Steroid hormone receptor ERR1
Alternative name(s)
Estrogen receptor-like 1 / Estrogen-related receptor alpha
Short name=ERR-alpha
Nuclear receptor subfamily 3 group B member 1
Gene names
Name: ESRRA
Synonyms: ERR1, ESRL1, NR3B1
Function
エストロゲン関連受容体α応答配列（ERRE）に結合し、単一のコンセンサス半配列（5'-TNAAGGTCA-3'）中鎖アシルCoAデヒドロゲナーゼ（MCAD）応答配列（NRRE-1)に結合する。PGC-1Aコアクチベータ-と結合して最大活性を発揮する。
Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.12
Subunit structure
単量体、まはたホモダイマーでDNAに結合する。AF2ドメインを介してPPARGC1A（コアクチベータ）と結合しエネルギー代謝にかかわる遺伝子の発現を増強する。
Binds DNA as a monomer or a homodimer. Interacts (via the AF2 domain) with coactivator PPARGC1A (via the L3 motif); the interaction greatly enhances transriptional activity of genes involved in energy metabolism. Interacts with PIAS4; the interaction enhances sumoylation. Ref.6 Ref.7 Ref.9 Ref.13 Ref.14
Subcellular location
Nucleus Ref.9.
Induction
Induced by PGC1alpha in a number of specific cell types including heart, kidney and muscle. Ref.6
Post-translational modification
Phosphorylation on Ser-19 enhances sumoylation on Lys-14 increasing repression of transcriptional activity. Ref.8 Ref.9
Sumoylated with SUMO2. Main site is Lys-14 which is enhanced by phosphorylation on Ser-19, cofactor activation, and by interaction with PIAS4. Sumoylation enhances repression of transcriptional activity, but has no effect on subcellular location nor on DNA binding. Ref.8 Ref.9
Reversibly acetylated. Acetylation by PCAF/KAT2 at Lys-129, Lys-138, Lys-160 and Lys-162 and PCAF/KAT2 decreases transcriptional activity probably by inhibiting DNA-binding activity; deacetylation involves SIRT1 and HDAC8 and increases DNA-binding. Ref.11
Sequence similarities
Belongs to the nuclear hormone receptor family. NR3 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
Short name=PGC-1-alpha
Short name=PPAR-gamma coactivator 1-alpha
Short name=PPARGC-1-alpha
Alternative name(s):
Ligand effect modulator 6
Gene names
Name: PPARGC1A
Synonyms: LEM6, PGC1, PGC1A, PPARGC1
Function
核内受容体、ステロイド受容体の転写活性のコアクチベータ-としてPPARGや甲状腺ホルモン受容体の転写活性を大幅に上昇させる。
Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism. Induces the expression of PERM1 in the skeletal muscle in an ESRRA-dependent manner. Also involved in the integration of the circadian rhythms and energy metabolism. Required for oscillatory expression of clock genes, such as ARNTL/BMAL1 and NR1D1, through the coactivation of RORA and RORC, and metabolic genes, such as PDK4 and PEPCK. Ref.3 Ref.12 Ref.13 Ref.14
Subunit structure
Homooligomer. Interacts with MYBBP1A; inhibits MYBBP1A transcriptional activation. Interacts with LRPPRC, PRDM16, LPIN1 and PML. Interacts (via LXXLL motif) with RORA and RORC (via AF-2 motif); activates RORA and RORC transcriptional activation. Ref.3 Ref.11
Subcellular location
Isoform 1: Nucleus Ref.3 Ref.4 Ref.5. Nucleus › PML body Ref.3 Ref.4 Ref.5.
Isoform B4: Nucleus Ref.3 Ref.4 Ref.5.
Isoform B4-8a: Cytoplasm. Nucleus Ref.3 Ref.4 Ref.5.
Isoform B5: Nucleus Ref.3 Ref.4 Ref.5. Nucleus › PML body Ref.3 Ref.4 Ref.5.
Isoform 9: Nucleus Ref.3 Ref.4 Ref.5.
