GPER1 (G protein-coupled estrogen receptor 1; formerly GPR30) is a class A rhodopsin-family seven-transmembrane receptor that binds 17beta-estradiol with nanomolar affinity and mediates rapid, non-genomic estrogen signaling, distinct from the nuclear estrogen receptors ESR1 and ESR2. Ligand binding activates heterotrimeric G proteins, stimulating adenylyl cyclase (Gs/cAMP), calcium mobilization and Src-dependent release of HB-EGF that transactivates EGFR, leading to PI3K/AKT and ERK1/2 activation. GPER1 is found at the plasma membrane, where it signals and recruits beta-arrestin2, and in the endoplasmic reticulum; it is constitutively endocytosed through clathrin-coated pits, traffics through Rab11 recycling endosomes to the trans-Golgi network and is degraded by the proteasome. Its C-terminal PDZ-binding motif engages scaffold proteins (DLG4/MAGUKs, NHERF1), and it associates with RAMP3. Through these signals GPER1 contributes to cardiovascular (vasodilation, cardioprotection, smooth muscle proliferation), metabolic (insulin secretion, adiposity), reproductive, immune and neural physiology, and to estrogen-driven growth of breast and other cancers. Whether estradiol is its physiological ligand has been debated, but binding and Gs coupling are conserved between human and teleost GPER.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location (by similarity): Golgi membrane. Reason: Golgi localization is reported (biosynthetic passage and return of endocytosed receptor to the TGN), though Sanden et al. did not see Golgi staining; non-core. Supporting Evidence: PMID:21540189 endocytosed GPER does not recycle to the cell surface, but instead returns to the trans-Golgi network (TGN) and does not re-enter the ER |
| GO:0001934 positive regulation of protein phosphorylation | IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | KEEP AS NON CORE | Summary: GPER activation leads to phosphorylation of ERK and HSP27. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 |
| GO:0001934 positive regulation of protein phosphorylation | IDA PMID:21427217 G-1-activated membrane estrogen receptors mediate increased ... | KEEP AS NON CORE | Summary: GPER activation leads to phosphorylation of ERK and HSP27. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 |
| GO:0001934 positive regulation of protein phosphorylation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: GPER activation leads to phosphorylation of ERK and HSP27. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 |
| GO:0001956 positive regulation of neurotransmitter secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred role in neurotransmitter secretion. Reason: This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. |
| GO:0002695 negative regulation of leukocyte activation | IDA PMID:23285008 G-protein coupled receptor 30 (GPR30): a novel regulator of ... | MARK AS OVER ANNOTATED | Summary: The study measured endothelial adhesion-molecule expression, not leukocytes. Reason: Chakrabarti & Davidge measured ICAM-1/VCAM-1 in HUVEC; no leukocyte activation was assayed. Reduced endothelial adhesion molecules might reduce leukocyte recruitment, but 'negative regulation of leukocyte activation' overstates the evidence. The finding is captured by negative regulation of inflammatory response. Supporting Evidence: PMID:23285008 Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). |
| GO:0003682 chromatin binding | IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | MARK AS OVER ANNOTATED | Summary: ChIP of GPR30 together with phosphorylated EGFR at the cyclin D1 promoter in CAFs. Reason: GPER1 is a seven-transmembrane GPCR. Changes in target-gene transcription (c-fos, CTGF, cyclin D1) follow from ERK/EGFR signaling. Madeo & Maggiolini propose a nuclear GPER1/EGFR complex at the cyclin D1 promoter, but this has not been independently established, and a direct transcriptional role of a 7TM receptor is mechanistically unexplained. Terms that place GPER1 in transcription regulation are therefore over-annotations of an indirect signaling effect. Supporting Evidence: PMID:20551055 E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter |
| GO:0004930 G protein-coupled receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA from PTN000658952 (GPR182/GPER family node); GPCR activity is correct for GPER1. Reason: GPER1 is a rhodopsin-family GPCR and the evidence supports the more specific child GO:0038054 G protein-coupled estrogen receptor activity (estrogen binding coupled to Gs activation). The general term is correct, so MODIFY to the specific descendant that this review accepts as the core molecular function. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000658952 SUPPORTS TRANSFER GPR182/GPER family node; GPCR activity is correctly placed; the more specific estrogen-receptor child applies to the GPER branch. Proposed replacements: G protein-coupled estrogen receptor activity Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping from IPR000276 (rhodopsin-like GPCR); correct but general. Reason: GPER1 is a rhodopsin-family GPCR and the evidence supports the more specific child GO:0038054 G protein-coupled estrogen receptor activity (estrogen binding coupled to Gs activation). The general term is correct, so MODIFY to the specific descendant that this review accepts as the core molecular function. Proposed replacements: G protein-coupled estrogen receptor activity Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production |
| GO:0004930 G protein-coupled receptor activity | TAS PMID:8920907 Cloning of human cDNA encoding a novel heptahelix receptor e... | MODIFY | Summary: Owman et al. 1996 cloned CMKRL2 (GPR30) as a heptahelix receptor of the chemokine receptor-like family; the ligand was then unknown. Reason: GPER1 is a rhodopsin-family GPCR and the evidence supports the more specific child GO:0038054 G protein-coupled estrogen receptor activity (estrogen binding coupled to Gs activation). The general term is correct, so MODIFY to the specific descendant that this review accepts as the core molecular function. The cloning paper inferred GPCR status from sequence only; later work identified estrogen as the ligand. Proposed replacements: G protein-coupled estrogen receptor activity Supporting Evidence: PMID:8920907 It contains seven regions of hydrophobic amino acids probably representing membrane-spanning domains of a novel heptahelix receptor PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity |
| GO:0005496 steroid binding | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA from PTN002795969 (GPER subfamily); estradiol binding is conserved from fish to human. Reason: Correct but general: the evidence is specific to estrogens (17beta-estradiol, and antiestrogens such as tamoxifen and ICI 182,780 acting as ligands). MODIFY to GO:1903924 estradiol binding. Note that Otto et al. 2008 failed to detect specific estradiol binding to GPR30, so the binding remains somewhat contested, but two independent groups and fish GPER data support it. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN002795969 SUPPORTS TRANSFER GPER node; estradiol binding conserved from teleost to human GPER, so the more specific estradiol binding term applies. Proposed replacements: estradiol binding Supporting Evidence: PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production |
| GO:0005496 steroid binding | IDA PMID:15539556 Identity of an estrogen membrane receptor coupled to a G pro... | MODIFY | Summary: Saturable, high-affinity (Kd 2.7 nM) estrogen-specific binding in GPR30-expressing membranes. Reason: Correct but general: the evidence is specific to estrogens (17beta-estradiol, and antiestrogens such as tamoxifen and ICI 182,780 acting as ligands). MODIFY to GO:1903924 estradiol binding. Note that Otto et al. 2008 failed to detect specific estradiol binding to GPR30, so the binding remains somewhat contested, but two independent groups and fish GPER data support it. Proposed replacements: estradiol binding Supporting Evidence: PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005496 steroid binding | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | MODIFY | Summary: GPR30 in the ER specifically binds estrogen and fluorescent estrogen derivatives. Reason: Correct but general: the evidence is specific to estrogens (17beta-estradiol, and antiestrogens such as tamoxifen and ICI 182,780 acting as ligands). MODIFY to GO:1903924 estradiol binding. Note that Otto et al. 2008 failed to detect specific estradiol binding to GPR30, so the binding remains somewhat contested, but two independent groups and fish GPER data support it. Proposed replacements: estradiol binding Supporting Evidence: PMID:15705806 GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives |
| GO:0005515 protein binding | IPI PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | REMOVE | Summary: E2-induced co-immunoprecipitation of GPR30 with phosphorylated EGFR in CAFs. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. Supporting Evidence: PMID:20551055 E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter |
| GO:0005515 protein binding | IPI PMID:21149639 G protein-coupled estrogen receptor 1/G protein-coupled rece... | REMOVE | Summary: Reciprocal co-IP of GPER1 with keratins KRT7/KRT8. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. Co-IP from cells does not show direct keratin filament binding. Supporting Evidence: PMID:21149639 One such intracellular structure was identified as cytokeratin (CK) intermediate filaments, including those composed of CK7 and CK8 |
| GO:0005515 protein binding | IPI PMID:21149639 G protein-coupled estrogen receptor 1/G protein-coupled rece... | REMOVE | Summary: Reciprocal co-IP of GPER1 with keratins KRT7/KRT8. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. Co-IP from cells does not show direct keratin filament binding. Supporting Evidence: PMID:21149639 One such intracellular structure was identified as cytokeratin (CK) intermediate filaments, including those composed of CK7 and CK8 |
