Cited by 184Retinoids in leukemia and cellular processesProtein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancer

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Rapid, Nongenomic Actions of Retinoic Acid on Phosphatidylinositol-3-Kinase Signaling Pathway Mediated by the Retinoic Acid Receptor

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Masiá, Susana, Alvarez, Susana, de Lera, Angel R., Barettino, Domingo·2007·Molecular Endocrinology

DOI 10.1210/me.2007-0062

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Abstract

Retinoic acid (RA) treatment of SH-SY5Y neuroblastoma cells results in activation of phosphatidylinositol-3-kinase (PI3K) signaling pathway, and this activation is required for RA-induced differentiation. Here we show that RA activates PI3K and ERK1/2 MAPK signaling pathways through a rapid, nongenomic mechanism that does not require new gene transcription or newly synthesized proteins. Activation of PI3K by RA appears to involve the classical nuclear receptor, retinoic acid receptor (RAR), on the basis of the pharmacological profile of the activation, loss, and gain of function experiments with mouse embryo fibroblast-RAR(alpha beta gamma)(L-/L-) null cells, and the physical association between liganded RAR and PI3K activity. The association of RAR with the two subunits of PI3K was differentially regulated by the ligand. Immunoprecipitation experiments performed in SH-SY5Y cells showed stable association between RARalpha and p85, the regulatory subunit of PI3K, independently of the presence of RA. In contrast, ligand administration increased the association of p110, the catalytic subunit of PI3K, to this complex. The intracellular localization of RAR proved to be relevant for PI3K activation. A chimerical RAR fusing c-Src myristylation domain to the N terminus of RARalpha (Myr-RARalpha) was targeted to plasma membrane. Transfection of Myr-RARalpha to mouse embryo fibroblast-RAR(alpha beta gamma)(L-/L-) null cells and COS-7 cells results in strong activation of the PI3K signaling pathway, although both in the absence as well in the presence of RA. Our results support a mechanism in which ligand binding to RAR would play a major role in the assembly and intracellular location of a signaling complex involving RAR and the subunits of PI3K.

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Authors: Masiá, S., Alvarez, S., de Lera, A. R., & Barettino, D.
Affiliations: Biology of Hormone Action Unit (S.M., D.B.). Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia [Consejo Superior de Investigaciones Cientificas (CSIC)], E-46010 Valencia, Spain;
Universidade de Vigo (S.A., A.R.d.L.), Departamento de Química Orgánica, Facultad de Ciencias, E-36200 Vigo, Spain
Consejo Superior de Investigaciones Científicas (ES)
Corresponding author: Barettino, Domingo
Venue: Molecular Endocrinology
Publisher: The Endocrine Society
Published: 2007-10-01
Volume: 21
Issue: 10
Pages: 2391-2402
ISSN: 0888-8809 (ISSN-L)
1944-9917
DOI: 10.1210/me.2007-0062
OpenAlex: W2015219861
Cited by: 184
References: 67
Citations by year: 2026: 3 · 2025: 6 · 2024: 8 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 9 · 2019: 16 · 2018: 12 · 2017: 5 · 2016: 13 · 2015: 11 · 2014: 16 · 2013: 15 · 2012: 11
FWCI: 5.01
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Molecular Endocrinology (publishedVersion)
PubMed (publishedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
Funders: European Commission
Generalitat Valenciana
European Regional Development Fund
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 › PI3K/AKT/mTOR signaling in cancer
Keywords: retinoic acid, non-genomic signaling, retinoic acid receptor, phosphatidylinositol 3-kinase, PI3K signaling, ERK signaling, neuronal differentiation, SH-SY5Y cells, p85 regulatory subunit, p110 catalytic subunit, RARα, subcellular localization
MeSH terms: Retinoic Acid Receptor alpha, Humans, Tretinoin, Signal Transduction, Receptors, Retinoic Acid, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, Cell Line, Tumor, Mitogen-Activated Protein Kinase 3

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Rapid, Nongenomic Actions of Retinoic Acid on Phosphatidylinositol-3-Kinase Signaling Pathway Mediated by the Retinoic Acid Receptor

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