Endothelin-1 (EDN1) encodes the primary vascular endothelium-derived vasoconstrictor peptide hormone, synthesized as a 212-amino-acid preproprotein that is proteolytically cleaved by furin into the 38-amino-acid intermediate big endothelin-1 (residues 53-90) and subsequently converted by endothelin-converting enzymes (ECE-1, ECE-2) into the mature 21-amino-acid bicyclic peptide endothelin-1 (ET-1, residues 53-73), stabilized by two intramolecular disulfide bridges (Cys1-Cys15 and Cys3-Cys11). Secreted predominantly toward the abluminal vascular smooth muscle layer, mature ET-1 binds with sub-nanomolar affinity to both class A G-protein-coupled endothelin receptors: EDNRA (ET-A) on vascular smooth muscle cells, cardiomyocytes, and cranial/cardiac neural crest cells, and EDNRB (ET-B) on vascular endothelial cells and smooth muscle. Through Gq/11-coupled phospholipase C activation, IP3- and Ca2+-mediated signaling, and MAPK/ERK and RhoA/ROCK cascades, EDN1 drives potent and sustained arterial and venous vasoconstriction, regulates systemic arterial blood pressure, promotes smooth muscle proliferation and cardiomyocyte hypertrophy, and directs pharyngeal arch, craniofacial, and cardiac outflow tract morphogenesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:19767294 Krüppel-like factor 15 regulates BMPER in endothelial cells. | KEEP AS NON CORE | Summary: Downstream transcriptional repression of target genes such as NOS3 following endothelin receptor activation. Reason: In PMID:19767294, exogenous ET-1 treatment of endothelial cells represses specific target gene transcription via endothelin receptor signaling; retained as a downstream cellular effect rather than a direct transcriptional repressor activity of the secreted peptide. |
| GO:0000165 MAPK cascade | IEA GO_REF:0000107 | MODIFY | Summary: Broad MAPK cascade annotation that should be refined to positive regulation of MAPK cascade. Reason: As an extracellular GPCR ligand, ET-1 positively regulates the MAPK/ERK cascade (GO:0043410, already present on EDN1 via IDA in PMID:10770212 and PMID:12847114) rather than acting as an intracellular kinase component. Proposed replacements: positive regulation of MAPK cascade |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of hypoxia-induced endothelial EDN1 transcription as a direct functional role in response to hypoxia. Reason: Orthology projection (GO_REF:0000107) reflects HIF-1-dependent transcriptional upregulation and increased endothelial secretion of EDN1 during hypoxia rather than mature ET-1 functioning as a hypoxia sensor. |
| GO:0001821 histamine secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream paracrine stimulation of mast cell histamine release by endothelin-1. Reason: Mature ET-1 stimulates degranulation and histamine release from mast cells expressing endothelin receptors in rodent models (projected via GO_REF:0000107); retained as a non-core paracrine physiological effect. |
| GO:0001975 response to amphetamine | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of amphetamine-induced changes in EDN1 expression as a direct role in response to amphetamine. Reason: Orthology projection (GO_REF:0000107) reflects altered vascular or neural Edn1 mRNA/peptide levels following amphetamine administration rather than EDN1 directly mediating amphetamine pharmacology. |
| GO:0003015 heart process | IEA GO_REF:0000107 | MODIFY | Summary: Imprecise organ-level heart process annotation replaced by specific endothelin cardiovascular functions. Reason: GO:0003015 (heart process) is an overly general organ-level term projected via GO_REF:0000107; lateral refinement to GO:0003100 (regulation of systemic arterial blood pressure by endothelin) and GO:0042310 (vasoconstriction), both already accepted on EDN1, captures the specific cardiovascular actions of mature ET-1. Proposed replacements: regulation of systemic arterial blood pressure by endothelin vasoconstriction |
| GO:0003094 glomerular filtration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream physiological modulation of renal glomerular filtration rate via renal vascular and mesangial endothelin receptors. Reason: ET-1 constricts renal afferent and efferent arterioles and contracts mesangial cells via EDNRA/EDNRB to reduce glomerular filtration rate (projected via GO_REF:0000107); retained as a non-core organ-level physiological outcome. |
| GO:0003100 regulation of systemic arterial blood pressure by endothelin | IBA GO_REF:0000033 | ACCEPT | Summary: Core physiological role of mature endothelin-1 in regulating systemic arterial blood pressure. Reason: Phylogenetically conserved core function of vertebrate endothelin-1 in regulating systemic arterial blood pressure via vascular smooth muscle EDNRA/EDNRB activation (GO_REF:0000033, PMID:2649896). |
