A) signals via nuclear retinoic acid receptors (RARs) of which there are three receptor subtypes - alpha, beta and gamma. RARs form heterodimers with the retinoid X receptor (RXR) which also has the alpha, beta and gamma subtypes. For both receptor types, more isoforms are produced via alternative splicing and promoter usage. RXR affinity for atRA is low but it binds 9-cis RA whose physiological relevance is being questioned. The canonical retinoid response element (RAREs) consists of direct repeats with consensus half-site sequence 5'- (A/G)G(G/T)TCA-3' separated by two or five nucleotides (D2 and D5) or more rarely by one (D1) as in the case of (RXREs) response element that RXR homodimers bind. RXR forms heterodimers with other nuclear receptors including members of peroxisome proliferator-activated receptors (PPARs) that can also respond to retinoic acid. RARs, like most nuclear receptors are modular characterized by the presence of a highly conserved DNA binding domain (DBD) with the two zinc fingers motifs, the C-terminal ligand binding domain (LBD) which also encompasses the ligand-dependent activation domain AF-2 while the ligand independent AF-1 is N-terminally situated; a flexible hinge connects the DBD and LBD domains. The LBD/AF-2 are important for ligand binding, dimerization and interaction with corepressors and coactivators. In the absence of ligand, RARs are bound by corepressors which contain an LxxH/IIxxxI/L or corepressor (CoRNR) motif that interacts with a hydrophobic groove in the receptor, masking the C-terminal helix12 (H12) of AF-2. Upon ligand binding, the receptor undergoes a conformational change resulting in loss of corepressors and binding of coactivators that interact with the receptor via an LxxLL binding motif. There is a re-positioning of H12 which now can fit the shorter LxxLL motif but not the CoRNR, which probably explains why corepressors and coactivators bind in a mutually exclusive manner. Both corepressors, which do not possess enzymatic activity, and coactivators act as adaptors to recruit other protein complexes with various enzymatic activities that modify histone tails. Another class of coregulators is represented by the unconventional ones such as LxxLL containing proteins that are ligand-dependent recruited and repress transcription thus providing a negative feedback loop or those that do not contain an LxxLL motif and activate transcription. atRA affects the expression of hundreds of genes either directly via the RARE/RXRE elements or indirectly via receptor interactions with other transcription factors. atRA signaling cross-talks to MAPK; MAPK and other kinases phosphorylate RARs with both positive and negative outcomes. Other, no-conventional functions such as non-genomic effects, RNA binding and translational control, have also been reported. To see the ontology report for annotations, GViewer and download, click here...(less)