A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK
Abstract
Retinoic acid (RA) regulates several gene programs by nuclear RA receptors (RARs) that are ligand-dependent transcriptional transregulators. The basic mechanism for switching on transcription of cognate-target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes. In addition to these classical genomic effects, we recently demonstrated that RA also induces the rapid activation of the p38MAPK/MSK1 pathway, with characteristic downstream consequences on the phosphorylation of RARs and the expression of their target genes. Here, we aimed at deciphering the underlying mechanism of the rapid non-genomic effects of RA. We highlighted a novel paradigm in which a fraction of the cellular RARα pool is present in membrane lipid rafts, where it forms complexes with G protein alpha Q (Gαq) in response to RA. This rapid RA-induced formation of RARα/Gαq complexes in lipid rafts is required for the activation of p38MAPK that occurs in response to RA. Accordingly, in RA-resistant cancer cells, characterized by the absence of p38MAPK activation, RARα present in membrane lipid rafts does not associate with Gαq, pointing out the essential contribution of RARα/Gαq complexes in RA signaling.
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In cells that respond to RA via the activation of p38MAPK, RARα is present in lipid rafts where it forms complexes with Gαq proteins.
“Indeed, in cells that respond to RA via the activation of p38MAPK, RAR ␣ is present in lipid rafts where it forms complexes with G ␣ q proteins ( 115 ) ( Fig. 5A ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [115]
RA activates p38MAPK in fibroblasts, mouse embryo carcinoma cells, mammary breast tumor cells, and leukemia cells.
“RA activates the p38 mitogen-activated protein kinase (p38MAPK) in fi broblasts, mouse embryo carcinoma cells, mammary breast tumor cells, and leukemia cells ( 96,111,114,115 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [115]
RA-induced activation of the two MAPK pathways is subsequent to activation of upstream cascades involving Rho-GTPases, PI3K and/or PKB/Akt.
“Nevertheless, the RA-induced activation of the two MAPK pathways is subsequent to the activation of upstream cascades involving Rho-GTPases ( 114, 115, 117 ), phosphoinositide 3-kinase (PI3K) and/or protein kinase B (PKB)/Akt ( 120, 121, 123 ), suggesting an atypical, nongenomic activation event similar to that described for steroid nuclear receptors ( 124, 125 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [115]
In these cancers and others, the RA-induced activation of the MAPK pathway is abrogated, and RARα and RXRα are aberrantly phosphorylated.
“Most interestingly, in these cancers and others, the RA-induced activation of the MAPK pathway is abrogated ( 115 ), and RAR ␣ and RXR ␣ are aberrantly phosphorylated ( 166-168 ).”
From Vitamin A and retinoid signaling: genomic and nongenomic effects (2013) · cites this paper as [115]
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“Retinoic acid (RA), a pleiotropic signaling molecule derived from vitamin A, regulates critical genetic programs that control development and homeostasis, cell proliferation and differentiation, as well as cell death or survival (Clagett-Dame and Knutson, 2011).”
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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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- Authors
- Piskunov, A., & Rochette-Egly, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Piskunov, A
- Venue
- Oncogene
- Published
- 2011-11-07
- Volume
- 31
- Issue
- 28
- Pages
- 3333-3345
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2055007053
- Cited by
- 95
- References
- 9
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 10 · 2018: 6 · 2017: 8 · 2016: 7 · 2015: 9 · 2014: 12 · 2013: 13 · 2012: 1
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-09-BLAN-0297, ANR-05-BLAN-0390)
- Institut National Du Cancer
- Institute of Cancer Research
- 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 › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- retinoic acid receptor alpha, RARα, lipid rafts, p38 MAPK activation, MSK1, retinoic acid resistance, cancer cells
- MeSH terms
- Retinoic Acid Receptor alpha, Enzyme Activation, Humans, Protein Binding, Tretinoin, Signal Transduction, Receptors, Retinoic Acid, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Protein Transport, Membrane Microdomains, GTP-Binding Protein alpha Subunits, Gq-G11, Cell Line, Tumor, p38 Mitogen-Activated Protein Kinases, Cell Proliferation
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