CDK-dependent phosphorylation of PHD1 on serine 130 alters its substrate preference in cells.

Ortmann, Brian, Bensaddek, Dalila, Carvalhal, Sara, Moser, Sandra C, Mudie, Sharon, Griffis, Eric R, Swedlow, Jason R, Lamond, Angus I and Rocha, Sonia (2016) CDK-dependent phosphorylation of PHD1 on serine 130 alters its substrate preference in cells. Journal of cell science, 129 (1). pp. 191-205.

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Official URL: https://jcs.biologists.org/content/129/1/191

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.

Item Type:	Article
Uncontrolled Keywords:	EGLN2, HIF, Cep192, Hypoxia
Depositing User:	Symplectic Admin
Date Deposited:	10 Jan 2018 13:21
Last Modified:	19 Jan 2023 06:46
DOI:	10.1242/jcs.179911
Open Access URL:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC47323...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3015793