| GO:0005515 protein binding | IPI PMID:23674134 G-protein-coupled receptor 30 interacts with receptor activi... | REMOVE | Summary: GPR30 interacts with RAMP3 (BRET, co-IP). Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. Supporting Evidence: PMID:23674134 we show that GPR30 and RAMP3 interact |
| GO:0005515 protein binding | IPI PMID:27448983 NHERF1, a novel GPER associated protein, increases stability... | MODIFY | Summary: NHERF1 PDZ2 binds the C-terminal PDZ-binding motif of GPER, stabilizing the receptor. Reason: The paper maps the interaction to GPER's C-terminal PDZ-binding motif and the NHERF1 PDZ2 domain, supporting the more informative GO:0030165 PDZ domain binding (consistent with GPER binding DLG4/MAGUK PDZ proteins). Proposed replacements: PDZ domain binding Supporting Evidence: PMID:27448983 This interaction was mediated by the PDZ2 domain of NHERF1 and the carboxyl terminal PDZ binding motif of GPER. |
| GO:0005515 protein binding | IPI PMID:38211639 G protein-coupled estrogen receptor (GPER)/GPR30 forms a com... | REMOVE | Summary: GPR30 is in a plasma membrane complex with beta1AR, MAGUKs and AKAP5; RAMP3 interaction also detected. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. Supporting Evidence: PMID:38211639 GPR30 constitutively and PDZ-dependently inhibits Ξ²1AR-mediated cAMP production. |
| GO:0005515 protein binding | IPI PMID:38211639 G protein-coupled estrogen receptor (GPER)/GPR30 forms a com... | REMOVE | Summary: GPR30 is in a plasma membrane complex with beta1AR, MAGUKs and AKAP5; RAMP3 interaction also detected. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. Supporting Evidence: PMID:38211639 GPR30 constitutively and PDZ-dependently inhibits Ξ²1AR-mediated cAMP production. |
| GO:0005515 protein binding | IPI PMID:38211639 G protein-coupled estrogen receptor (GPER)/GPR30 forms a com... | REMOVE | Summary: GPR30 is in a plasma membrane complex with beta1AR, MAGUKs and AKAP5; RAMP3 interaction also detected. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. Supporting Evidence: PMID:38211639 GPR30 constitutively and PDZ-dependently inhibits Ξ²1AR-mediated cAMP production. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: High-throughput GPCR-RAMP interactome mapping detected GPER1 with RAMP1-3. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: High-throughput GPCR-RAMP interactome mapping detected GPER1 with RAMP1-3. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: High-throughput GPCR-RAMP interactome mapping detected GPER1 with RAMP1-3. Reason: Generic 'protein binding' is uninformative. The interaction is reported, but no more specific molecular function of GPER1 is established by the cited experiment, so the row is removed under the protein-binding policy; removal does not mean the interaction is false. |
| GO:0005634 nucleus | IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | KEEP AS NON CORE | Summary: Nuclear GPER1 immunostaining/fractionation in endothelial cells and CAFs. Reason: Nuclear localization of GPER1 was reported in HUVEC and in E2-stimulated CAFs. For a 7TM protein this likely reflects nuclear-envelope/perinuclear membranes; the finding is experimental and retained as non-core, but the functional significance is unclear. Supporting Evidence: PMID:23285008 We found that GPR30 was located predominantly in the endothelial cell nuclei. PMID:20551055 Nuclear localization induced by E2 was confirmed by cellular immunofluorescence methods. |
| GO:0005634 nucleus | IDA PMID:23285008 G-protein coupled receptor 30 (GPR30): a novel regulator of ... | KEEP AS NON CORE | Summary: Nuclear GPER1 immunostaining/fractionation in endothelial cells and CAFs. Reason: Nuclear localization of GPER1 was reported in HUVEC and in E2-stimulated CAFs. For a 7TM protein this likely reflects nuclear-envelope/perinuclear membranes; the finding is experimental and retained as non-core, but the functional significance is unclear. Supporting Evidence: PMID:23285008 We found that GPR30 was located predominantly in the endothelial cell nuclei. PMID:20551055 Nuclear localization induced by E2 was confirmed by cellular immunofluorescence methods. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Nuclear GPER1 immunostaining/fractionation in endothelial cells and CAFs. Reason: Nuclear localization of GPER1 was reported in HUVEC and in E2-stimulated CAFs. For a 7TM protein this likely reflects nuclear-envelope/perinuclear membranes; the finding is experimental and retained as non-core, but the functional significance is unclear. Supporting Evidence: PMID:23285008 We found that GPR30 was located predominantly in the endothelial cell nuclei. PMID:20551055 Nuclear localization induced by E2 was confirmed by cellular immunofluorescence methods. |
| GO:0005635 nuclear envelope | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | KEEP AS NON CORE | Summary: GPR30 staining at the nuclear envelope (continuous with ER). Reason: Consistent with ER membrane localization; non-core. Supporting Evidence: PMID:15705806 GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence: nucleoplasm. Reason: HPA antibody-based immunofluorescence. A seven-transmembrane receptor in the soluble nucleoplasm, nucleolus or cytosol is not compatible with its topology; GPER antibodies have known specificity problems. Treated as over-annotation rather than removed, since the curated image data were not re-examined. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. |
| GO:0005730 nucleolus | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence: nucleolus. Reason: HPA antibody-based immunofluorescence. A seven-transmembrane receptor in the soluble nucleoplasm, nucleolus or cytosol is not compatible with its topology; GPER antibodies have known specificity problems. Treated as over-annotation rather than removed, since the curated image data were not re-examined. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | TOO GENERAL | Summary: Cytoplasm (ISS/IEA). Reason: True but uninformative; entailed by ER membrane, endosome and TGN localizations accepted or kept in this review. Supporting Evidence: PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | TOO GENERAL | Summary: Cytoplasm (ISS/IEA). Reason: True but uninformative; entailed by ER membrane, endosome and TGN localizations accepted or kept in this review. Supporting Evidence: PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | TOO GENERAL | Summary: Cytoplasm (ISS/IEA). Reason: True but uninformative; entailed by ER membrane, endosome and TGN localizations accepted or kept in this review. Supporting Evidence: PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005769 early endosome | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: GPER buds into EEA1+ early endosomes. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. |
| GO:0005769 early endosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: GPER buds into EEA1+ early endosomes. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. |
| GO:0005783 endoplasmic reticulum | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | ACCEPT | Summary: GPER1 is in the ER, where its main steady-state pool resides. Reason: Endoplasmic reticulum is a root organelle term, so under the organelle policy it is kept rather than modified to a sub-compartment. The evidence is whole-organelle co-localization, which cannot by itself separate ER membrane from lumen. The sub-compartment is added rather than substituted, and is already asserted in this review by the GO:0005789 endoplasmic reticulum membrane rows (EXP and IEA, accepted) and in core_functions. The ER is where its main steady-state pool resides and where the receptor signals in many cell types, so the row is core. Supporting Evidence: PMID:15705806 GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005783 endoplasmic reticulum | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | ACCEPT | Summary: GPER1 is in the ER, where its main steady-state pool resides. Reason: Endoplasmic reticulum is a root organelle term, so under the organelle policy it is kept rather than modified to a sub-compartment. The evidence is whole-organelle co-localization, which cannot by itself separate ER membrane from lumen. The sub-compartment is added rather than substituted, and is already asserted in this review by the GO:0005789 endoplasmic reticulum membrane rows (EXP and IEA, accepted) and in core_functions. The ER is where its main steady-state pool resides and where the receptor signals in many cell types, so the row is core. Supporting Evidence: PMID:15705806 GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:18566127 G protein-coupled receptor 30 localizes to the endoplasmic r... | ACCEPT | Summary: GPER1 localizes to the ER membrane in many cell types. Reason: Independently shown by several groups (Revankar 2005; Otto 2008; Cheng 2011 colocalization with calnexin). ER is the major steady-state pool of the receptor. Supporting Evidence: PMID:18566127 In transiently transfected cells as well as cells endogenously expressing GPR30, we confirmed that the receptor localized to the endoplasmic reticulum. PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: GPER1 localizes to the ER membrane in many cell types. Reason: Independently shown by several groups (Revankar 2005; Otto 2008; Cheng 2011 colocalization with calnexin). ER is the major steady-state pool of the receptor. Supporting Evidence: PMID:18566127 In transiently transfected cells as well as cells endogenously expressing GPR30, we confirmed that the receptor localized to the endoplasmic reticulum. PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GPER1 detected in Golgi/TGN. Reason: Golgi localization is reported (biosynthetic passage and return of endocytosed receptor to the TGN), though Sanden et al. did not see Golgi staining; non-core. Supporting Evidence: PMID:21540189 endocytosed GPER does not recycle to the cell surface, but instead returns to the trans-Golgi network (TGN) and does not re-enter the ER |
| GO:0005794 Golgi apparatus | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | KEEP AS NON CORE | Summary: GPER1 detected in Golgi/TGN. Reason: Golgi localization is reported (biosynthetic passage and return of endocytosed receptor to the TGN), though Sanden et al. did not see Golgi staining; non-core. Supporting Evidence: PMID:21540189 endocytosed GPER does not recycle to the cell surface, but instead returns to the trans-Golgi network (TGN) and does not re-enter the ER |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: GPER1 detected in Golgi/TGN. Reason: Golgi localization is reported (biosynthetic passage and return of endocytosed receptor to the TGN), though Sanden et al. did not see Golgi staining; non-core. Supporting Evidence: PMID:21540189 endocytosed GPER does not recycle to the cell surface, but instead returns to the trans-Golgi network (TGN) and does not re-enter the ER |
| GO:0005802 trans-Golgi network | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: Endocytosed GPER returns to the TGN. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 endocytosed GPER does not recycle to the cell surface, but instead returns to the trans-Golgi network (TGN) and does not re-enter the ER |
| GO:0005829 cytosol | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence: cytosol. Reason: HPA antibody-based immunofluorescence. A seven-transmembrane receptor in the soluble nucleoplasm, nucleolus or cytosol is not compatible with its topology; GPER antibodies have known specificity problems. Treated as over-annotation rather than removed, since the curated image data were not re-examined. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | TOO GENERAL | Summary: UniProt subcellular location: cytoskeleton. Reason: Entailed by the more specific keratin filament localization. Supporting Evidence: PMID:21149639 One such intracellular structure was identified as cytokeratin (CK) intermediate filaments, including those composed of CK7 and CK8 |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GPER1 is a seven-transmembrane receptor active at the plasma membrane. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21427217 GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005886 plasma membrane | IDA PMID:15539556 Identity of an estrogen membrane receptor coupled to a G pro... | ACCEPT | Summary: GPER1 is a seven-transmembrane receptor active at the plasma membrane. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21427217 GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005886 plasma membrane | IDA NOT PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | REMOVE | Summary: Revankar et al. 2005 concluded GPR30 is localized to the ER and not the plasma membrane (NOT annotation). Reason: This negative localization has been contradicted by multiple subsequent studies showing functional GPER1 at the plasma membrane (PM cAMP production and beta-arrestin2 recruitment; constitutive internalization from clathrin-coated pits explaining low surface levels). Retaining a NOT plasma membrane alongside the accepted plasma membrane rows would be contradictory; the evidence supports PM localization. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21540189 However, in many cell types, GPER is predominately localized to the endoplasmic reticulum (ER), and only minor amounts of receptor are detectable at the cell surface |
| GO:0005886 plasma membrane | IDA PMID:19931550 Conserved estrogen binding and signaling functions of the G ... | ACCEPT | Summary: GPER1 is a seven-transmembrane receptor active at the plasma membrane. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21427217 GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005886 plasma membrane | IDA PMID:21149639 G protein-coupled estrogen receptor 1/G protein-coupled rece... | ACCEPT | Summary: GPER1 is a seven-transmembrane receptor active at the plasma membrane. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21427217 GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005886 plasma membrane | IDA PMID:21427217 G-1-activated membrane estrogen receptors mediate increased ... | ACCEPT | Summary: GPER1 is a seven-transmembrane receptor active at the plasma membrane. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21427217 GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005886 plasma membrane | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | ACCEPT | Summary: GPER1 is a seven-transmembrane receptor active at the plasma membrane. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21427217 GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005886 plasma membrane | IDA PMID:23674134 G-protein-coupled receptor 30 interacts with receptor activi... | ACCEPT | Summary: GPER1 is a seven-transmembrane receptor active at the plasma membrane. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. PMID:21427217 GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0005886 plasma membrane | TAS PMID:8920907 Cloning of human cDNA encoding a novel heptahelix receptor e... | ACCEPT | Summary: Heptahelix receptor cloning paper. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: PMID:8920907 It contains seven regions of hydrophobic amino acids probably representing membrane-spanning domains of a novel heptahelix receptor PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-374207 | ACCEPT | Summary: Reactome places GPER at the plasma membrane in estrogen and G-protein reactions. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Reactome places GPER at the plasma membrane in estrogen and G-protein reactions. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Reactome places GPER at the plasma membrane in estrogen and G-protein reactions. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Reactome places GPER at the plasma membrane in estrogen and G-protein reactions. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9036301 | ACCEPT | Summary: Reactome places GPER at the plasma membrane in estrogen and G-protein reactions. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9036307 | ACCEPT | Summary: Reactome places GPER at the plasma membrane in estrogen and G-protein reactions. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9036308 | ACCEPT | Summary: Reactome places GPER at the plasma membrane in estrogen and G-protein reactions. Reason: GPER1 functions at the plasma membrane: GPER1-dependent cAMP production and beta-arrestin2 recruitment occur at the PM, and the receptor constitutively internalizes, which explains its low steady-state surface levels and the apparent ER predominance in some cells. Supporting Evidence: Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0007154 cell communication | IEA GO_REF:0000117 | TOO GENERAL | Summary: ARBA prediction of 'cell communication'. Reason: True but uninformative; entailed by the accepted G protein-coupled receptor signaling pathway terms. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0007186 G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: GPER1 is a GPCR that transduces estrogen signals through heterotrimeric G proteins. Reason: Core process for a GPCR. GPER1 couples to Gs (cAMP) and, via Gbetagamma/Src, to EGFR transactivation, so the general GPCR signaling pathway term is appropriate across rows (IBA, IEA, TAS, IMP). Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity Reactome:R-HSA-9036301 Binding of E2 to GPER induces the exchange of GDP for GTP on the G alpha (s) heterotrimer G protein, activating it file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: GPER1 is a GPCR that transduces estrogen signals through heterotrimeric G proteins. Reason: Core process for a GPCR. GPER1 couples to Gs (cAMP) and, via Gbetagamma/Src, to EGFR transactivation, so the general GPCR signaling pathway term is appropriate across rows (IBA, IEA, TAS, IMP). Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity Reactome:R-HSA-9036301 Binding of E2 to GPER induces the exchange of GDP for GTP on the G alpha (s) heterotrimer G protein, activating it file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0007186 G protein-coupled receptor signaling pathway | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | ACCEPT | Summary: GPER1 is a GPCR that transduces estrogen signals through heterotrimeric G proteins. Reason: Core process for a GPCR. GPER1 couples to Gs (cAMP) and, via Gbetagamma/Src, to EGFR transactivation, so the general GPCR signaling pathway term is appropriate across rows (IBA, IEA, TAS, IMP). Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity Reactome:R-HSA-9036301 Binding of E2 to GPER induces the exchange of GDP for GTP on the G alpha (s) heterotrimer G protein, activating it file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:8920907 Cloning of human cDNA encoding a novel heptahelix receptor e... | ACCEPT | Summary: GPER1 is a GPCR that transduces estrogen signals through heterotrimeric G proteins. Reason: Core process for a GPCR. GPER1 couples to Gs (cAMP) and, via Gbetagamma/Src, to EGFR transactivation, so the general GPCR signaling pathway term is appropriate across rows (IBA, IEA, TAS, IMP). Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity Reactome:R-HSA-9036301 Binding of E2 to GPER induces the exchange of GDP for GTP on the G alpha (s) heterotrimer G protein, activating it file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:15539556 Identity of an estrogen membrane receptor coupled to a G pro... | ACCEPT | Summary: Estradiol activates a stimulatory G protein directly coupled to GPER1 and increases adenylyl cyclase activity. Reason: Directly shown for human GPER1 (Thomas et al. 2005) and corroborated by GPER1-dependent cAMP production in native cells (Sanden et al. 2011) and in fish GPER (Thomas et al. 2010). Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Estradiol activates a stimulatory G protein directly coupled to GPER1 and increases adenylyl cyclase activity. Reason: Directly shown for human GPER1 (Thomas et al. 2005) and corroborated by GPER1-dependent cAMP production in native cells (Sanden et al. 2011) and in fish GPER (Thomas et al. 2010). Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Estrogen/G-1 activation of GPER raises cytosolic calcium. Reason: Calcium mobilization is a documented second-messenger output of GPER1 activation, but a downstream consequence of receptor signaling and context dependent; keep as non-core. Supporting Evidence: PMID:15705806 Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Estrogen/G-1 activation of GPER raises cytosolic calcium. Reason: Calcium mobilization is a documented second-messenger output of GPER1 activation, but a downstream consequence of receptor signaling and context dependent; keep as non-core. Supporting Evidence: PMID:15705806 Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | KEEP AS NON CORE | Summary: GPR30 knockdown abolished E2-induced proliferation of breast CAFs. Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:20551055 GPR30 was required for CAF proliferation and migration induced by E2. |
| GO:0008285 negative regulation of cell population proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred anti-proliferative effect. Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Regulates arterial blood pressure by stimulating vasodilation and reducing vascular smooth muscle and microvascular endothelial cell proliferation. |
| GO:0010628 positive regulation of gene expression | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | MARK AS OVER ANNOTATED | Summary: Marker expression changes after GPER activation. Reason: 'regulation of gene expression' rows record changes in marker protein/gene levels after GPER activation (e.g. cyclin D1, p21, alpha-actin, SM22alpha). These are indirect read-outs of signaling, not a gene-expression regulatory function of GPER1. Supporting Evidence: PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 PMID:23840305 G-1 induces SMC differentiation evidenced by increased Ξ±-smooth muscle actin (Ξ±-actin) and smooth muscle protein 22Ξ± (SM22Ξ±) protein expressions |
| GO:0010628 positive regulation of gene expression | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Marker expression changes after GPER activation. Reason: 'regulation of gene expression' rows record changes in marker protein/gene levels after GPER activation (e.g. cyclin D1, p21, alpha-actin, SM22alpha). These are indirect read-outs of signaling, not a gene-expression regulatory function of GPER1. Supporting Evidence: PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 PMID:23840305 G-1 induces SMC differentiation evidenced by increased Ξ±-smooth muscle actin (Ξ±-actin) and smooth muscle protein 22Ξ± (SM22Ξ±) protein expressions |
| GO:0010629 negative regulation of gene expression | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | MARK AS OVER ANNOTATED | Summary: Marker expression changes after GPER activation. Reason: 'regulation of gene expression' rows record changes in marker protein/gene levels after GPER activation (e.g. cyclin D1, p21, alpha-actin, SM22alpha). These are indirect read-outs of signaling, not a gene-expression regulatory function of GPER1. Supporting Evidence: PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 |
| GO:0010629 negative regulation of gene expression | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Marker expression changes after GPER activation. Reason: 'regulation of gene expression' rows record changes in marker protein/gene levels after GPER activation (e.g. cyclin D1, p21, alpha-actin, SM22alpha). These are indirect read-outs of signaling, not a gene-expression regulatory function of GPER1. Supporting Evidence: PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 |
| GO:0010948 negative regulation of cell cycle process | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | KEEP AS NON CORE | Summary: G-1 slows CASMC cell-cycle progression (GPER-dependent). Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:23840305 GPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 |
| GO:0014069 postsynaptic density | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0014069 postsynaptic density | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0016020 membrane | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro2GO membrane. Reason: True but entailed by plasma membrane and ER membrane. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. |
| GO:0019228 neuronal action potential | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred: GPER activation increases LHRH neuron firing. Reason: GPER1 modulates neuronal excitability via second messengers but is not part of the action potential machinery; 'neuronal action potential' overstates its role. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Increases firing activity and intracellular calcium oscillations in luteinizing hormone-releasing hormone (LHRH) neurons. |
| GO:0030263 apoptotic chromosome condensation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred apoptotic execution term. Reason: GPER1 activation triggers mitochondrial apoptosis in spermatocytes (ortholog data), but chromosome condensation and nuclear fragmentation are executed by caspase-activated nucleases and other effectors, not by the receptor. These execution-phase terms are over-annotations. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. |
| GO:0030264 nuclear fragmentation involved in apoptotic nuclear change | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Ortholog-transferred apoptotic execution term. Reason: GPER1 activation triggers mitochondrial apoptosis in spermatocytes (ortholog data), but chromosome condensation and nuclear fragmentation are executed by caspase-activated nucleases and other effectors, not by the receptor. These execution-phase terms are over-annotations. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. |
| GO:0030284 nuclear estrogen receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA from node PANTHER:PTN002795969 (GPER subfamily of PTHR24226, GPR182/GPER1), with human GPER1 and mouse Gper1 as descendant evidence; the node and the clade are correct (all members are GPER 7TM receptors), but the term propagated is the nuclear-receptor activity. Reason: GO:0030284 is defined as 'A nuclear receptor activity regulated by estrogen binding and modulating the transcription of specific gene sets transcribed by RNA polymerase II' and is_a GO:0003707 nuclear steroid receptor activity, under DNA-binding transcription factor activity (GO:0003700). GPER1 is a class A seven-transmembrane GPCR (Pfam 7tm_1, PROSITE G_PROTEIN_RECEP_F1) with no nuclear-receptor zinc-finger DNA-binding domain or nuclear-receptor ligand-binding domain, flagged by rule FRR:0009. The papers behind the experimental rows show estrogen binding coupled to heterotrimeric G-protein (Gs) activation, adenylyl cyclase stimulation and calcium mobilization, i.e. exactly the definition of GO:0038054 G protein-coupled estrogen receptor activity ('Combining with estrogen and transmitting the signal across the membrane by activating an associated G-protein'). Thomas et al. explicitly describe GPR30 as unrelated to nuclear estrogen receptors. The essence of the annotation (GPER1 is an estrogen receptor) is retained; the receptor class is wrong. Estradiol binding by GPER1 remains contested (Otto et al. 2008 found no specific binding), but the IUPHAR naming, independent binding data from two groups and conservation of binding in fish GPER support keeping the receptor activity at the GPCR term. The PANTHER node itself is appropriate (it contains only GPER orthologs, and GPER estrogen binding/Gs signaling is conserved to fish); the defect is the term choice, which was inherited from the experimental GO:0030284 annotations on human and mouse GPER. The IBD should be placed with GO:0038054 instead. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002795969 SOURCE BAD GPER subfamily node; clade placement is sound (only GPER 7TM receptors descend from it) but the IBD uses the nuclear-receptor activity term instead of GO:0038054. UniProtKB:Q99527 SOURCE BAD Target's own IDA rows (PMID:15539556, PMID:15705806) show GPCR-type estrogen receptor activity but were typed with GO:0030284; a legitimate descendant evidence, not circular, but carries the term error. MGI:MGI:1924104 SOURCE BAD Mouse Gper1 annotation to GO:0030284 carries the same receptor-class error. Proposed replacements: G protein-coupled estrogen receptor activity Supporting Evidence: PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. |