Tissue specificity
Heart, skeletal muscle, liver and kidney. Expressed at lower levels in brain and pancreas and at very low levels in the intestine and white adipose tissue. In skeletal muscle, levels were lower in obese than in lean subjects and fasting induced a 2-fold increase in levels in the skeletal muscle in obese subjects. Ref.1 Ref.2 Ref.3
Induction
Transcription is repressed by ZNF746 which binds to 'insulin response sequences' its promoter. Ref.12 Ref.13
Post-translational modification
Phosphorylation by AMPK in skeletal muscle increases activation of its own promoter By similarity. Phosphorylated by CLK2 By similarity.
Heavily acetylated by GCN5 and biologically inactive under conditions of high nutrients. Deacetylated by SIRT1 in low nutrients/high NAD conditions. Ref.12
Sequence similarities
Contains 1 RRM (RNA recognition motif) domain.
Steroid hormone receptor ERR2
Alternative name(s):
ERR beta-2
Estrogen receptor-like 2
Estrogen-related receptor beta
Short name=ERR-beta
Nuclear receptor subfamily 3 group B member 2
Gene names
Name: ESRRB
Synonyms: ERRB2, ESRL2, NR3B2
Function
Nuclear receptor, may regulate ESR1 transcriptional activity. Induces the expression of PERM1 in the skeletal muscle. Ref.7 Ref.8
Subunit structure
Binds DNA as a monomer. Ref.9
Subcellular location
Nucleus Ref.10.
Post-translational modification
Acetylated by PCAF/KAT2 (in vitro). Ref.11
Involvement in disease
Deafness, autosomal recessive, 35 (DFNB35) [MIM:608565]: A form of non-syndromic deafness characterized by non-progressive, prelingual hearing loss.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.12
Sequence similarities
Belongs to the nuclear hormone receptor family. NR3 subfamily.
Contains 1 nuclear receptor DNA-binding domain.
G-protein coupled estrogen receptor 1
Alternative name(s):
Chemoattractant receptor-like 2
Flow-induced endothelial G-protein coupled receptor 1
Short name=FEG-1
G protein-coupled estrogen receptor 1
G-protein coupled receptor 30
GPCR-Br
IL8-related receptor DRY12
Lymphocyte-derived G-protein coupled receptor
Short name=LYGPR
Membrane estrogen receptor
Short name=mER
Gene names
Name: GPER1
Synonyms: CEPR, CMKRL2, DRY12, GPER, GPR30
Function
G-protein coupled estrogen receptor that binds to 17-beta-estradiol (E2) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Stimulates cAMP production, calcium mobilization and tyrosine kinase Src inducing the release of heparin-bound epidermal growth factor (HB-EGF) and subsequent transactivation of the epidermal growth factor receptor (EGFR), activating downstream signaling pathways such as PI3K/Akt and ERK/MAPK. Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. Has a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a RAMP3-dependent manner. Regulates arterial blood pressure by stimulating vasodilation and reducing vascular smooth muscle and microvascular endothelial cell proliferation. Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. Stimulates uterine epithelial cell proliferation. Enhances uterine contractility in response to oxytocin. Contributes to thymic atrophy by inducing apoptosis. Attenuates TNF-mediated endothelial expression of leukocyte adhesion molecules. Promotes neuritogenesis in developing hippocampal neurons. Plays a role in acute neuroprotection against NMDA-induced excitotoxic neuronal death. Increases firing activity and intracellular calcium oscillations in luteinizing hormone-releasing hormone (LHRH) neurons. Inhibits early osteoblast proliferation at growth plate during skeletal development. Inhibits mature adipocyte differentiation and lipid accumulation. Involved in the recruitment of beta-arrestin 2 ARRB2 at the plasma membrane in epithelial cells. Functions also as a receptor for aldosterone mediating rapid regulation of vascular contractibility through the PI3K/ERK signaling pathway. Involved in cancer progression regulation. Stimulates cancer-associated fibroblast (CAF) proliferation by a rapid genomic response through the EGFR/ERK transduction pathway. Associated with EGFR, may act as a transcription factor activating growth regulatory genes (c-fos, cyclin D1). Promotes integrin alpha-5/beta-1 and fibronectin (FN) matrix assembly in breast cancer cells. Ref.14 Ref.16 Ref.17 Ref.21 Ref.22 Ref.24 Ref.25 Ref.27 Ref.28 Ref.30 Ref.32 Ref.33 Ref.35 Ref.36
