Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase

Ivan Munoz, Michael Morgan, Julien Peltier, Florian Weiland, Mateusz Gregorczyk, Fiona C. M. Brown, Thomas Macartney, Rachel Toth, Matthias Trost (Lead / Corresponding author), John Rouse (Lead / Corresponding author)

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Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quantitative phosphoproteomic screening which identified MAP1S, CEP131 and DLG5—regulators of microtubule and centrosome function—as cellular substrates of CDKL5. Antibodies against MAP1S phospho-Ser 900 and CEP131 phospho-Ser 35 confirmed CDKL5-dependent phosphorylation of these targets in human cells. The phospho-acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPXSA, although CDKL5 can tolerate residues other than Ala immediately C-terminal to the phospho-acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity in vitro and in cells. These data reveal the first cellular substrates of CDKL5, which may represent important biomarkers in the diagnosis and treatment of CDKL5 disorder, and illuminate the functions of this poorly characterized kinase.

Original languageEnglish
Article numbere99559
Pages (from-to)1-19
Number of pages19
JournalThe EMBO Journal
Issue number24
Early online date28 Sept 2018
Publication statusPublished - 14 Dec 2018


  • CDKL5 disorder
  • centrosome
  • cilia
  • kinase
  • microtubule

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology


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    • MRC PPU - Scientific Programme Leader (MRC) of Chromosome Biology

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