Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.

Autor:	Munier CC; Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Eindhoven, The Netherlands., De Maria L; Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Edman K; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Gunnarsson A; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Longo M; Division of Cell and Developmental Biology (C.M.), College of Life Sciences, University of Dundee, Dundee, Scotland, UK., MacKintosh C; Division of Cell and Developmental Biology (C.M.), College of Life Sciences, University of Dundee, Dundee, Scotland, UK., Patel S; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK., Snijder A; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Wissler L; Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Brunsveld L; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Eindhoven, The Netherlands., Ottmann C; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Technische Universiteit Eindhoven, Eindhoven, The Netherlands., Perry MWD; Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. Electronic address: Matthew.Perry@astrazeneca.com.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Jan-Jun; Vol. 296, pp. 100551. Date of Electronic Publication: 2021 Mar 17.
DOI:	10.1016/j.jbc.2021.100551
Abstrakt:	The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that plays a central role in inflammation. The GR activity is also modulated via protein-protein interactions, including binding of 14-3-3 proteins induced by GR phosphorylation. However, the specific phosphorylation sites on the GR that trigger these interactions and their functional consequences are less clear. Hence, we sought to examine this system in more detail. We used phosphorylated GR peptides, biophysical studies, and X-ray crystallography to identify key residues within the ligand-binding domain of the GR, T524 and S617, whose phosphorylation results in binding of the representative 14-3-3 protein 14-3-3ζ. A kinase screen identified misshapen-like kinase 1 (MINK1) as responsible for phosphorylating T524 and Rho-associated protein kinase 1 for phosphorylating S617; cell-based approaches confirmed the importance of both GR phosphosites and MINK1 but not Rho-associated protein kinase 1 alone in inducing GR-14-3-3 binding. Together our results provide molecular-level insight into 14-3-3-mediated regulation of the GR and highlight both MINK1 and the GR-14-3-3 axis as potential targets for future therapeutic intervention. Competing Interests: Conflict of interest L. D. M., K. E., A. G., A. S., L. W., and M. W. D. P. are employed by and/or own shares in AstraZeneca. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu