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DYRK1A phosphorylates MEF2D and decreases its transcriptional activity

Pin Wang1,2, Juan Zhao1,2, Xiulian Sun1,3,4

  • 1NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.

Journal of Cellular and Molecular Medicine
|June 10, 2021
PubMed

Insights

Dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) phosphorylates Myocyte enhancer factor 2D (MEF2D), reducing its transcriptional activity. This finding reveals a novel regulatory mechanism for MEF2D target gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Myocyte enhancer factor 2D (MEF2D) regulates crucial cellular processes like growth, differentiation, survival, and apoptosis.
  • MEF2D's transcriptional activity, essential for target gene expression, is modulated by phosphorylation.
  • The specific kinases regulating MEF2D phosphorylation and function remain largely unknown.

Purpose of the Study:

  • To investigate the regulatory role of dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) in MEF2D phosphorylation and function.
  • To elucidate the impact of DYRK1A-mediated MEF2D phosphorylation on MEF2D's transcriptional activity and target gene expression.

Main Methods:

  • In vitro kinase assays to determine direct binding and phosphorylation of MEF2D by DYRK1A.
  • Site-directed mutagenesis to create phosphorylation-deficient MEF2D (Ser251A).
  • Cellular co-localization studies (HEK293, U87MG) and subcellular fractionation to assess protein localization and nuclear export.

Main Results:

  • DYRK1A directly binds and phosphorylates MEF2D at Ser251 in vitro.
  • DYRK1A-mediated phosphorylation increases MEF2D protein levels but decreases its transcriptional activity.
  • Phosphorylation-deficient MEF2D (Ser251A) exhibits enhanced transcriptional activity compared to wild-type MEF2D.
  • DYRK1A and MEF2D co-localize in cells, and DYRK1A may promote MEF2D nuclear export, reducing transcriptional output.

Conclusions:

  • DYRK1A acts as a novel regulator of MEF2D transcriptional activity.
  • DYRK1A-mediated phosphorylation of MEF2D influences its protein stability and subcellular localization.
  • This interaction provides insights into the regulation of MEF2D target genes and potential implications in diseases like Down's syndrome.
Keywords:
DYRK1AMEF2Dglioblastomaphosphorylationtranscriptional activity

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