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FUNCTION Receptor for retinoic acid (PubMed:17205979). Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes (PubMed:17205979). The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (PubMed:17205979). In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone deacetylation, chromatin condensation and transcriptional suppression (By similarity). On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation (PubMed:17205979, PubMed:19078967, PubMed:9230306). Formation of heterocomplex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression (By similarity). Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2 (By similarity). RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis (PubMed:15901285). Has a role in the survival of early spermatocytes at the beginning prophase of meiosis (PubMed:15901285, PubMed:17905941). In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes (PubMed:10660575, PubMed:17905941). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (PubMed:19389355). Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (By similarity). In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response (By similarity).SUBUNIT Heterodimer; with RXRA (PubMed:17205979). Binds DNA preferentially as a heterodimer (By similarity). RXRA serves as enhancer to induce RARA binding to RARE (By similarity). Interacts with RXRG (By similarity). Interacts with NCOA3 and NCOA6 coactivators, leading to a strong increase of transcription of target genes (PubMed:10788465, PubMed:9192892). Interacts with NCOA7; the interaction requires ligand-binding (By similarity). Interacts (via the ligand-binding domain) with PRAME; interaction is direct and ligand (retinoic acid)-dependent (By similarity). Interacts with PRKAR1A; the interaction negatively regulates RARA transcriptional activity (By similarity). Interacts with NCOR1; the interaction occurs in the absence of ligand and represses transcriptional activity (PubMed:17205979). Interacts with NCOR2 (By similarity). Interacts with PRMT2 (By similarity). Interacts with LRIF1 (By similarity). Interacts with ASXL1 and NCOA1 (By similarity). Interacts with ACTN4 (By similarity). Interacts with CDK7; the interaction is enhanced by interaction with GTF2H3 (PubMed:9230306). Interacts with GTF2H3; the interaction requires prior phosphorylation on Ser-369 which then enhances interaction with CDK7 (PubMed:19078967). In a complex with HDAC3, HDAC5 and HDAC7; the HDACs serve as corepressors of RARA, causing its deacetylation and inhibition of RARE DNA element binding; association with HDAC3, HDAC5 and HDAC7 is increased upon oscillatory shear stress (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863).INTERACTION Nuclear localization depends on ligand binding, phosphorylation and sumoylation (PubMed:10660575, PubMed:12079996). Translocation to the nucleus is dependent on activation of PKC and the downstream MAPK phosphorylation (PubMed:10660575, PubMed:12079996). Increased nuclear localization upon pulsatile shear stress (By similarity).ALTERNATIVE PRODUCTS Expressed in Sertoli cells and germ cells.INDUCTION By retinoic acid.DOMAIN Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Phosphorylated on serine and threonine residues. Phosphorylation does not change during cell cycle. Phosphorylation on Ser-77 is crucial for the N-terminal AF1 transcriptional activity. Under stress conditions, MAPK8 enhances phosphorylation on Thr-181, Ser-445 and Ser-461 leading to RARA ubiquitination and degradation. Phosphorylation by AKT1 inhibits the transactivation activity. On retinoic acid stimulation, phosphorylation on Ser-369 by RPS6KA5 promotes interaction with GTF2H3 and the CDK7-mediated phosphorylation of Ser-77.PTM Ubiquitinated by UBR5, leading to its degradation: UBR5 specifically recognizes and binds ligand-bound RARA when it is not associated with coactivators (NCOAs). In presence of NCOAs, the UBR5-degron is not accessible, preventing its ubiquitination and degradation.PTM Sumoylated with SUMO2, mainly on Lys-399 which is also required for SENP6 binding. On all-trans retinoic acid (ATRA) binding, a conformational change may occur that allows sumoylation on two additional site, Lys-166 and Lys-171. Probably desumoylated by SENP6. Sumoylation levels determine nuclear localization and regulate ATRA-mediated transcriptional activity (By similarity).PTM Acetylated; acetylation is increased upon pulsatile shear stress and decreased upon oscillatory shear stress.DISRUPTION PHENOTYPE Seminiferous tubules of 6 month-old animals display varying degrees of testicular degeneration, with moderate to severe levels of germ-cell degeneration. Epithelial cells in the epididymis show general disorganization. Sperm count is reduced to about 1.7% of wild-type and sperm mobility reduced by half. Rara and Rarg, but not Rara and Rarb, double knockout mice exhibit growth retardation after 3 weeks. Defects are found in the growth plates with deficiency in cartilage. Growth retardation was noticable in limb sketal elements such as femurs. Early lethality and male sterility due to squamous metaplasia of the seminal vesicles and prostate are also observed.SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily.
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