"B26","doi-asserted-by":"publisher","first-page":"6047","DOI":"10.3390\/IJMS22116047","article-title":"Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) in human disease, an overview.","volume":"22","author":"Lindberg","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e76775","DOI":"10.1371\/journal.pone.0076775","article-title":"Drosophila Dyrk2 plays a role in the development of the visual system.","volume":"8","author":"Luebbering","year":"2013","journal-title":"PLoS One"},{"key":"B28","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1002\/dneu.22117","article-title":"Phosphorylation of Dpsyl2 (CRMP2) and Dpsyl3 (CRMP4) is required for positioning of caudal primary motor neurons in the zebrafish spinal cord.","volume":"73","author":"Morimura","year":"2013","journal-title":"Dev. Neurobiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1074\/jbc.270.2.823","article-title":"Proline-directed and non-proline-directed phosphorylation of PHF-tau.","volume":"270","author":"Morishima-Kawashima","year":"1995","journal-title":"J. Biol. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.ijdevneu.2007.10.004","article-title":"NFAT signaling in neural development and axon growth.","volume":"26","author":"Nguyen","year":"2008","journal-title":"Int. J. Dev. Neurosci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/emm.2002.27","article-title":"Genome-wide expression profiling of 8-chloroadenosine- and 8-chloro-cAMP-treated human neuroblastoma cells using radioactive human cDNA microarray.","volume":"34","author":"Park","year":"2002","journal-title":"Exp. Mol. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/978-3-030-45493-7_5","article-title":"Dysregulation of neurite outgrowth and cell migration in autism and other neurodevelopmental disorders.","volume":"25","author":"Prem","year":"2020","journal-title":"Adv. Neurobiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.mce.2006.12.041","article-title":"The expression of the testis-specific Dyrk4 kinase is highly restricted to step 8 spermatids but is not required for male fertility in mice.","volume":"267","author":"Sacher","year":"2007","journal-title":"Mol. Cell. Endocrinol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3093","DOI":"10.1007\/s11064-017-2345-2","article-title":"Regulation of glioma cells migration by DYRK2.","volume":"42","author":"Shen","year":"2017","journal-title":"Neurochem. Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3390\/jdb5040013","article-title":"Emerging roles of DYRK kinases in embryogenesis and Hedgehog pathway control.","volume":"5","author":"Singh","year":"2017","journal-title":"J. Dev. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1002\/cm.21021","article-title":"Dyrk kinases regulate phosphorylation of doublecortin, cytoskeletal organization, and neuronal morphology.","volume":"69","author":"Slepak","year":"2012","journal-title":"Cytoskeleton"},{"key":"B37","doi-asserted-by":"publisher","first-page":"173","DOI":"10.3389\/fcell.2020.00173","article-title":"Inhibition of gamma-secretase promotes axon regeneration after a complete spinal cord injury.","volume":"8","author":"Sobrido-Came\u00e1n","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1387\/ijdb.160175sj","article-title":"DYRK2 displays muscle fiber type specific function during zebrafish early somitogenesis.","volume":"61","author":"Sun","year":"2017","journal-title":"Int. J. Dev. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/j.ijbiomac.2017.06.087","article-title":"Dyrk2 involved in regulating LPS-induced neuronal apoptosis.","volume":"104","author":"Sun","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1007\/s00343-010-9073-7","article-title":"Characterization of DYRK2 (dual-specificity tyrosine-phosphorylation-regulated kinase 2) from Zebrafish (Dario rerio).","volume":"28","author":"Sun","year":"2010","journal-title":"Chin. J. Oceanol. Limnol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.ydbio.2012.07.032","article-title":"Dpysl2 (CRMP2) and Dpysl3 (CRMP4) phosphorylation by Cdk5 and DYRK2 is required for proper positioning of Rohon-Beard neurons and neural crest cells during neurulation in zebrafish.","volume":"370","author":"Tanaka","year":"2012","journal-title":"Dev. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"100233","DOI":"10.1074\/JBC.REV120.015217","article-title":"Emerging roles of DYRK2 in cancer.","volume":"296","author":"Tandon","year":"2021","journal-title":"J. Biol. Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1002\/pro.3307","article-title":"The human protein atlas: A spatial map of the human proteome.","volume":"27","author":"Thul","year":"2018","journal-title":"Protein Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/s12935-018-0574-3","article-title":"Harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor induces caspase-mediated apoptosis in neuroblastoma.","volume":"18","author":"Uhl","year":"2018","journal-title":"Cancer Cell Int."},{"key":"B45","doi-asserted-by":"publisher","first-page":"3718","DOI":"10.1038\/s41467-019-11661-4","article-title":"Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes.","volume":"10","author":"Wang","year":"2019","journal-title":"Nat. Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e50850","DOI":"10.7554\/eLife.50850","article-title":"Sequential phosphorylation of NDEL1 by the DYRK2-GSK3\u03b2 complex is critical for neuronal morphogenesis.","volume":"8","author":"Woo","year":"2019","journal-title":"eLife"},{"key":"B47","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1042\/bj3550609","article-title":"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.","volume":"355","author":"Woods","year":"2001","journal-title":"Biochem. J."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1016\/j.ijbiomac.2017.11.095","article-title":"Dyrk2 mediated the release of proinflammatory cytokines in LPS-induced BV2 cells.","volume":"109","author":"Xu","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1038\/s42003-021-02734-6","article-title":"Mice lacking DYRK2 exhibit congenital malformations with lung hypoplasia and altered Foxf1 expression gradient.","volume":"4","author":"Yogosawa","year":"2021","journal-title":"Commun. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"e57381","DOI":"10.7554\/ELIFE.57381","article-title":"The novel ciliogenesis regulator dyrk2 governs hedgehog signaling during mouse embryogenesis.","volume":"9","author":"Yoshida","year":"2020","journal-title":"eLife"},{"key":"B51","doi-asserted-by":"publisher","first-page":"2953","DOI":"10.1002\/1873-3468.13601","article-title":"Multiple functions of DYRK2 in cancer and tissue development.","volume":"593","author":"Yoshida","year":"2019","journal-title":"FEBS Lett."},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.1016\/j.gendis.2021.12.004","article-title":"New insights into the roles for DYRK family in mammalian development and congenital diseases.","author":"Yoshida","year":"2022","journal-title":"Genes Dis."},{"key":"B53","doi-asserted-by":"publisher","first-page":"6787","DOI":"10.1093\/nar\/gkv608","article-title":"Complementing tissue characterization by integrating transcriptome profiling from the human protein atlas and from the FANTOM5 consortium.","volume":"43","author":"Yu","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"770627","DOI":"10.3389\/fnins.2021.770627","article-title":"Study of neuronal apoptosis ceRNA network in hippocampal sclerosis of human temporal lobe epilepsy by RNA-Seq.","volume":"15","author":"Yu","year":"2021","journal-title":"Front. Neurosci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.yebeh.2017.10.010","article-title":"Epilepsy is a neurological and a systemic disorder.","volume":"78","author":"Yuen","year":"2018","journal-title":"Epilepsy Behav."},{"key":"B56","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.canlet.2014.11.044","article-title":"CXCR2\/CXCL5 axis contributes to epithelial-mesenchymal transition of HCC cells through activating PI3K\/Akt\/GSK-3\u03b2\/Snail signaling.","volume":"358","author":"Zhou","year":"2015","journal-title":"Cancer Lett."},{"key":"B57","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1161\/CIRCULATIONAHA.121.055727","article-title":"DYRK1B-STAT3 drives cardiac hypertrophy and heart failure by impairing mitochondrial bioenergetics.","volume":"145","author":"Zhuang","year":"2022","journal-title":"Circulation"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.994256\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T05:33:53Z","timestamp":1662615233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.994256\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,8]]},"references-count":57,"alternative-id":["10.3389\/fnins.2022.994256"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2022.994256","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,8]]},"article-number":"994256"}}