| GO:0030284 nuclear estrogen receptor activity | IDA PMID:15539556 Identity of an estrogen membrane receptor coupled to a G pro... | MODIFY | Summary: Thomas et al. 2005 showed high-affinity, specific estrogen binding in plasma membranes of GPR30-expressing cells, with E2 activating a directly coupled stimulatory G protein and adenylyl cyclase; they explicitly state GPR30 is unrelated to nuclear estrogen receptors. Reason: GO:0030284 is defined as 'A nuclear receptor activity regulated by estrogen binding and modulating the transcription of specific gene sets transcribed by RNA polymerase II' and is_a GO:0003707 nuclear steroid receptor activity, under DNA-binding transcription factor activity (GO:0003700). GPER1 is a class A seven-transmembrane GPCR (Pfam 7tm_1, PROSITE G_PROTEIN_RECEP_F1) with no nuclear-receptor zinc-finger DNA-binding domain or nuclear-receptor ligand-binding domain, flagged by rule FRR:0009. The papers behind the experimental rows show estrogen binding coupled to heterotrimeric G-protein (Gs) activation, adenylyl cyclase stimulation and calcium mobilization, i.e. exactly the definition of GO:0038054 G protein-coupled estrogen receptor activity ('Combining with estrogen and transmitting the signal across the membrane by activating an associated G-protein'). Thomas et al. explicitly describe GPR30 as unrelated to nuclear estrogen receptors. The essence of the annotation (GPER1 is an estrogen receptor) is retained; the receptor class is wrong. Estradiol binding by GPER1 remains contested (Otto et al. 2008 found no specific binding), but the IUPHAR naming, independent binding data from two groups and conservation of binding in fish GPER support keeping the receptor activity at the GPCR term. Proposed replacements: G protein-coupled estrogen receptor activity Supporting Evidence: PMID:15539556 GPR30, an orphan receptor unrelated to nuclear estrogen receptors, has all the binding and signaling characteristics of a mER PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:15539556 A high-affinity (dissociation constant 2.7 nm), limited capacity, displaceable, single binding site specific for estrogens was detected in plasma membranes of SKBR3 breast cancer cells |
| GO:0030284 nuclear estrogen receptor activity | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | MODIFY | Summary: Revankar et al. 2005 showed that GPR30 binds estrogen and fluorescent estrogen derivatives and that estrogen activation of GPR30 triggers calcium mobilization and PIP3 synthesis; this is rapid GPCR signaling, not nuclear-receptor transcription factor activity. Reason: GO:0030284 is defined as 'A nuclear receptor activity regulated by estrogen binding and modulating the transcription of specific gene sets transcribed by RNA polymerase II' and is_a GO:0003707 nuclear steroid receptor activity, under DNA-binding transcription factor activity (GO:0003700). GPER1 is a class A seven-transmembrane GPCR (Pfam 7tm_1, PROSITE G_PROTEIN_RECEP_F1) with no nuclear-receptor zinc-finger DNA-binding domain or nuclear-receptor ligand-binding domain, flagged by rule FRR:0009. The papers behind the experimental rows show estrogen binding coupled to heterotrimeric G-protein (Gs) activation, adenylyl cyclase stimulation and calcium mobilization, i.e. exactly the definition of GO:0038054 G protein-coupled estrogen receptor activity ('Combining with estrogen and transmitting the signal across the membrane by activating an associated G-protein'). Thomas et al. explicitly describe GPR30 as unrelated to nuclear estrogen receptors. The essence of the annotation (GPER1 is an estrogen receptor) is retained; the receptor class is wrong. Estradiol binding by GPER1 remains contested (Otto et al. 2008 found no specific binding), but the IUPHAR naming, independent binding data from two groups and conservation of binding in fish GPER support keeping the receptor activity at the GPCR term. Proposed replacements: G protein-coupled estrogen receptor activity Supporting Evidence: PMID:15705806 GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives PMID:15705806 Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus |
| GO:0030284 nuclear estrogen receptor activity | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer from mouse Gper1 (Q8BMP4), whose own GO:0030284 annotation carries the same receptor-class error. Reason: GO:0030284 is defined as 'A nuclear receptor activity regulated by estrogen binding and modulating the transcription of specific gene sets transcribed by RNA polymerase II' and is_a GO:0003707 nuclear steroid receptor activity, under DNA-binding transcription factor activity (GO:0003700). GPER1 is a class A seven-transmembrane GPCR (Pfam 7tm_1, PROSITE G_PROTEIN_RECEP_F1) with no nuclear-receptor zinc-finger DNA-binding domain or nuclear-receptor ligand-binding domain, flagged by rule FRR:0009. The papers behind the experimental rows show estrogen binding coupled to heterotrimeric G-protein (Gs) activation, adenylyl cyclase stimulation and calcium mobilization, i.e. exactly the definition of GO:0038054 G protein-coupled estrogen receptor activity ('Combining with estrogen and transmitting the signal across the membrane by activating an associated G-protein'). Thomas et al. explicitly describe GPR30 as unrelated to nuclear estrogen receptors. The essence of the annotation (GPER1 is an estrogen receptor) is retained; the receptor class is wrong. Estradiol binding by GPER1 remains contested (Otto et al. 2008 found no specific binding), but the IUPHAR naming, independent binding data from two groups and conservation of binding in fish GPER support keeping the receptor activity at the GPCR term. This electronic row is only as good as the mouse source annotation, which should be corrected to GO:0038054 upstream. Proposed replacements: G protein-coupled estrogen receptor activity Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt 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 file:human/GPER1/GPER1-uniprot.txt Belongs to the G protein-coupled receptor 1 family. |
| GO:0030335 positive regulation of cell migration | IMP PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | KEEP AS NON CORE | Summary: GPR30 was required for E2-induced CAF migration. Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:20551055 GPR30 was required for CAF proliferation and migration induced by E2. |
| GO:0030424 axon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0030424 axon | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0030425 dendrite | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0030425 dendrite | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0030518 nuclear receptor-mediated steroid hormone signaling pathway | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | MODIFY | Summary: Revankar et al. 2005: estrogen acting through ER-localized GPR30 elicits calcium mobilization and PIP3 synthesis. Reason: GO:0030518 and GO:0030520 are defined as nuclear receptor-mediated pathways ('initiated by ... binding to an intracellular receptor of the nuclear receptor protein family'). GPER1 is a GPCR, not a member of the nuclear receptor family, so these terms are wrong in receptor class (the same issue as GO:0030284). The receptor-neutral parent GO:0043401 steroid hormone receptor signaling pathway captures the claim correctly. Proposed replacements: steroid hormone receptor signaling pathway Supporting Evidence: PMID:15705806 Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus |
| GO:0030520 estrogen receptor signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBA from PTN002795969 to a nuclear-receptor estrogen signaling pathway term. Reason: GO:0030518 and GO:0030520 are defined as nuclear receptor-mediated pathways ('initiated by ... binding to an intracellular receptor of the nuclear receptor protein family'). GPER1 is a GPCR, not a member of the nuclear receptor family, so these terms are wrong in receptor class (the same issue as GO:0030284). The receptor-neutral parent GO:0043401 steroid hormone receptor signaling pathway captures the claim correctly. The IBA likely co-propagates with the GO:0030284 error on the same node. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002795969 SOURCE BAD Same GPER node; the term is defined as a nuclear-receptor-mediated pathway, which does not fit a GPCR clade. RGD:619845 SOURCE BAD Rat Gper1 descendant annotation to the nuclear-receptor pathway term. Proposed replacements: steroid hormone receptor signaling pathway Supporting Evidence: PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production Reactome:R-HSA-374207 This orphan receptor is unrelated to nuclear estrogen receptors, but shows all the binding and signaling characteristics of a membrane estrogen receptor (mER). |
| GO:0030659 cytoplasmic vesicle membrane | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: GPER in intracellular vesicle membranes after endocytosis. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: GPER in intracellular vesicle membranes after endocytosis. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Here, we show that GPER constitutively buds intracellularly into EEA-1+ endosomes from clathrin-coated pits. |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Mitochondrial membrane localization transferred from rodent Gper1. Reason: Reported by similarity only (rodent neurons); unconfirmed in human cells and of unclear significance; non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Mitochondrion membrane |
| GO:0031966 mitochondrial membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mitochondrial membrane localization transferred from rodent Gper1. Reason: Reported by similarity only (rodent neurons); unconfirmed in human cells and of unclear significance; non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Mitochondrion membrane |
| GO:0032024 positive regulation of insulin secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GPER contributes to glucose-stimulated insulin secretion in beta cells (rodent data). Reason: Physiological, receptor-dependent (Gper1 knockout mice are glucose intolerant) but tissue-specific; non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. |
| GO:0032024 positive regulation of insulin secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: GPER contributes to glucose-stimulated insulin secretion in beta cells (rodent data). Reason: Physiological, receptor-dependent (Gper1 knockout mice are glucose intolerant) but tissue-specific; non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. |
