Glycogen Synthase Kinase 3β-Mediated Serine Phosphorylation of the Human Glucocorticoid Receptor Redirects Gene Expression Profiles
Open accessAbstract
Aberrant glycogen synthase kinase 3beta (GSK-3beta) activity is associated with the progression of several pathological conditions such as diabetes, Alzheimer's, and cancer. GSK-3beta regulates cellular processes by directly phosphorylating metabolic enzymes and transcription factors. Here, we discovered a new target for GSK-3beta phosphorylation: the human glucocorticoid receptor (GR). Glucocorticoid signaling is essential for life and regulates diverse biological functions from cell growth to metabolism to apoptosis. Specifically, we found hormone-dependent GR phosphorylation on serine 404 by GSK-3beta. Cells expressing a GR that is incapable of GSK-3beta phosphorylation had a redirection of the global transcriptional response to hormone, including the activation of additional signaling pathways, in part due to the altered ability of unphosphorylatable GR to recruit transcriptional cofactors CBP/p300 and the p65 (RelA) subunit of NF-kappaB. Furthermore, GSK-3beta-mediated GR phosphorylation inhibited glucocorticoid-dependent NF-kappaB transrepression and attenuated the glucocorticoid-dependent cell death of osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3beta and the GR pathways, resulting in altered hormone-regulated signaling. Our results also provide a mechanism by which GSK-3beta activity can dictate how cells will ultimately respond to glucocorticoids.
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Multiple kinases differentially phosphorylate the GR at serine residues S203, S211 and S226, regulating GR nuclear translocation and GR-dependent gene transcription.
“Multiple kinases have been reported to differentially phosphorylate the GR at its serine residues, S203, S211 and S226, an effect which regulates GR nuclear translocation and GR-dependent gene transcription.25, 26, 27, 28, 29”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [26]
Different GR phosphoisoforms selectively occupy promoters of different GR target genes.
“different GR phosphoisoforms have been reported to selectively occupy promoters of different GR target genes”
From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [26]
Ligand-induced phosphorylation at Ser-404 impacts GR transcriptional activity by impairing both activation and repression of target genes.
“Ligand-induced phosphorylation at Ser-404 has been shown to impact transcriptional activity of GR by impairing both activation and repression of target genes74.”
From Corticosteroids (2016) · cites this paper as [74]
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- Authors
- Galliher-Beckley, A. J., Williams, J. G., Collins, J. B., & Cidlowski, J. A.
- Affiliations
- National Institutes of Health (US)
- Laboratory of Structural Biology
- Molecular Endocrinology Group, Laboratory of Signal Transduction
- Corresponding author
- Cidlowski, John Anthony
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-12-01
- Volume
- 28
- Issue
- 24
- Pages
- 7309-7322
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2593428
- OpenAlex
- W2114853205
- Cited by
- 136
- References
- 49
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 8 · 2020: 7 · 2019: 11 · 2018: 9 · 2017: 7 · 2016: 5 · 2015: 7 · 2014: 11 · 2013: 15 · 2012: 9
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- glycogen synthase kinase-3β, glucocorticoid receptor, serine phosphorylation, glucocorticoid signaling, transcriptional regulation, CBP/p300, NF-κB p65, transcriptional cofactors
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Amino Acid Sequence, Animals, Cell Line, Dexamethasone, Gene Expression Regulation, Glucocorticoids, Humans, Phosphorylation, Receptors, Glucocorticoid, Serine, Transcription, Genetic, Signal Transduction, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Glycogen Synthase Kinase 3, Mice
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