| GO:0003100 regulation of systemic arterial blood pressure by endothelin | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | ACCEPT | Summary: Core physiological role of mature endothelin-1 in regulating systemic arterial blood pressure. Reason: Intravenous administration of mature ET-1 produces a potent, sustained pressor response and elevates systemic arterial blood pressure in vivo (PMID:2649896). |
| GO:0003253 cardiac neural crest cell migration involved in outflow tract morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Essential developmental role of EDN1-EDNRA paracrine signaling in cardiac neural crest migration during outflow tract morphogenesis. Reason: Paracrine ET-1 secreted by pharyngeal arch epithelium signals through EDNRA on migrating cardiac neural crest cells to pattern the cardiac outflow tract and great vessels in mouse genetic models (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0003357 noradrenergic neuron differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of endothelin signaling in sympathetic noradrenergic neuron differentiation from neural crest progenitors. Reason: Endothelin signaling promotes differentiation of neural crest-derived noradrenergic sympathetic neurons in vertebrate development (projected via GO_REF:0000107); retained as a non-core developmental process. |
| GO:0005102 signaling receptor binding | IEA GO_REF:0000107 | MODIFY | Summary: General signaling receptor binding annotation refined to hormone activity and specific endothelin A and B receptor binding. Reason: GO:0005102 (signaling receptor binding) is true but too general; mature ET-1 specifically functions as a peptide hormone (GO:0005179) that binds EDNRA (GO:0031707) and EDNRB (GO:0031708). |
| GO:0005125 cytokine activity | IDA PMID:19767294 Krüppel-like factor 15 regulates BMPER in endothelial cells. | MODIFY | Summary: Misclassification of the vasoactive peptide hormone endothelin-1 as a cytokine, laterally corrected to hormone activity and endothelin receptor binding. Reason: Both GO:0005125 (cytokine activity) and GO:0005179 (hormone activity) are sibling children of GO:0048018 (receptor ligand activity); this lateral correction replaces GO:0005125 because mature ET-1 is a 21-amino-acid disulfide-bridged vasoactive peptide hormone (GO:0005179) that binds EDNRA (GO:0031707) and EDNRB (GO:0031708) rather than a classical immunomodulatory cytokine. |
| GO:0005179 hormone activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a secreted vasoactive peptide hormone. Reason: Mature ET-1 is the primary endothelium-derived 21-residue vasoactive peptide hormone that signals via EDNRA and EDNRB to regulate vascular tone, blood pressure, and cellular proliferation (PMID:2649896, PMID:10770212). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0005179 hormone activity | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a secreted vasoactive peptide hormone. Reason: Mature ET-1 is the primary endothelium-derived 21-residue vasoactive peptide hormone that signals via EDNRA and EDNRB to regulate vascular tone, blood pressure, and cellular proliferation (PMID:2649896, PMID:10770212). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0005179 hormone activity | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a secreted vasoactive peptide hormone. Reason: Mature ET-1 is the primary endothelium-derived 21-residue vasoactive peptide hormone that signals via EDNRA and EDNRB to regulate vascular tone, blood pressure, and cellular proliferation (PMID:2649896, PMID:10770212). Supporting Evidence: PMID:2649896 Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. |
| GO:0005515 protein binding | IPI PMID:17446437 Association of ATP1A1 and dear single-nucleotide polymorphis... | REMOVE | Summary: Uninformative generic protein binding annotation from a genetic association study. Reason: PMID:17446437 is a human hypertension genetic association study of ATP1A1 and DEAR (a putative dual ET-1/angiotensin II receptor in rat); bare GO:0005515 (protein binding) carries no informative molecular function and is removed per the protein-binding policy. |
| GO:0005515 protein binding | IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec... | MODIFY | Summary: Generic protein binding row for EDN1 interaction with EDNRB (P24530) that should be refined to endothelin B receptor binding. Reason: Interaction of mature ET-1 with UniProtKB:P24530 (human EDNRB) represents specific ligand binding to the endothelin B receptor (GO:0031708) (PMID:23597562). Proposed replacements: endothelin B receptor binding |
| GO:0005515 protein binding | IPI PMID:23597562 Inhibition of tumor angiogenesis and growth by a small-molec... | MODIFY | Summary: Generic protein binding row for EDN1 interaction with EDNRA (P25101) that should be refined to endothelin A receptor binding. Reason: Interaction of mature ET-1 with UniProtKB:P25101 (human EDNRA) represents specific ligand binding to the endothelin A receptor (GO:0031707) (PMID:23597562). Proposed replacements: endothelin A receptor binding |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | IDA PMID:15691296 Ursodeoxycholic acid reduces increased circulating endotheli... | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | IDA PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-388560 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8876868 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9731924 | ACCEPT | Summary: Core extracellular localization where mature endothelin-1 is secreted and engages cell-surface receptors. Reason: Mature ET-1 and big ET-1 are secreted from vascular endothelial and neuroendocrine cells into the extracellular space and plasma (PMID:10770212, PMID:15691296, PMID:16820593). Supporting Evidence: PMID:15691296 Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. |
| GO:0005737 cytoplasm | IDA PMID:12379507 Effects of endothelin-1 on release of adrenomedullin and C-t... | MODIFY | Summary: Broad cytoplasmic localization from whole-cell immunocytochemical blotting refined to secretory transport vesicles and Weibel-Palade bodies. Reason: Preproendothelin-1 is cotranslationally translocated into the ER lumen, processed to big ET-1 and mature ET-1 in the trans-Golgi network, and trafficked through secretory pathway transport vesicles (GO:0030133, which EDN1 already carries in GOA via Reactome:R-HSA-8877620, where ECE2 cleaves big ET-1 in acidified secretory pathway vesicles) and regulated endothelial storage granules (Weibel-Palade bodies, GO:0033093, which rests on the existing GO_REF:0000107 IEA row from rat Edn1 UniProtKB:P22388, as the R-HSA-8877620 note specifically concerns ECE2's absence from Weibel-Palade bodies) rather than residing free in the cytosol. PMID:12379507 stained whole dispersed human aortic endothelial cells on a protein-binding membrane without subcellular fractionation. Proposed replacements: transport vesicle Weibel-Palade body Supporting Evidence: PMID:12379507 Peptides (adrenomedullin, CNP and ET-1) within individual cells were stained, as was peptide secreted and adjacent to the cell. Reactome:R-HSA-8877620 ECE2 was found to be localized to the acidified environment of vesicles of the secretory pathway in human endothelial cells but was not detected in Weibel-Palade storage granules (Russell & Davenport 1999). |
| GO:0006366 transcription by RNA polymerase II | IEA GO_REF:0000107 | MODIFY | Summary: Broad transcription by RNA polymerase II annotation that should be refined to positive and negative regulation of transcription by RNA polymerase II. Reason: Secreted ET-1 is not part of the core transcriptional machinery; instead, EDN1 receptor signaling regulates target gene transcription (GO:0045944 positive regulation of transcription by RNA polymerase II and GO:0000122 negative regulation of transcription by RNA polymerase II). |
| GO:0006874 intracellular calcium ion homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Non-core intracellular calcium ion homeostasis annotation reflecting downstream GPCR-induced Ca2+ mobilization. Reason: Endothelin receptor activation triggers acute IP3-dependent intracellular Ca2+ release and cytosolic Ca2+ elevation (GO:0007204); retained as non-core downstream context. |
| GO:0006874 intracellular calcium ion homeostasis | IDA PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati... | KEEP AS NON CORE | Summary: Non-core intracellular calcium ion homeostasis annotation reflecting downstream GPCR-induced Ca2+ mobilization. Reason: Endothelin receptor activation triggers acute IP3-dependent intracellular Ca2+ release and cytosolic Ca2+ elevation (GO:0007204); retained as non-core downstream context. |
| GO:0006874 intracellular calcium ion homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Non-core intracellular calcium ion homeostasis annotation reflecting downstream GPCR-induced Ca2+ mobilization. Reason: Endothelin receptor activation triggers acute IP3-dependent intracellular Ca2+ release and cytosolic Ca2+ elevation (GO:0007204); retained as non-core downstream context. |
| GO:0007005 mitochondrion organization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of downstream cellular remodeling as a direct role of secreted endothelin-1 in mitochondrion organization. Reason: Mature ET-1 is an extracellular GPCR peptide ligand; changes in mitochondrial fission or bioenergetics in ET-1-treated cardiomyocytes or vascular cells are indirect downstream consequences of receptor-mediated Ca2+/MAPK signaling (projected via GO_REF:0000107) rather than direct participation of EDN1 in mitochondrion organization. |
| GO:0007166 cell surface receptor signaling pathway | IDA PMID:1713452 Cloning and functional expression of human cDNA for the ETB ... | MODIFY | Summary: Broad cell surface receptor signaling pathway annotation that should be refined to endothelin receptor signaling pathway. Reason: GO:0007166 (cell surface receptor signaling pathway) is true but less specific than GO:0086100 (endothelin receptor signaling pathway) and GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway), which are directly supported for EDN1. |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:17078114 Mechanisms of endothelin 1-stimulated proliferation in color... | MODIFY | Summary: Broad G protein-coupled receptor signaling pathway annotation that should be refined to endothelin receptor signaling pathway. Reason: GO:0007186 (G protein-coupled receptor signaling pathway) is true but less specific than GO:0086100 (endothelin receptor signaling pathway) and GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway), which are directly supported for EDN1. |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | ACCEPT | Summary: Core intracellular signaling outcome of mature endothelin-1 elevating cytosolic free calcium concentration via Gq/11-PLC activation. Reason: Binding of mature ET-1 to Gq/11-coupled EDNRA and EDNRB activates phospholipase C-beta, generating IP3 to trigger rapid Ca2+ release from endoplasmic/sarcoplasmic reticulum stores and extracellular Ca2+ influx (PMID:1917960, PMID:10770212). |
| GO:0007267 cell-cell signaling | IDA PMID:12379507 Effects of endothelin-1 on release of adrenomedullin and C-t... | MODIFY | Summary: Broad cell-cell signaling annotation that should be refined to endothelin receptor signaling pathway. Reason: GO:0007267 (cell-cell signaling) is true but less specific than GO:0086100 (endothelin receptor signaling pathway) and GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway), which are directly supported for EDN1. |
| GO:0007411 axon guidance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of endothelin-1 as a vascular-derived paracrine guidance cue for sympathetic axons. Reason: Vascular-derived ET-1 acts via EDNRA on postganglionic sympathetic neurons to guide axon extension along arterial trajectories during development (projected via GO_REF:0000107); retained as a non-core developmental process. |
| GO:0008217 regulation of blood pressure | IEA GO_REF:0000107 | MODIFY | Summary: Broad cardiovascular annotation (regulation of blood pressure) that should be refined to regulation of systemic arterial blood pressure by endothelin and vasoconstriction. Reason: GO:0008217 (regulation of blood pressure) is true but less specific than GO:0003100 (regulation of systemic arterial blood pressure by endothelin) and GO:0042310 (vasoconstriction), both already accepted on EDN1. Proposed replacements: regulation of systemic arterial blood pressure by endothelin vasoconstriction |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:17078114 Mechanisms of endothelin 1-stimulated proliferation in color... | KEEP AS NON CORE | Summary: Downstream mitogenic activity of endothelin-1 stimulating vascular smooth muscle, mesangial, and neuroblast cell proliferation. Reason: Exogenous ET-1 acts as a comitogen that stimulates DNA synthesis and cell population proliferation via EDNRA/EDNRB-coupled Ca2+ and MAPK cascades (PMID:17078114); retained as a downstream cellular response. |
| GO:0008284 positive regulation of cell population proliferation | IDA PMID:1917960 Effects of endothelins on signal transduction and proliferat... | KEEP AS NON CORE | Summary: Downstream mitogenic activity of endothelin-1 stimulating vascular smooth muscle, mesangial, and neuroblast cell proliferation. Reason: Exogenous ET-1 acts as a comitogen that stimulates DNA synthesis and cell population proliferation via EDNRA/EDNRB-coupled Ca2+ and MAPK cascades (PMID:1917960); retained as a downstream cellular response. |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream mitogenic activity of endothelin-1 stimulating vascular smooth muscle, mesangial, and neuroblast cell proliferation. Reason: Mature ET-1 stimulates proliferation of vascular smooth muscle cells, fibroblasts, and mesangial cells downstream of EDNRA/EDNRB activation (confirmed in human cells in PMID:1917960 and PMID:17078114); retained as a non-core downstream cellular response. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of xenobiotic-induced endothelial EDN1 expression as a direct role in response to xenobiotic stimulus. Reason: Orthology projection (GO_REF:0000107) reflects transcriptional induction or release of EDN1 when endothelial or hepatic cells are exposed to xenobiotics rather than EDN1 directly mediating xenobiotic detoxification or sensing. |