| GO:0032591 dendritic spine membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0032962 positive regulation of inositol trisphosphate biosynthetic process | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | MODIFY | Summary: Revankar et al. 2005 reported synthesis of phosphatidylinositol 3,4,5-trisphosphate (PIP3, a membrane lipid) in the nucleus after GPR30 activation; GO:0032962 concerns soluble inositol trisphosphate (IP3). Reason: The cached abstract explicitly describes PIP3, a product of PI3K, not inositol 1,4,5-trisphosphate. GO has no PIP3 biosynthesis regulation term, and the PI3K output is already captured from the same paper by GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction. Full text was not available, so a source_defects entry asks the curators to check whether IP3 was in fact measured. Proposed replacements: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction Supporting Evidence: PMID:15705806 Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus |
| GO:0038054 G protein-coupled estrogen receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: GPER1 binds 17beta-estradiol and signals through heterotrimeric G proteins (Gs/cAMP; also Gi/o-dependent Src/EGFR transactivation). This is the core molecular function. Reason: Directly supported for human GPER1 by membrane binding plus Gs activation (Thomas et al. 2005), cAMP production and beta-arrestin2 recruitment at the plasma membrane (Sanden et al. 2011), conservation of estrogen binding and Gs signaling in fish GPER (Thomas et al. 2010), and Reactome curation. Binding has been disputed (Otto et al. 2008), noted as a suggested question, but the weight of evidence and IUPHAR nomenclature support the term. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production Reactome:R-HSA-9036301 Binding of E2 to GPER induces the exchange of GDP for GTP on the G alpha (s) heterotrimer G protein, activating it file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0042311 vasodilation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred (acts upstream of) vasodilation. Reason: GPER activation relaxes arteries in rodents; physiological but downstream; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Regulates arterial blood pressure by stimulating vasodilation |
| GO:0042734 presynaptic membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Presynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with BSN to the active zone of presynaptic density. |
| GO:0043065 positive regulation of apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred pro-apoptotic role. Reason: Receptor-triggered pro-apoptotic signaling reported in spermatocytes, thymocytes and endothelial cells of rodents; tissue-specific, non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. file:human/GPER1/GPER1-uniprot.txt Contributes to thymic atrophy by inducing apoptosis. |
| GO:0043198 dendritic shaft | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0043401 steroid hormone receptor signaling pathway | IDA PMID:19931550 Conserved estrogen binding and signaling functions of the G ... | ACCEPT | Summary: Thomas et al. 2010 showed estrogen binding and Gs/cAMP signaling by human and croaker GPER. Reason: GO:0043401 ('signals mediated by a steroid hormone binding to a receptor') does not require a nuclear receptor and fits GPER1 estrogen signaling. It is retained alongside the GPCR signaling terms. Supporting Evidence: PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production |
| GO:0043410 positive regulation of MAPK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GPER activation stimulates ERK/MAPK signaling. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0043410 positive regulation of MAPK cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: GPER activation stimulates ERK/MAPK signaling. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0043679 axon terminus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Presynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with BSN to the active zone of presynaptic density. |
| GO:0044327 dendritic spine head | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:0045095 keratin filament | IDA PMID:21149639 G protein-coupled estrogen receptor 1/G protein-coupled rece... | KEEP AS NON CORE | Summary: GPER1 traffics on cytokeratin (KRT7/KRT8) intermediate filaments in epithelial cells. Reason: Reported in one study (Sanden et al. 2011); non-core. Supporting Evidence: PMID:21149639 One such intracellular structure was identified as cytokeratin (CK) intermediate filaments, including those composed of CK7 and CK8 |
| GO:0045599 negative regulation of fat cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred inhibition of adipocyte differentiation. Reason: Tissue-specific downstream outcome; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Inhibits mature adipocyte differentiation and lipid accumulation. |
| GO:0045599 negative regulation of fat cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred inhibition of adipocyte differentiation. Reason: Tissue-specific downstream outcome; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Inhibits mature adipocyte differentiation and lipid accumulation. |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | ACCEPT | Summary: GPER1 signaling transactivates EGFR via Src-dependent release of HB-EGF, a hallmark mechanism of GPER signaling. Reason: EGFR transactivation is the principal route by which GPER1 couples to PI3K/Akt and ERK and is directly part of the receptor's signal transduction mechanism, so it is accepted as a core-adjacent regulatory role. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt 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 PMID:20551055 E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: GPER1 signaling transactivates EGFR via Src-dependent release of HB-EGF, a hallmark mechanism of GPER signaling. Reason: EGFR transactivation is the principal route by which GPER1 couples to PI3K/Akt and ERK and is directly part of the receptor's signal transduction mechanism, so it is accepted as a core-adjacent regulatory role. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt 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 PMID:20551055 E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter |
| GO:0045745 positive regulation of G protein-coupled receptor signaling pathway | IDA PMID:15539556 Identity of an estrogen membrane receptor coupled to a G pro... | MODIFY | Summary: The paper shows estradiol activating Gs and adenylyl cyclase through GPER1 itself. Reason: GPER1 is the receptor in this pathway, not a regulator of some other GPCR's signaling. 'positive regulation of G protein-coupled receptor signaling pathway' mis-casts the receptor's own signaling; the observation is captured by GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway. (GPER1 does modulate beta1-adrenergic receptor signaling, but negatively; Tutzauer et al. 2024.) Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:38211639 GPR30 constitutively and PDZ-dependently inhibits Ξ²1AR-mediated cAMP production. |
| GO:0045745 positive regulation of G protein-coupled receptor signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning prediction. Reason: GPER1 is itself the GPCR; its participation is in GPCR signaling (GO:0007186), not in positive regulation of it. The only documented regulation of another GPCR's signaling is negative (inhibition of beta1AR cAMP production). Proposed replacements: G protein-coupled receptor signaling pathway Supporting Evidence: Reactome:R-HSA-9036301 Binding of E2 to GPER induces the exchange of GDP for GTP on the G alpha (s) heterotrimer G protein, activating it PMID:38211639 GPR30 constitutively and PDZ-dependently inhibits Ξ²1AR-mediated cAMP production. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | MARK AS OVER ANNOTATED | Summary: E2 via GPR30 induces c-fos, CTGF and cyclin D1 expression in CAFs. Reason: GPER1 is a seven-transmembrane GPCR. Changes in target-gene transcription (c-fos, CTGF, cyclin D1) follow from ERK/EGFR signaling. Madeo & Maggiolini propose a nuclear GPER1/EGFR complex at the cyclin D1 promoter, but this has not been independently established, and a direct transcriptional role of a 7TM receptor is mechanistically unexplained. Terms that place GPER1 in transcription regulation are therefore over-annotations of an indirect signaling effect. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:20551055 E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: E2 via GPR30 induces c-fos, CTGF and cyclin D1 expression in CAFs. Reason: GPER1 is a seven-transmembrane GPCR. Changes in target-gene transcription (c-fos, CTGF, cyclin D1) follow from ERK/EGFR signaling. Madeo & Maggiolini propose a nuclear GPER1/EGFR complex at the cyclin D1 promoter, but this has not been independently established, and a direct transcriptional role of a 7TM receptor is mechanistically unexplained. Terms that place GPER1 in transcription regulation are therefore over-annotations of an indirect signaling effect. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:20551055 E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: E2 via GPR30 induces c-fos, CTGF and cyclin D1 expression in CAFs. Reason: GPER1 is a seven-transmembrane GPCR. Changes in target-gene transcription (c-fos, CTGF, cyclin D1) follow from ERK/EGFR signaling. Madeo & Maggiolini propose a nuclear GPER1/EGFR complex at the cyclin D1 promoter, but this has not been independently established, and a direct transcriptional role of a 7TM receptor is mechanistically unexplained. Terms that place GPER1 in transcription regulation are therefore over-annotations of an indirect signaling effect. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:20551055 E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: Endocytosed GPER accumulates in perinuclear Rab11+ endosomes. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Disruption of the TGN by brefeldin A induces the accumulation of endocytosed GPER in Rab11+ perinuclear endosomes and prevents GPER degradation. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Endocytosed GPER accumulates in perinuclear Rab11+ endosomes. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Disruption of the TGN by brefeldin A induces the accumulation of endocytosed GPER in Rab11+ perinuclear endosomes and prevents GPER degradation. |
