P38MAPK‐dependent phosphorylation and degradation of SRC‐3/AIB1 and RARα‐mediated transcription
Open accessAbstract
Nuclear retinoic acid (RA) receptors (RARs) activate gene expression through dynamic interactions with coregulators in coordination with the ligand and phosphorylation processes. Here we show that during RA-dependent activation of the RARalpha isotype, the p160 coactivator pCIP/ACTR/AIB-1/RAC-3/TRAM-1/SRC-3 is phosphorylated by p38MAPK. SRC-3 phosphorylation has been correlated to an initial facilitation of RARalpha-target genes activation, via the control of the dynamics of the interactions of the coactivator with RARalpha. Then, phosphorylation inhibits transcription via promoting the degradation of SRC-3. In line with this, inhibition of p38MAPK markedly enhances RARalpha-mediated transcription and RA-dependent induction of cell differentiation. SRC-3 phosphorylation and degradation occur only within the context of RARalpha complexes, suggesting that the RAR isotype defines a phosphorylation code through dictating the accessibility of the coactivator to p38MAPK. We propose a model in which RARalpha transcriptional activity is regulated by SRC-3 through coordinated events that are fine-tuned by RA and p38MAPK.
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Phosphorylation of SRC-3 results in its dissociation from RARs.
“The coactivator SRC-3 is also phosphorylated ( 148 ), resulting in its dissociation from RARs.”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [148]
Cites
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“The basic mechanism of RARs transcriptional activity relies on their ability to recruit coactivators after RA-induced conformational changes of the ligand-binding domain (LBD) (Chambon, 1996).”
BackgroundNuclear receptors: integration of multiple signalling pathways through phosphorylation
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Self-citationRas/Mitogen-Activated Protein Kinase Signaling Activates Ets-1 and Ets-2 by CBP/p300 Recruitment
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Expanding functional diversity of the coactivators
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Self-citationPhosphorylation of the retinoic acid receptor-alpha by protein kinase A
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Retinoic acid receptors: From molecular mechanisms to cancer therapy
di Masi, A., Leboffe, L., De Marinis, E., Pagano, F., Cicconi, L., Rochette-Egly, C., Lo-Coco, F., Ascenzi, P., & Nervi, C. (2015) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2014.12.003 · Cited by 403 · see citing works
Self-citationVitamin A and retinoid signaling: genomic and nongenomic effects
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Self-citationNuclear receptor coactivators: structural and functional biochemistry
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A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARα to target promoters
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Self-citationFerry, C., Gianni, M., Lalevée, S., Bruck, N., Plassat, J.-L., Raska, I., Garattini, E., & Rochette-Egly, C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808815200 · Cited by 24 · see citing works
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- Authors
- Giannì, M., Parrella, E., Raska, I., Gaillard, E., Nigro, E. A., Gaudon, C., Garattini, E., & Rochette‐Egly, C.
- Affiliations
- Mario Negri Institute for Pharmacological Research (IT)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Rochette‐Egly, Cécile
- Venue
- The EMBO Journal
- Published
- 2006-02-02
- Volume
- 25
- Issue
- 4
- Pages
- 739-751
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- OpenAlex
- W2142390652
- Cited by
- 81
- References
- 9
- Citations by year
- 2026: 1 · 2025: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 6 · 2013: 10 · 2012: 3
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- p38 MAPK, SRC-3, AIB1, RARα, retinoic acid receptor, protein degradation, transcriptional regulation, nuclear receptor coregulators, retinoic acid signaling, cell differentiation, transcriptional repression
- MeSH terms
- Retinoic Acid Receptor alpha, Acetyltransferases, Animals, Antineoplastic Agents, Chlorocebus aethiops, Gene Expression Regulation, Humans, Phosphorylation, Protein Processing, Post-Translational, Transcription, Genetic, Tretinoin, Oncogene Proteins, Trans-Activators, Receptors, Retinoic Acid, HL-60 Cells, COS Cells, Multiprotein Complexes, p38 Mitogen-Activated Protein Kinases, Mice, Histone Acetyltransferases, Nuclear Receptor Coactivator 3
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