BioPAX pathway converted from "PPARA binds RXRA" in the Reactome database. LEFT-TO-RIGHT PPARA binds RXRA PPARA binds RXRA forming PPARA:RXRA heterodimer at promoter of target gene Peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a type II nuclear receptor (its subcellular location is independent of ligand binding) related to PPAR-beta/delta and PPAR-gamma. PPAR-alpha is expressed highly in the liver where if functions to control lipid metabolism, especially fatty acid oxidation. <br>PPAR-alpha forms heterodimers with Retinoid X receptor alpha (RXR-alpha). The heterodimers bind peroxisome proliferator receptor elements (PPREs) in and around genes regulated by PPAR-alpha. Authored: May, B, 2009-05-30 16:45:51 Reviewed: Kersten, S, 2009-06-08 Edited: May, B, 2009-05-30 16:45:51 Edited: May, B, 2009-06-08 RXRA Retinoic acid receptor RXR-alpha RXRA_HUMAN Reactome DB_ID: 381319 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:P19793 RXRA RXRA NR2B1 FUNCTION Receptor for retinoic acid that acts as a transcription factor (PubMed:11162439, PubMed:11915042). Forms homo- or heterodimers with retinoic acid receptors (RARs) and binds to target response elements in response to their ligands, all-trans or 9-cis retinoic acid, to regulate gene expression in various biological processes (PubMed:10195690, PubMed:11162439, PubMed:11915042, PubMed:28167758, PubMed:17761950, PubMed:16107141, PubMed:18800767, PubMed:19167885). The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 to regulate transcription (PubMed:10195690, PubMed:11162439, PubMed:11915042, PubMed:17761950, PubMed:28167758). The high affinity ligand for retinoid X receptors (RXRs) is 9-cis retinoic acid (PubMed:1310260). 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:20215566). On ligand binding, the corepressors dissociate from the receptors and coactivators are recruited leading to transcriptional activation (PubMed:20215566, PubMed:9267036). Serves as a common heterodimeric partner for a number of nuclear receptors, such as RARA, RARB and PPARA (PubMed:10195690, PubMed:11915042, PubMed:28167758, PubMed:29021580). The RXRA/RARB heterodimer can act as a transcriptional repressor or transcriptional activator, depending on the RARE DNA element context (PubMed:29021580). The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes (PubMed:10195690). Together with RARA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (PubMed:28167758). Acts as an enhancer of RARA binding to RARE DNA element (PubMed:28167758). May facilitate the nuclear import of heterodimerization partners such as VDR and NR4A1 (PubMed:12145331, PubMed:15509776). Promotes myelin debris phagocytosis and remyelination by macrophages (PubMed:26463675). Plays a role in the attenuation of the innate immune system in response to viral infections, possibly by negatively regulating the transcription of antiviral genes such as type I IFN genes (PubMed:25417649). Involved in the regulation of calcium signaling by repressing ITPR2 gene expression, thereby controlling cellular senescence (PubMed:30216632).SUBUNIT Homodimer (PubMed:10669605, PubMed:17761950). Heterodimer (via C-terminus) with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity; association with RARA is enhanced by pulsatile shear stress (PubMed:28167758, PubMed:10698945, PubMed:15509776). Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity (PubMed:10195690, PubMed:11915042, PubMed:11698662). Heterodimerizes with PPARG (PubMed:10882139, PubMed:11698662). Heterodimerizes (via NR LBD) with RARB (PubMed:29021580). Heterodimerizes with NR1H4; the heterodimerization enhances the binding affinity for LXXLL motifs from coactivators (PubMed:30275017). Interacts with NCOA3 and NCOA6 coactivators (PubMed:9267036, PubMed:10567404). Interacts with coactivator FAM120B (By similarity). Interacts with coactivator PELP1, SENP6, SFPQ, DNTTIP2 and RNF8 (PubMed:16574651, PubMed:16912044, PubMed:11259580, PubMed:15047147, PubMed:14981089). Interacts with PRMT2 (PubMed:12039952). Interacts with ASXL1 (By similarity). Interacts with BHLHE40/DEC1, BHLHE41/DEC2, NCOR1 and NCOR2 (PubMed:19786558). Interacts in a ligand-dependent fashion with MED1 and NCOA1 (PubMed:19786558, PubMed:10882139, PubMed:11698662). Interacts with VDR (PubMed:28698609). Interacts with EP300; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). Heterodimer (via C-terminus) with NR4A1 (via DNA-binding