| GO:0048786 presynaptic active zone | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Presynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with BSN to the active zone of presynaptic density. |
| GO:0050728 negative regulation of inflammatory response | IDA PMID:23285008 G-protein coupled receptor 30 (GPR30): a novel regulator of ... | KEEP AS NON CORE | Summary: G-1 attenuated TNF-induced ICAM-1/VCAM-1 upregulation in HUVEC, blocked by G-15. Reason: Receptor-dependent anti-inflammatory effect in endothelium; physiologically relevant but downstream and tissue-specific. Supporting Evidence: PMID:23285008 Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). PMID:23285008 Activation of endothelial GPR30 attenuated TNF induced upregulation of the pro-inflammatory leukocyte adhesion molecules, suggesting an anti-inflammatory role for this receptor. |
| GO:0050769 positive regulation of neurogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred: GPER promotes neuritogenesis in hippocampal neurons. Reason: Tissue-specific downstream outcome; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Promotes neuritogenesis in developing hippocampal neurons. |
| GO:0050769 positive regulation of neurogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred: GPER promotes neuritogenesis in hippocampal neurons. Reason: Tissue-specific downstream outcome; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Promotes neuritogenesis in developing hippocampal neurons. |
| GO:0050804 modulation of chemical synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer from mouse: modulation of synaptic transmission. Reason: GPER1 is present at synapses and estrogen acting through it modulates synaptic function in rodents; non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. |
| GO:0051050 positive regulation of transport | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA prediction of 'positive regulation of transport'. Reason: Extremely broad, uninformative ARBA prediction; GPER1 influences insulin secretion and neurotransmitter release indirectly, which are already captured as more specific non-core terms. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. |
| GO:0051055 negative regulation of lipid biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-transferred inhibition of lipid accumulation. Reason: Tissue-specific downstream outcome; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Inhibits mature adipocyte differentiation and lipid accumulation. |
| GO:0051055 negative regulation of lipid biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred inhibition of lipid accumulation. Reason: Tissue-specific downstream outcome; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Inhibits mature adipocyte differentiation and lipid accumulation. |
| GO:0051281 positive regulation of release of sequestered calcium ion into cytosol | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | KEEP AS NON CORE | Summary: Estrogen activation of GPR30 caused intracellular calcium mobilization. Reason: Calcium mobilization is a documented second-messenger output of GPER1 activation, but a downstream consequence of receptor signaling and context dependent; keep as non-core. Supporting Evidence: PMID:15705806 Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus |
| GO:0051480 regulation of cytosolic calcium ion concentration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from an ortholog: GPER increases calcium oscillations in LHRH neurons. Reason: Calcium mobilization is a documented second-messenger output of GPER1 activation, but a downstream consequence of receptor signaling and context dependent; keep as non-core. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Increases firing activity and intracellular calcium oscillations in luteinizing hormone-releasing hormone (LHRH) neurons. |
| GO:0051726 regulation of cell cycle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: GPER signaling influences cell-cycle progression (IBA/IEA/ISS). Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 |
| GO:0051726 regulation of cell cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: GPER signaling influences cell-cycle progression (IBA/IEA/ISS). Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 |
| GO:0051726 regulation of cell cycle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: GPER signaling influences cell-cycle progression (IBA/IEA/ISS). Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:23840305 G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21 PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | KEEP AS NON CORE | Summary: Estrogen activation of GPR30 induced PIP3 synthesis (PI3K activation). Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:15705806 Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0051898 negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | KEEP AS NON CORE | Summary: In coronary artery smooth muscle cells, G-1 suppressed Akt phosphorylation. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Here the effect is inhibitory. Supporting Evidence: PMID:23840305 GPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. |
| GO:0055037 recycling endosome | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | KEEP AS NON CORE | Summary: GPER co-traffics with Rab11+ recycling endosomes. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Like Ξ²1AR, which recycles to the plasma membrane, GPER co-traffics with transferrin+, Rab11+ recycling endosomes. |
| GO:0055037 recycling endosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: GPER co-traffics with Rab11+ recycling endosomes. Reason: Part of the constitutive endocytic/trafficking itinerary of GPER1 (clathrin-coated pits -> early endosomes -> Rab11 recycling endosomes -> TGN -> proteasomal degradation); real but not the site of its core activity. Supporting Evidence: PMID:21540189 Like Ξ²1AR, which recycles to the plasma membrane, GPER co-traffics with transferrin+, Rab11+ recycling endosomes. |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | KEEP AS NON CORE | Summary: In coronary artery smooth muscle cells, G-1 suppressed ERK1/2 phosphorylation (GPER-dependent, siRNA). Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Here the effect is inhibitory. Supporting Evidence: PMID:23840305 GPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. PMID:23840305 In order to determine the effect and specificity of G-1 on proliferation we knocked-down expression of GPER via siRNA transfection studies |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Estradiol/G-1 activation of GPER1 induces ERK1/2 phosphorylation in CAFs, myometrium and other cells. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | KEEP AS NON CORE | Summary: Estradiol/G-1 activation of GPER1 induces ERK1/2 phosphorylation in CAFs, myometrium and other cells. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:21427217 G-1-activated membrane estrogen receptors mediate increased ... | KEEP AS NON CORE | Summary: Estradiol/G-1 activation of GPER1 induces ERK1/2 phosphorylation in CAFs, myometrium and other cells. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Estradiol/G-1 activation of GPER1 induces ERK1/2 phosphorylation in CAFs, myometrium and other cells. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Estradiol/G-1 activation of GPER1 induces ERK1/2 phosphorylation in CAFs, myometrium and other cells. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Estradiol/G-1 activation of GPER1 induces ERK1/2 phosphorylation in CAFs, myometrium and other cells. Reason: Downstream signaling output of GPER1 (via Src-dependent HB-EGF release and EGFR transactivation, or via cAMP), documented in several cell types; the receptor regulates rather than executes the cascade, and the sign is context dependent. Keep as non-core. Supporting Evidence: PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21427217 membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27 file:human/GPER1/GPER1-uniprot.txt 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 |
| GO:0070474 positive regulation of uterine smooth muscle contraction | IDA PMID:21427217 G-1-activated membrane estrogen receptors mediate increased ... | KEEP AS NON CORE | Summary: G-1 increased the contractile response of human myometrial strips to oxytocin. Reason: Physiological, receptor-dependent but tissue-specific outcome; non-core. Supporting Evidence: PMID:21427217 estrogen membrane receptor activation increased the myometrial contractile response to oxytocin |
| GO:0071333 cellular response to glucose stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse: GPER supports insulin secretion in response to glucose. Reason: GPER1 does not sense glucose; it is an estrogen receptor that potentiates beta-cell insulin secretion. 'cellular response to glucose stimulus' over-interprets that role. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. |
| GO:0071333 cellular response to glucose stimulus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse: GPER supports insulin secretion in response to glucose. Reason: GPER1 does not sense glucose; it is an estrogen receptor that potentiates beta-cell insulin secretion. 'cellular response to glucose stimulus' over-interprets that role. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. |
