title: CDK-dependent phosphorylation of PHD1 on serine 130 alters its substrate preference in cells.
abstract: PHD1 (also known as EGLN2) belongs to a family of prolyl hydroxylases (PHDs) that are involved in the control of the cellular response to hypoxia. PHD1 is also able to regulate mitotic progression through the regulation of the crucial centrosomal protein Cep192, establishing a link between the oxygen-sensing and the cell cycle machinery. Here, we demonstrate that PHD1 is phosphorylated by CDK2, CDK4 and CDK6 at S130. This phosphorylation fluctuates with the cell cycle and can be induced through oncogenic activation. Functionally, PHD1 phosphorylation leads to increased induction of hypoxia-inducible factor (HIF) protein levels and activity during hypoxia. PHD1 phosphorylation does not alter its intrinsic enzymatic activity, but instead decreases the interaction between PHD1 and HIF1α. Interestingly, although phosphorylation of PHD1 at S130 lowers its activity towards HIF1α, this modification increases the activity of PHD1 towards Cep192. These results establish a mechanism by which cell cycle mediators, such as CDKs, temporally control the activity of PHD1, directly altering the regulation of HIF1α and Cep192.
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Ortmann
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Dalila
authors.initials: D
authors.lastname: Bensaddek
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Carvalhal
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Moser
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Mudie
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Griffis
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Swedlow
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Angus I
authors.initials: AI
authors.lastname: Lamond
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK s.rocha@dundee.ac.uk.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D000595:Amino Acid Sequence; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000737:chemistry / Q000378:metabolism*; D007399:Interphase / Q000187:drug effects; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D009857:Oncogenes; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008934:Mitogens; D010768:Phosphoserine; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D018844:Cyclin-Dependent Kinases
keywords: Cep192; EGLN2; HIF; Hypoxia