Phosphorylation by PKA potentiates retinoic acid receptor α activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7
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Nuclear retinoic acid receptors (RARs) work as ligand-dependent heterodimeric RAR/retinoid X receptor transcription activators, which are targets for phosphorylations. The N-terminal activation function (AF)-1 domain of RARα is phosphorylated by the cyclin-dependent kinase (cdk) 7/cyclin H complex of the general transcription factor TFIIH and the C-terminal AF-2 domain by the cAMP-dependent protein kinase A (PKA). Here, we report the identification of a molecular pathway by which phosphorylation by PKA propagates cAMP signaling from the AF-2 domain to the AF-1 domain. The first step is the phosphorylation of S369, located in loop 9–10 of the AF-2 domain. This signal is transferred to the cyclin H binding domain (at the N terminus of helix 9 and loop 8–9), resulting in enhanced cyclin H interaction and, thereby, greater amounts of RARα phosphorylated at S77 located in the AF-1 domain by the cdk7/cyclin H complex. This molecular mechanism relies on the integrity of the ligand-binding domain and the cyclin H binding surface. Finally, it results in higher DNA-binding efficiency, providing an explanation for how cAMP synergizes with retinoic acid for transcription.
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Phosphorylation of S369 induces an allosteric network affecting the structural conformation/flexibility of the adjacent loop L8-9 and the subsequent binding of the cyclin H/cdk7 subcomplex of TFIIH.
“Indeed RA-activated MSK1 phosphorylates RAR ␣ at S369 ( 96 ), and phosphorylation of this residue induces an allosteric network affecting the structural conformation/fl exibility of the adjacent loop L8-9 ( 44 ) and the subsequent binding of the cyclin H/cdk7subcomplex of TFIIH ( 132 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [132]
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The ETS-domain transcription factor family
Sharrocks, A. D. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35099076 · Cited by 1,086 · see citing works
Rochette-Egly, C., Adam, S., Rossignol, M., Egly, J.-M., & Chambon, P. (1997) · Cell · doi:10.1016/s0092-8674(00)80317-7 · Cited by 308 · see citing works
Self-citationNuclear receptors: integration of multiple signalling pathways through phosphorylation
Rochette-Egly, C. (2003) · Cellular Signalling · doi:10.1016/s0898-6568(02)00115-8 · Cited by 291 · see citing works
Self-citationVariable Control of Ets-1 DNA Binding by Multiple Phosphates in an Unstructured Region
Pufall, M. A., Lee, G. M., Nelson, M. L., Kang, H.-S., Velyvis, A., Kay, L. E., McIntosh, L. P., & Graves, B. J. (2005) · Science · doi:10.1126/science.1111915 · Cited by 246 · see citing works
Phosphorylation of the retinoic acid receptor-alpha by protein kinase A
Rochette-Egly, C. (1995) · Molecular Endocrinology · doi:10.1210/me.9.7.860 · Cited by 124 · see citing works
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Gudas, L. J., & Wagner, J. A. (2011) · Journal of Cellular Physiology · doi:10.1002/jcp.22417 · Cited by 395 · see citing works
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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
Al Tanoury, Z., Piskunov, A., & Rochette-Egly, C. (2013) · Journal of Lipid Research · doi:10.1194/jlr.r030833 · Cited by 408 · see citing works
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Bruck, N., Vitoux, D., Ferry, C., Duong, V., Bauer, A., de Thé, H., & Rochette‐Egly, C. (2009) · The EMBO Journal · doi:10.1038/emboj.2008.256 · Cited by 108 · see citing works
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Lalevee, S., Bour, G., Quinternet, M., Samarut, E., Kessler, P., Vitorino, M., Bruck, N., Delsuc, M., Vonesch, J., Kieffer, B., et al. (2010) · The FASEB Journal · doi:10.1096/fj.10-160572 · Cited by 32 · see citing works
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Chebaro, Y., Sirigu, S., Amal, I., Lutzing, R., Stote, R. H., Rochette-Egly, C., Rochel, N., & Dejaegere, A. (2017) · PLOS ONE · doi:10.1371/journal.pone.0171043 · Cited by 8 · see citing works
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- Authors
- Gaillard, E., Bruck, N., Brelivet, Y., Bour, G., Lalevée, S., Bauer, A., Poch, O., Moras, D., & Rochette-Egly, C.
- Affiliations
- *Département de Biologie Cellulaire et de Transduction du Signal and
- Département de Biologie et Génomique Structurales, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, Unité Mixte de Recherche 7104, BP 10142, 67404 Illkirch Cedex, France
- Centre National de la Recherche Scientifique (FR)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-06-20
- Volume
- 103
- Issue
- 25
- Pages
- 9548-9553
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1480444
- OpenAlex
- W2075917461
- Cited by
- 76
- References
- 5
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 2 · 2021: 4 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 4 · 2013: 8 · 2012: 3
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (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 › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- retinoic acid receptor alpha, protein kinase A, PKA phosphorylation, AF-2 domain, cAMP signaling, retinoid X receptor, transcriptional activation, ligand-binding domain, DNA binding, signal transduction
- MeSH terms
- Retinoic Acid Receptor alpha, Amino Acid Sequence, Animals, Cell Line, Chlorocebus aethiops, DNA, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Phosphoserine, Protein Binding, Signal Transduction, Cyclins, Protein Structure, Tertiary, Cyclic AMP-Dependent Protein Kinases, Receptors, Retinoic Acid, Cyclin-Dependent Kinases, Dimerization, Protein Structure, Quaternary, Cyclin H
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