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

Claire C. Munier, Leonardo De Maria, Karl Edman, Anders Gunnarsson, Marianna Longo, Carol MacKintosh, Saleha Patel, Arjan Snijder, Lisa Wissler, Luc Brunsveld, Christian Ottmann, Matthew W. D. Perry (Lead / Corresponding author)

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    9 Citations (Scopus)
    117 Downloads (Pure)

    Abstract

    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 Rhoassociated 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.

    Original languageEnglish
    Article number100551
    Number of pages15
    JournalJournal of Biological Chemistry
    Volume296
    Early online date17 Mar 2021
    DOIs
    Publication statusPublished - 2021

    Keywords

    • 14‐3‐3 protein
    • glucocorticoid receptor
    • MINK1 kinase
    • nuclear receptor
    • phosphorylation
    • protein‐protein interaction

    ASJC Scopus subject areas

    • Molecular Biology
    • Biochemistry
    • Cell Biology

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