Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)

Ami Oi, Syouichi Katayama, Naoya Hatano, Yasunori Sugiyama, Isamu Kameshita, Noriyuki Sueyoshi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase primarily expressed in the central nervous system and is known to cause X-linked neurodevelopmental disorders such as Rett syndrome. However, the mechanisms regulating CDKL5 have not yet been fully clarified. Therefore, in this study, we investigated the protein kinase that directly phosphorylates CDKL5, identifying it as dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), an enzyme binding to and phosphorylating CDKL5. We showed that subcellular distribution of CDKL5 was regulated by its phosphorylation by DYRK1A. In mouse neuroblastoma Neuro2a cells, CDKL5 was localized in both the cytosol and nucleus, whereas DYRK1A showed a typical nuclear localization. When CDKL5 and DYRK1A were co-expressed, the cytosolic localization of CDKL5 was significantly increased. Results of site-directed mutagenesis revealed that the phosphorylation site was Ser-308, in the vicinity of the nuclear localization signal. A mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changed CDKL5 localization to the cytosol, whereas the corresponding alanine-substituted analog, CDKL5(S308A), was primarily localized to the nucleus. Taken together, these results strongly suggested that DYRK1A bound to CDKL5 and phosphorylated it on Ser-308, thus interfering with its nuclear localization.

Original languageEnglish
Pages (from-to)239-245
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume482
Issue number2
DOIs
Publication statusPublished - Jan 8 2017
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 5
Phosphorylation
Cyclin-Dependent Kinases
Cytosol
Protein Kinases
Dyrk kinase
Rett Syndrome
Nuclear Localization Signals
Mutagenesis
Neurology
Site-Directed Mutagenesis
Neuroblastoma
Aspartic Acid
Alanine
Serine

Keywords

  • CDKL5
  • Down syndrome
  • DYRK1A
  • Protein phosphorylation
  • Rett syndrome

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). / Oi, Ami; Katayama, Syouichi; Hatano, Naoya; Sugiyama, Yasunori; Kameshita, Isamu; Sueyoshi, Noriyuki.

In: Biochemical and Biophysical Research Communications, Vol. 482, No. 2, 08.01.2017, p. 239-245.

Research output: Contribution to journalArticle

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