Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators.
14-3-3 protein
MINK1 kinase
glucocorticoid receptor
nuclear receptor
phosphorylation
protein–protein interaction
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
Historique:
received:
06
08
2020
revised:
08
03
2021
accepted:
16
03
2021
pubmed:
22
3
2021
medline:
24
8
2021
entrez:
21
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33744286
pii: S0021-9258(21)00329-X
doi: 10.1016/j.jbc.2021.100551
pmc: PMC8080530
pii:
doi:
Substances chimiques
14-3-3 Proteins
0
Receptors, Glucocorticoid
0
Threonine
2ZD004190S
MINK1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100551Subventions
Organisme : Medical Research Council
ID : MC_EX_G0801767
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.
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