UniProt functional annotation for P10276



	UniProt functional annotation for P10276

UniProt code: P10276.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Receptor for retinoic acid (PubMed:19850744, PubMed:16417524, PubMed:20215566). 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:28167758). The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (PubMed:28167758). 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 (PubMed:16417524). On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation (PubMed:9267036, PubMed:19850744, PubMed:20215566). Formation of a complex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression (PubMed:28167758). Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2 (PubMed:28167758). RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis (By similarity). Has a role in the survival of early spermatocytes at the beginning prophase of meiosis (By similarity). In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes (By similarity). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (PubMed:28167758). In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response (PubMed:28167758). {ECO:0000250|UniProtKB:P11416, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:20215566, ECO:0000269|PubMed:28167758, ECO:0000269|PubMed:9267036}.

Subunit: Heterodimer; with RXRA (via C-terminus); association with RXRA is enhanced by pulsatile shear stress (PubMed:28167758, PubMed:10698945, PubMed:10882070, PubMed:20215566, PubMed:15509776). Binds DNA preferentially as a heterodimer (PubMed:10698945, PubMed:28167758). RXRA serves as enhancer to induce RARA binding to RARE (PubMed:30468856). Interacts with RXRG (PubMed:28167758). Interacts with coactivators NCOA3 and NCOA6 (PubMed:9267036, PubMed:10567404). Interacts with NCOA7; the interaction requires ligand-binding (PubMed:11971969). Interacts (via the ligand-binding domain) with PRAME; the interaction is ligand (retinoic acid)-dependent (PubMed:16179254). Interacts with AKT1; the interaction phosphorylates RARA and represses transactivation (PubMed:16417524). Interacts with PRKAR1A; the interaction negatively regulates RARA transcriptional activity (PubMed:20215566). Interacts with NCOR1 and NCOR2 (PubMed:20543827). Interacts with PRMT2 (PubMed:12039952). Interacts with LRIF1 (PubMed:17455211). Interacts with ASXL1 and NCOA1 (PubMed:16606617). Interacts with ACTN4 (PubMed:22351778). 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 (PubMed:28167758). Interacts with CDK7 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250|UniProtKB:P11416, ECO:0000269|PubMed:10567404, ECO:0000269|PubMed:10698945, ECO:0000269|PubMed:10882070, ECO:0000269|PubMed:11971969, ECO:0000269|PubMed:12039952, ECO:0000269|PubMed:15509776, ECO:0000269|PubMed:16179254, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:16606617, ECO:0000269|PubMed:17455211, ECO:0000269|PubMed:20078863, ECO:0000269|PubMed:20215566, ECO:0000269|PubMed:20543827, ECO:0000269|PubMed:22351778, ECO:0000269|PubMed:28167758, ECO:0000269|PubMed:30468856, ECO:0000269|PubMed:9267036}.

Subcellular location: Nucleus {ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:28167758}. Cytoplasm {ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:28167758}. Note=Nuclear localization depends on ligand binding, phosphorylation and sumoylation (PubMed:19850744). Translocation to the nucleus in the absence of ligand is dependent on activation of PKC and the downstream MAPK phosphorylation (By similarity). Increased nuclear localization upon pulsatile shear stress (PubMed:28167758). {ECO:0000250|UniProtKB:P11416, ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:28167758}.

Tissue specificity: Expressed in monocytes. {ECO:0000269|PubMed:26463675}.

Induction: Down-regulated by aging (PubMed:26463675). Induced by pulsatile shear stress (PubMed:28167758). {ECO:0000269|PubMed:26463675, ECO:0000269|PubMed:28167758}.

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. {ECO:0000305|PubMed:30468856}.

Ptm: Phosphorylated on serine and threonine residues. Phosphorylation does not change during cell cycle. Phosphorylation on Ser-77 is crucial for transcriptional activity (By similarity). Phosphorylation by AKT1 is required for the repressor activity but has no effect on DNA binding, protein stability nor subcellular localization. Phosphorylated by PKA in vitro. This phosphorylation on Ser-219 and Ser-369 is critical for ligand binding, nuclear localization and transcriptional activity in response to FSH signaling. {ECO:0000250, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:20215566}.

Ptm: Sumoylated with SUMO2, mainly on Lys-399 which is also required for SENP6 binding. On all-trans retinoic acid (ATRA) binding, a confromational 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. {ECO:0000269|PubMed:15809060, ECO:0000269|PubMed:19850744}.

Ptm: Trimethylation enhances heterodimerization with RXRA and positively modulates the transcriptional activation.

Ptm: Ubiquitinated.

Ptm: Acetylated; acetylation is increased upon pulsatile shear stress and decreased upon oscillatory shear stress. {ECO:0000269|PubMed:28167758}.

Disease: Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation. {ECO:0000269|PubMed:12691149, ECO:0000269|PubMed:8302850, ECO:0000269|PubMed:8562957}.

Miscellaneous: [Isoform Alpha-1-deltaBC]: Does not bind nor transactivate RARE on its own but may do so as a heterodimer with Alpha-1. {ECO:0000305}.

