Nuclear and extra-nuclear effects of retinoid acid receptors: How they are interconnected

Abstract

The nuclear retinoic acid receptors (RAR a, P and y) and their isoforms are ligand-dependent regulators of transcription, which mediate the effects of all-trans retinoic acid (RA), the active endogenous metabolite of Vitamin A. They heterodimerize with Retinoid X Receptors (RXRs a, P and y), and regulate the expression of a battery of target genes involved in cell growth and differentiation. During the two last decades, the description of the crystallographic structures of RARs, the characterization of the polymorphic response elements of their target genes, and the identifcation of the multiprotein complexes involved in their transcriptional activity have provided a wealth of information on their pleiotropic effects. However, the regulatory scenario became even more complicated once it was discovered that RARs are phosphoproteins and that RA can activate kinase signaling cascades via a pool of RARs present in membrane lipid rafts. Now it is known that these RA-activated kinases translocate to the nucleus where they phosphorylate RARs and other retinoid signaling factors. The phosphorylation state of the RARs dictates whether the transcriptional programs which are known to be induced by RA are facilitated and/or switched on. Thus, kinase signaling pathways appear to be crucial for fne-tuning the appropriate physiological activity of RARs.