Retinoic acid receptor alpha
Short name=RAR-alpha
Alternative name(s):
Nuclear receptor subfamily 1 group B member 1
Gene names
Name: RARA
Synonyms: NR1B1
Function
全トランス、または9-cisレチノイン酸をリガンドとするRXRとRARがヘテロダイマーとなりレチノイン酸レスポンスエレメントRARE（5'-AGGTCA-3がタンデムDR1-DR5として知られている）に結合しさまざまな遺伝子発現を調節する。リガンドがない時は、RXR-RARヘテロダイマーは転写抑制因子也ヒストンアセチル化因子、クロマチン濃縮などの多くの転写を抑制するタンパク質と複合体を作り、リガンドが結合するとコリプレッサーが外れてコアクチベーターが結合し転写が活性化される。RARAはレチノイン酸による生殖細胞発生調節の中心的役割をもつ。。
Receptor for retinoic acid. 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. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function By similarity. Regulates expression of target genes in a ligand-dependent manner by recruiting chromatin complexes containing KMT2E/MLL5. Mediates retinoic acid-induced granulopoiesis. Ref.19 Ref.22 Ref.23 Ref.24
Subunit structure
RXRAとヘテロダイマーを形成し、ヘテロダイマーの方がDNA結合活性が高い。CDK7と相互作用する。AKT1によるリン酸化を受けて活性が低下する。
Heterodimer; with RXRA. Binds DNA preferentially as a heterodimer. Interacts with CDK7 By similarity. Interacts with coactivators NCOA3 and NCOA6. Interacts with NCOA7; the interaction requires ligand-binding. Interacts with KMT2E/MLL5. Interacts (via the ligand-binding domain) with PRAME; the interaction is ligand (retinoic acid)-dependent. Interacts with AKT1; the interaction phosphorylates RARA and represses transactivation. Interacts with PRKAR1A; the interaction negatively regulates RARA transcriptional activity. Interacts with NCOR1 and NCOR2. Interacts with PRMT2. Interacts with LRIF1. Interacts with ASXL1 and NCOA1. Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.23 Ref.24 Ref.27
Subcellular location
核移行はリガンドの結合、リン酸化、SUMO化による。リガンド無しの核移行はPKCの活性化とMAPKによるリン酸化による。
Nucleus. Cytoplasm. Note: Nuclear localization depends on ligand binding, phosphorylation and sumoylation. Transloaction to the nucleus in the absence of ligand is dependent on activation of PKC and the downstream MAPK phosphorylation. Ref.17 Ref.22
Domain
N末端ドメイン、DNA結合ドメイン、Ｃ末端のリガンド結合ドメインよりなる。
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.
Post-translational modification
セリン、トレオニンのリン酸化を受ける。AKT1によるリン酸化はリプレッサー活性に必須。PKAによるリン酸化を受けリガンド結合に必須である。FSHによるシグナルにより核移行と転写活性化活性をもつ
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. Ref.19 Ref.24
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. Ref.17 Ref.22
Trimethylation enhances heterodimerization with RXRA and positively modulates the transcriptional activation.
Ubiquitinated.
Involvement in disease
急性前骨髄球性白血病患者で染色体の異常がみられる。転座により、PML遺伝子と融合しPML-RARAがんタンパク質を形成する。
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.
Sequence similarities
Belongs to the nuclear hormone receptor family. NR1 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
Retinoic acid receptor RXR-alpha
Alternative name(s):
Nuclear receptor subfamily 2 group B member 1
Retinoid X receptor alpha
:Function
Receptor for retinoic acid. 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. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes. Ref.10 Ref.11 Ref.13 Ref.21
Subunit structure
Homodimer. Heterodimer with RARA; required for ligand-dependent retinoic acid receptor transcriptional activity. Heterodimer with PPARA (via the leucine-like zipper in the LBD); the interaction is required for PPARA transcriptional activity. Also heterodimerizes with PPARG. Interacts with NCOA3 and NCOA6 coactivators. Interacts with FAM120B By similarity. Interacts with PELP1, SENP6, SFPQ, DNTTIP2 and RNF8. 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. Interacts with PRMT2. Interacts with ASXL1 and NCOA1 By similarity. Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.21
Subcellular location
Nucleus Ref.13.
Tissue specificity
Highly expressed in liver, also found in lung, kidney and heart.
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).
Post-translational modification
Phosphorylated on serine and threonine residues mainly in the N-terminal modulating domain. Constiutively phosphorylated on Ser-21 in the presence or absence of ligand. 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. This phosphorylation is required for repression of cAMP-mediated transcriptional activity of RARA. Ref.11
Sumoylation negatively regulates transcriptional activity. Desumoylated specifically by SENP6. Ref.18
Sequence similarities
Belongs to the nuclear hormone receptor family. NR2 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
Retinoic acid receptor RXR-beta
Alternative name(s):
Nuclear receptor subfamily 2 group B member 2
Retinoid X receptor beta
:Function
Receptor for retinoic acid. 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. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 By similarity. Specifically binds 9-cis retinoic acid (9C-RA).
Subunit structure
Homodimer By similarity. Heterodimer with a RAR molecule. Binds DNA preferentially as a RAR/RXR heterodimer. Ref.1
Subcellular location
Nucleus.
Tissue specificity
Expressed in a variety of tumor cell lines. Ref.10
Domain
Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain.
Sequence similarities
Belongs to the nuclear hormone receptor family. NR2 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
