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

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 nongenomic effects of RA. We highlighted a novel paradigm in which a fraction of the cellular RAR alpha pool is present in membrane lipid rafts, where it forms complexes with G protein alpha Q (G alpha q) in response to RA. This rapid RA-induced formation of RAR alpha/G alpha q 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, RAR alpha present in membrane lipid rafts does not associate with Gaq, pointing out the essential contribution of RAR alpha/G alpha q complexes in RA signaling. Oncogene (2012) 31, 3333-3345; doi: 10.1038/onc.2011.499; published online 7 November 2011