Similarity: Belongs to the nuclear hormone receptor family. NR1 subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAB00112.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=AAB00113.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAB62809.1; Type=Erroneous initiation; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Receptor for retinoic acid (PubMed:19850744, PubMed:16417524, PubMed:20215566). 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:28167758). The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (PubMed:28167758). 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 (PubMed:16417524). On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation (PubMed:9267036, PubMed:19850744, PubMed:20215566). Formation of a complex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression (PubMed:28167758). Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2 (PubMed:28167758). RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis (By similarity). Has a role in the survival of early spermatocytes at the beginning prophase of meiosis (By similarity). In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes (By similarity). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (PubMed:28167758). In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response (PubMed:28167758). {ECO:0000250\|UniProtKB:P11416, ECO:0000269\|PubMed:16417524, ECO:0000269\|PubMed:19850744, ECO:0000269\|PubMed:20215566, ECO:0000269\|PubMed:28167758, ECO:0000269\|PubMed:9267036}.


Subunit:		Heterodimer; with RXRA (via C-terminus); association with RXRA is enhanced by pulsatile shear stress (PubMed:28167758, PubMed:10698945, PubMed:10882070, PubMed:20215566, PubMed:15509776). Binds DNA preferentially as a heterodimer (PubMed:10698945, PubMed:28167758). RXRA serves as enhancer to induce RARA binding to RARE (PubMed:30468856). Interacts with RXRG (PubMed:28167758). Interacts with coactivators NCOA3 and NCOA6 (PubMed:9267036, PubMed:10567404). Interacts with NCOA7; the interaction requires ligand-binding (PubMed:11971969). Interacts (via the ligand-binding domain) with PRAME; the interaction is ligand (retinoic acid)-dependent (PubMed:16179254). Interacts with AKT1; the interaction phosphorylates RARA and represses transactivation (PubMed:16417524). Interacts with PRKAR1A; the interaction negatively regulates RARA transcriptional activity (PubMed:20215566). Interacts with NCOR1 and NCOR2 (PubMed:20543827). Interacts with PRMT2 (PubMed:12039952). Interacts with LRIF1 (PubMed:17455211). Interacts with ASXL1 and NCOA1 (PubMed:16606617). Interacts with ACTN4 (PubMed:22351778). 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 (PubMed:28167758). Interacts with CDK7 (By similarity). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863). {ECO:0000250\|UniProtKB:P11416, ECO:0000269\|PubMed:10567404, ECO:0000269\|PubMed:10698945, ECO:0000269\|PubMed:10882070, ECO:0000269\|PubMed:11971969, ECO:0000269\|PubMed:12039952, ECO:0000269\|PubMed:15509776, ECO:0000269\|PubMed:16179254, ECO:0000269\|PubMed:16417524, ECO:0000269\|PubMed:16606617, ECO:0000269\|PubMed:17455211, ECO:0000269\|PubMed:20078863, ECO:0000269\|PubMed:20215566, ECO:0000269\|PubMed:20543827, ECO:0000269\|PubMed:22351778, ECO:0000269\|PubMed:28167758, ECO:0000269\|PubMed:30468856, ECO:0000269\|PubMed:9267036}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:19850744, ECO:0000269\|PubMed:28167758}. Cytoplasm {ECO:0000269\|PubMed:19850744, ECO:0000269\|PubMed:28167758}. Note=Nuclear localization depends on ligand binding, phosphorylation and sumoylation (PubMed:19850744). Translocation to the nucleus in the absence of ligand is dependent on activation of PKC and the downstream MAPK phosphorylation (By similarity). Increased nuclear localization upon pulsatile shear stress (PubMed:28167758). {ECO:0000250\|UniProtKB:P11416, ECO:0000269\|PubMed:19850744, ECO:0000269\|PubMed:28167758}.
Tissue specificity:		Expressed in monocytes. {ECO:0000269\|PubMed:26463675}.
Induction:		Down-regulated by aging (PubMed:26463675). Induced by pulsatile shear stress (PubMed:28167758). {ECO:0000269\|PubMed:26463675, ECO:0000269\|PubMed:28167758}.
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. {ECO:0000305\|PubMed:30468856}.
Ptm:		Phosphorylated on serine and threonine residues. Phosphorylation does not change during cell cycle. Phosphorylation on Ser-77 is crucial for transcriptional activity (By similarity). Phosphorylation by AKT1 is required for the repressor activity but has no effect on DNA binding, protein stability nor subcellular localization. Phosphorylated by PKA in vitro. This phosphorylation on Ser-219 and Ser-369 is critical for ligand binding, nuclear localization and transcriptional activity in response to FSH signaling. {ECO:0000250, ECO:0000269\|PubMed:16417524, ECO:0000269\|PubMed:20215566}.
Ptm:		Sumoylated with SUMO2, mainly on Lys-399 which is also required for SENP6 binding. On all-trans retinoic acid (ATRA) binding, a confromational 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. {ECO:0000269\|PubMed:15809060, ECO:0000269\|PubMed:19850744}.
Ptm:		Trimethylation enhances heterodimerization with RXRA and positively modulates the transcriptional activation.
Ptm:		Ubiquitinated.
Ptm:		Acetylated; acetylation is increased upon pulsatile shear stress and decreased upon oscillatory shear stress. {ECO:0000269\|PubMed:28167758}.
Disease:		Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled-coil domain functions in blocking RA-mediated transactivation and cell differentiation. {ECO:0000269\|PubMed:12691149, ECO:0000269\|PubMed:8302850, ECO:0000269\|PubMed:8562957}.
Miscellaneous:		[Isoform Alpha-1-deltaBC]: Does not bind nor transactivate RARE on its own but may do so as a heterodimer with Alpha-1. {ECO:0000305}.
Similarity:		Belongs to the nuclear hormone receptor family. NR1 subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAB00112.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=AAB00113.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAB62809.1; Type=Erroneous initiation; Evidence={ECO:0000305};