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Previous studies verified that phosphorylation at different amino acids determined MEF2's transcriptional activity which was essential in regulating downstream target genes expression. What regulates phosphorylation of MEF2D and affects its function has not been fully elucidated. Here, we uncovered that dual\u2010specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A), a kinase critical in Down's syndrome pathogenesis, directly bound to and phosphorylated MEF2D at Ser251 in vitro. Phosphorylation of MEF2D by DYRK1A significantly increased MEF2D protein level but attenuated its transcriptional activity, which resulted in decreased transcriptions of MEF2D target genes. Phosphorylation mutated Ser251A MEF2D exhibited enhanced transcriptional activity compared with wild type MEF2D. MEF2D and DYRK1A were observed co\u2010localized in HEK293 and U87MG cells. Moreover, DYRK1A\u2010mediated MEF2D phosphorylation in vitro might influence its nuclear export upon subcellular fractionation, which partially explained the reduction of MEF2D transcriptional activity by DYRK1A. Our results indicated that DYRK1A might be a regulator of MEF2D transcriptional activity and indirectly get involved in regulation of MEF2D target genes.<\/jats:p>","DOI":"10.1111\/jcmm.16505","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T20:03:58Z","timestamp":1623355438000},"page":"6082-6093","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["DYRK1A phosphorylates MEF2D and decreases its transcriptional activity"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4457-1695","authenticated-orcid":false,"given":"Pin","family":"Wang","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Otorhinolaryngology Qilu Hospital Cheeloo College of Medicine Shandong University  Jinan China"},{"name":"Department of Otorhinolaryngology Qilu Hospital of Shandong University  Jinan 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