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A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK

Oncogene volume 31, pages 3333–3345 (2012)Cite this article

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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Acknowledgements

We are grateful to the members of the cell culture facilities for their help and to all the members of the team for their helpful discussions and suggestions. Special thanks to Nathalie Bruck for GTPases analysis and to Regis Lutzing for generating the RARγWT MEF rescue line. This work was supported by funds from CNRS, INSERM, the Agence Nationale pour la Recherche (ANR-05-BLAN-0390-02 and ANR-09-BLAN-0297-01), the Association pour la Recherche sur le Cancer (ARC-07-1-3169), the Fondation pour la Recherche Médicale (DEQ20090515423) and the Institut National du Cancer (INCa-PL09-194 and PL07-96099). AP was supported by the Fondation pour la Recherche Médicale and by the Lady TATA Memorial Trust.

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  1. Department of functional genomics and cancer, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM, U964,

    A Piskunov & C Rochette-Egly

  2. CNRS, UMR7104,

    A Piskunov & C Rochette-Egly

  3. Université de Strasbourg, Illkirch Cedex, France

    A Piskunov & C Rochette-Egly

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Correspondence to C Rochette-Egly.

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Piskunov, A., Rochette-Egly, C. A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK. Oncogene 31, 3333–3345 (2012). https://doi.org/10.1038/onc.2011.499

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