Subunit structure
Homodimer Probable. Heterodimer; heterodimerizes with other G-protein-coupled receptor (GPCRs) like CRHR1, HTR1A and PAQR8. Interacts (via C-terminus tail motif) with DLG4 (via N-terminus tandem pair of PDZ domains); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner By similarity. Interacts with RAMP3. Interacts with KRT7 and KRT8. Interacts with EGFR; the interaction increases after agonist-induced stimulation in cancer-associated fibroblasts (CAF). Interacts with EGFR and ESR1. Ref.23 Ref.24 Ref.30 Ref.36
Subcellular location
Nucleus. Cytoplasm By similarity. Cytoplasm › perinuclear region. Cytoplasm › cytoskeleton. Cell membrane; Multi-pass membrane protein. Basolateral cell membrane; Multi-pass membrane protein. Cytoplasmic vesicle membrane; Multi-pass membrane protein. Early endosome. Recycling endosome. Golgi apparatus membrane; Multi-pass membrane protein By similarity. Golgi apparatus › trans-Golgi network. Endoplasmic reticulum membrane; Multi-pass membrane protein. Cell projection › dendrite By similarity. Cell projection › dendritic spine membrane; Multi-pass membrane protein By similarity. Cell projection › axon By similarity. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Mitochondrion membrane; Multi-pass membrane protein By similarity. Note: Colocalized with BSN to the active zone of presynaptic density. Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes By similarity. Endocytosed in a agonist- and arrestin-independent manner. Colocalized with RAMP3 and clathrin-coated pits at the plasma membrane. Colocalized with transferrin receptor at the plasma membrane and perinuclear region. Accumulated and colocalized with RAB11 proteins in recycling endosomes and trans-Golgi network (TGN), but does neither recycle back to the cell surface nor traffics to late endosome or lysosome. Colocalized with calnexin in the endoplasmic reticulum. Traffics to intracellular sites via cytokeratin intermediate filaments like KRT7 and KRT8 after constitutive endocytosis in epithelial cells. Colocalized with EGFR in the nucleus of agonist-induced cancer-associated fibroblasts (CAF). Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.24 Ref.27 Ref.29 Ref.30 Ref.31 Ref.33 Ref.36
Tissue specificity
Expressed in placenta, endothelial and epithelial cells, non laboring and laboring term myometrium, fibroblasts and cancer-associated fibroblasts (CAF), prostate cancer cells and invasive adenocarcinoma (at protein level). Ubiquitously expressed, but is most abundant in placenta. In brain regions, expressed as a 2.8 kb transcript in basal forebrain, frontal cortex, thalamus, hippocampus, caudate and putamen. Ref.24 Ref.25 Ref.27 Ref.30 Ref.31 Ref.33
Induction
Up-regulated by EGF and TGF-alpha in endometrial, ovarian and breast tumor cells. Up-regulated by progestin and by phorbol 12-myristate 13-acetate (PMA) in breast cancer cell lines. Ref.15 Ref.23
Post-translational modification
Ubiquitinated; ubiquitination occurs at the plasma membrane and leads to proteasome-mediated degradation. Ref.29
Glycosylated. Ref.27
Miscellaneous
Does not bind estradiol according to Ref.20 and Ref.18.
Sequence similarities
Belongs to the G-protein coupled receptor 1 family.
Caution
Data is conflicting regarding whether it fulfills the criteria of a membrane-bound estrogen receptor (Ref.17, Ref.19 and PubMed:16780796) or not (PubMed:12193550, Ref.18 and Ref.20).
Data is conflicting regarding whether it is localized either at the cell membrane (PM) (Ref.16, Ref.27, Ref.29, Ref.31, Ref.30 and Ref.36) or at the endoplasmic reticulum (ER) (Ref.17 and Ref.20).
Biophysicochemical properties
Kinetic parameters:
KM=3.3 mM for 17-beta-estradiol (Ref.26) Ref.16 Ref.17 Ref.26
KM=6.6 mM for 17-beta-estradiol (Ref.17)
KM=3.3 mM for 17-beta-estradiol (Ref.16)
