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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\u2014regulators of microtubule and centrosome function\u2014as cellular substrates of CDKL5. Antibodies against MAP1S phospho\u2010Ser\n                    <jats:sup>900<\/jats:sup>\n                    and CEP131 phospho\u2010Ser\n                    <jats:sup>35<\/jats:sup>\n                    confirmed CDKL5\u2010dependent phosphorylation of these targets in human cells. The phospho\u2010acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPX\n                    <jats:underline>S<\/jats:underline>\n                    A, although CDKL5 can tolerate residues other than Ala immediately C\u2010terminal to the phospho\u2010acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.15252\/embj.201899559","type":"journal-article","created":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T08:59:30Z","timestamp":1538125170000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase"],"prefix":"10.1038","volume":"37","author":[{"given":"Ivan M","family":"Mu\u00f1oz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Peltier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Weiland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Gregorczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona CM","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Macartney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Toth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-700X","authenticated-orcid":false,"given":"Matthias","family":"Trost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-8303","authenticated-orcid":false,"given":"John","family":"Rouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,28]]},"reference":[{"key":"BFEMBJ201899559_CR1","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nature02166","volume":"426","author":"JS Andersen","year":"2003","unstructured":"Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, Mann M (2003) Proteomic characterization of the human centrosome by protein correlation profiling. 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