| GO:0071356 cellular response to tumor necrosis factor | IDA PMID:23285008 G-protein coupled receptor 30 (GPR30): a novel regulator of ... | MARK AS OVER ANNOTATED | Summary: GPER activation modulated the endothelial response to TNF. Reason: GPER1 does not sense TNF; G-1 activation of GPER1 modified the TNF response. 'cellular response to tumor necrosis factor' implies GPER1 is part of the TNF response machinery, which is an over-interpretation. Supporting Evidence: PMID:23285008 Treatment with the selective GPR30 agonist G-1 partially attenuated the TNF induced upregulation of pro-inflammatory proteins such as intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). |
| GO:0071375 cellular response to peptide hormone stimulus | IDA PMID:21427217 G-1-activated membrane estrogen receptors mediate increased ... | MARK AS OVER ANNOTATED | Summary: GPER activation enhanced oxytocin-induced contraction. Reason: GPER1 is not an oxytocin receptor and was not shown to respond to oxytocin; it potentiated the oxytocin response. The term overstates GPER1's role. Supporting Evidence: PMID:21427217 estrogen membrane receptor activation increased the myometrial contractile response to oxytocin |
| GO:0071389 cellular response to mineralocorticoid stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred response to aldosterone. Reason: UniProt reports that GPER also mediates rapid aldosterone effects on vascular contractility; this claim is contested in the literature and not central to GPER1 function. Retained as non-core pending direct evidence. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Also functions as a receptor for aldosterone mediating rapid regulation of vascular contractibility through the PI3K/ERK signaling pathway. |
| GO:0071392 cellular response to estradiol stimulus | IBA GO_REF:0000033 | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:15539556 Identity of an estrogen membrane receptor coupled to a G pro... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:15705806 A transmembrane intracellular estrogen receptor mediates rap... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:19931550 Conserved estrogen binding and signaling functions of the G ... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:20551055 Nuclear alternate estrogen receptor GPR30 mediates 17beta-es... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:21149639 G protein-coupled estrogen receptor 1/G protein-coupled rece... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:21427217 G-1-activated membrane estrogen receptors mediate increased ... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:21540189 Down-modulation of the G-protein-coupled estrogen receptor, ... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IDA PMID:23285008 G-protein coupled receptor 30 (GPR30): a novel regulator of ... | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0071392 cellular response to estradiol stimulus | IEA GO_REF:0000120 | ACCEPT | Summary: GPER1 mediates rapid cellular responses to 17beta-estradiol (cAMP, calcium, ERK activation, gene induction). Reason: GPER1 is an estradiol receptor, so it directly participates in the cellular response to estradiol; consistent with the experimental rows from several groups and with the IBA. Supporting Evidence: PMID:15539556 E2 treatment of transfected cell membranes caused activation of a stimulatory G protein that is directly coupled to the receptor, indicating GPR30 is a G protein-coupled receptor (GPCR), and also increased adenylyl cyclase activity PMID:20551055 CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1 PMID:21149639 We conclude that GPER1-mediated stimulation of cAMP production and Ξ²-arrestin2 recruitment occur in the PM. |
| GO:0090200 positive regulation of release of cytochrome c from mitochondria | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred: GPER triggers mitochondrial apoptosis in spermatocytes. Reason: Receptor-triggered pro-apoptotic signaling reported in spermatocytes, thymocytes and endothelial cells of rodents; tissue-specific, non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. |
| GO:0098686 hippocampal mossy fiber to CA3 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuronal/postsynaptic localization transferred from rodent Gper1. Reason: Ortholog-transferred neuronal localization (rodent synaptosome and immuno-EM data, e.g. colocalization with DLG4/PSD95 and BSN). Plausible for neuronal GPER1, which binds DLG4 via its PDZ motif; non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Colocalized with DLG4/PSD95 and neurabin-2 PPP1R9B in neuronal synaptosomes |
| GO:1903078 positive regulation of protein localization to plasma membrane | IDA PMID:23674134 G-protein-coupled receptor 30 interacts with receptor activi... | KEEP AS NON CORE | Summary: Co-expression of GPR30 increased RAMP3 at the plasma membrane in HEK293 cells. Reason: Supported by Lenhart et al.; a trafficking effect on a partner protein, not GPER1's core receptor function. Supporting Evidence: PMID:23674134 the presence of GPR30 leads to increased expression of RAMP3 at the plasma membrane in HEK293 cells |
| GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | KEEP AS NON CORE | Summary: G-1 inhibited human coronary artery SMC proliferation in a GPER-dependent manner. Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:23840305 GPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. PMID:23840305 In order to determine the effect and specificity of G-1 on proliferation we knocked-down expression of GPER via siRNA transfection studies |
| GO:1990239 steroid hormone binding | IDA PMID:19931550 Conserved estrogen binding and signaling functions of the G ... | MODIFY | Summary: Thomas et al. 2010 compared croaker and human GPER estrogen binding (human Kd ~3 nM). Reason: Correct but general: the evidence is specific to estrogens (17beta-estradiol, and antiestrogens such as tamoxifen and ICI 182,780 acting as ligands). MODIFY to GO:1903924 estradiol binding. Note that Otto et al. 2008 failed to detect specific estradiol binding to GPR30, so the binding remains somewhat contested, but two independent groups and fish GPER data support it. Proposed replacements: estradiol binding Supporting Evidence: PMID:19931550 croaker and human GPER have very similar estrogen binding characteristics, typical of estrogen membrane receptors, and activate the same estrogen signaling pathways via stimulatory G proteins (Gs) resulting in increased cAMP production file:human/GPER1/GPER1-uniprot.txt Binds 17-beta-estradiol (E2) in plasma membranes with high affinity (Kd is 3.3 nM) and displays rapid kinetics of association and dissociation. |
| GO:2000353 positive regulation of endothelial cell apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred pro-apoptotic effect in endothelial cells. Reason: Receptor-triggered pro-apoptotic signaling reported in spermatocytes, thymocytes and endothelial cells of rodents; tissue-specific, non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. |
| GO:2000724 positive regulation of cardiac vascular smooth muscle cell differentiation | IMP PMID:23840305 Activation of GPER Induces Differentiation and Inhibition of... | KEEP AS NON CORE | Summary: G-1 induced CASMC differentiation markers. Reason: Cell-type-specific outcome of GPER1 signaling (pro-proliferative in CAFs and uterine epithelium, anti-proliferative in vascular smooth muscle). Real, receptor-dependent, but pleiotropic and indirect; non-core. Supporting Evidence: PMID:23840305 G-1 induces SMC differentiation evidenced by increased Ξ±-smooth muscle actin (Ξ±-actin) and smooth muscle protein 22Ξ± (SM22Ξ±) protein expressions |
| GO:2001238 positive regulation of extrinsic apoptotic signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog-transferred extrinsic apoptotic signaling effect (thymocytes). Reason: Receptor-triggered pro-apoptotic signaling reported in spermatocytes, thymocytes and endothelial cells of rodents; tissue-specific, non-core. This ISS row is transferred from a rodent Gper1 ortholog; GPER1 is a 1:1 ortholog, so transfer of a receptor-dependent phenotype is reasonable, but the term describes a tissue-specific downstream effect of GPER signaling rather than the receptor's own activity. Supporting Evidence: file:human/GPER1/GPER1-uniprot.txt Contributes to thymic atrophy by inducing apoptosis. |
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Download this section (compressed HTML)Q: Is 17beta-estradiol the physiological agonist of GPER1, given that some groups (e.g. Otto et al. 2008) detect no specific estradiol binding or GPER1-dependent cAMP/calcium responses?
Q: Should GO:0030284 nuclear estrogen receptor activity on GPER orthologs (IDA, IBA from PTN002795969, and Ensembl projections) be systematically repointed to GO:0038054, and should GO:0030520 on the same PAINT node be changed to a receptor-neutral term?
Q: Does GPER1 genuinely localize to and act within the nucleus (chromatin association at the cyclin D1 promoter), or do nuclear signals reflect nuclear-envelope membranes or antibody cross-reactivity?
Q: Which heterotrimeric G proteins (Gs versus Gi/o) does GPER1 couple to in native cells, and does this account for opposite effects on ERK/Akt in different cell types?
Experiment: Radioligand and fluorescent-ligand binding with GPER1-null versus reconstituted cells (including purified receptor in nanodiscs) to settle whether estradiol binds GPER1 directly, with BRET-based G-protein activation sensors to define coupling specificity.
Type: binding assay / BRET G-protein activation
Experiment: Validate nuclear GPER1 claims with knockout-validated antibodies and epitope-tagged endogenous GPER1 (CRISPR knock-in), combined with ChIP-qPCR at the cyclin D1 promoter in GPER1-knockout controls.
Type: imaging / ChIP
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