domain); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). In the absence of hormonal ligand, interacts with TACC1 (PubMed:20078863).SUBUNIT (Microbial infection) Interacts (via the DNA binding domain) with HCV core protein; the interaction enhances the transcriptional activities of the RXRA/RARA and the RXRA/PPARA heterodimers.TISSUE SPECIFICITY Expressed in lung fibroblasts (at protein level) (PubMed:30216632). Expressed in monocytes (PubMed:26463675). Highly expressed in liver, also found in kidney and brain (PubMed:24275569, PubMed:2159111, PubMed:14702039).INDUCTION Down-regulated by aging (PubMed:26463675). Induced by pulsatile shear stress (PubMed:28167758).DOMAIN Composed of three domains: a modulating N-terminal domain (AF1 domain), a DNA-binding domain and a C-terminal ligand-binding domain (AF2 domain).PTM Acetylated by EP300; acetylation enhances DNA binding and transcriptional activity.PTM Phosphorylated on serine and threonine residues mainly in the N-terminal modulating domain (By similarity). Constitutively phosphorylated on Ser-21 in the presence or absence of ligand (By similarity). Under stress conditions, hyperphosphorylated by activated JNK on Ser-56, Ser-70, Thr-82 and Ser-260 (By similarity). Phosphorylated on Ser-27, in vitro, by PKA (PubMed:11162439). This phosphorylation is required for repression of cAMP-mediated transcriptional activity of RARA (PubMed:11162439).PTM Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily. Homo sapiens NCBI Taxonomy 9606 UniProt P19793 1 EQUAL 462 EQUAL Reactome Database ID Release 83 381319 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-381319 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome PPARA Peroxisome proliferator-activated receptor alpha PPAR-alpha Reactome DB_ID: 400186 UniProt:Q07869 PPARA PPARA NR1C1 PPAR FUNCTION Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2.SUBUNIT Heterodimer; with RXRA. This heterodimerization is required for DNA binding and transactivation activity. Interacts with NCOA3 coactivator. Interacts with CITED2; the interaction stimulates its transcriptional activity. Also interacts with PPARBP in vitro. Interacts with AKAP13, LPIN1, PRDM16 and coactivator NCOA6. Interacts with ASXL1 and ASXL2. Interacts with PER2. Interacts with SIRT1; the interaction seems to be modulated by NAD(+) levels (PubMed:24043310). Interacts with CRY1 and CRY2 (By similarity).TISSUE SPECIFICITY Skeletal muscle, liver, heart and kidney. Expressed in monocytes (PubMed:28167758).INDUCTION Down-regulated by aging.SIMILARITY Belongs to the nuclear hormone receptor family. NR1 subfamily. UniProt Q07869 1 EQUAL 468 EQUAL Reactome Database ID Release 83 400186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-400186 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: Peroxisome Proliferator Receptor Element (PPRE) Reactome DB_ID: 422139 Reactome Database ID Release 83 422139 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-ALL-422139 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: ChEBI 61120 additional information MI MI:0361 PPARA:RXRA heterodimer Reactome DB_ID: 400138 1 1 1 Reactome Database ID Release 83 400138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-400138 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome Database ID Release 83 400204 Database identifier. Use this URL to connect to the web page of this instance in Reactome: Reactome R-HSA-400204 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: 16503871 Pubmed 2005 Peroxisome proliferator-activated receptor alpha (PPARalpha) and athero-sclerosis Gouni-Berthold, I Krone, W Curr Drug Targets Cardiovasc Haematol Disord 5:513-23 10529898 Pubmed 1999 Peroxisome proliferator-activated receptors: nuclear control of metabolism Desvergne, B Wahli, W Endocr Rev 20:649-88 18288277 Pubmed 2008 Peroxisome proliferator activated receptors and lipoprotein metabolism Kersten, Sander PPAR Res 2008:132960 16476485 Pubmed 2006 From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions Feige, JN Gelman, L Michalik, L Desvergne, B Wahli, W Prog Lipid Res 45:120-59 8386511 Pubmed 1993 PPAR-RXR heterodimer activates a peroxisome proliferator response element upstream of the bifunctional enzyme gene Bardot, O Aldridge, TC Latruffe, N Green, S Biochem Biophys Res Commun 192:37-45 11330046 Pubmed 2000 Peroxisome proliferator-activated receptors, coactivators, and downstream targets Qi, C Zhu, Y Reddy, Janardan K Cell Biochem Biophys 32:187-204