| GO:0010193 response to ozone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of ozone-induced pulmonary EDN1 upregulation as a direct functional role in response to ozone. Reason: Orthology projection (GO_REF:0000107) reflects elevated pulmonary and circulating Edn1 mRNA/peptide levels following inhalation of ozone rather than EDN1 acting as an ozone sensor or detoxifying factor. |
| GO:0010460 positive regulation of heart rate | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | KEEP AS NON CORE | Summary: Downstream chronotropic effect of systemic endothelin-1 administration on heart rate. Reason: In PMID:2649896, intravenous ET-1 bolus produces an initial transient vasodilatory/baroreflex tachycardia followed by sustained hypertension; retained as a non-core systemic hemodynamic response. |
| GO:0010467 gene expression | IEA GO_REF:0000107 | MODIFY | Summary: Broad gene expression annotation that should be refined to positive and negative regulation of transcription by RNA polymerase II. Reason: Secreted ET-1 is not part of the core transcriptional machinery; instead, EDN1 receptor signaling regulates target gene transcription (GO:0045944 positive regulation of transcription by RNA polymerase II and GO:0000122 negative regulation of transcription by RNA polymerase II). |
| GO:0010595 positive regulation of endothelial cell migration | TAS PMID:8999856 Permissive role of nitric oxide in endothelin-induced migrat... | KEEP AS NON CORE | Summary: Paracrine/autocrine promotion of endothelial cell migration via EDNRB signaling. Reason: ET-1 stimulates migration and angiogenic sprouting of vascular endothelial cells primarily via EDNRB activation (PMID:8999856); retained as a non-core vascular remodeling role. |
| GO:0010613 positive regulation of cardiac muscle hypertrophy | IDA PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | ACCEPT | Summary: Downstream trophic role of endothelin-1 in promoting cardiomyocyte hypertrophy via Gq/11 and MAPK signaling. Reason: In PMID:12847114, ET-1 stimulation of cardiomyocytes activates Gq/11, ERK, and JNK cascades to induce hypertrophic gene expression, increased cell size, and sarcomeric assembly. |
| GO:0010629 negative regulation of gene expression | IDA PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | KEEP AS NON CORE | Summary: Downstream repression of target gene expression (such as endothelial NOS3) following endothelin receptor activation. Reason: In PMID:16820593, ET-1 signaling activates PKCdelta to downregulate endothelial nitric oxide synthase (eNOS/NOS3) mRNA and protein expression; retained as a non-core downstream transcriptional effect. |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream repression of target gene expression (such as endothelial NOS3) following endothelin receptor activation. Reason: In PMID:16820593, ET-1 signaling activates PKCdelta to downregulate endothelial nitric oxide synthase (eNOS/NOS3) mRNA and protein expression; retained as a non-core downstream transcriptional effect. |
| GO:0014033 neural crest cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of paracrine endothelin-1 signaling in cranial and cardiac neural crest cell differentiation. Reason: Epithelial ET-1 signals through EDNRA on cranial and cardiac neural crest cells to direct craniofacial and pharyngeal arch differentiation in vertebrate embryos (projected via GO_REF:0000107); retained as a non-core developmental process. |
| GO:0014034 neural crest cell fate commitment | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of paracrine endothelin-1 in patterning neural crest cell fate commitment in the pharyngeal arches. Reason: ET-1/EDNRA signaling establishes ventral pharyngeal arch identity (Dlx5/Dlx6 induction) and fate commitment of cranial neural crest cells in mouse development (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0014823 response to activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of exercise/activity-induced changes in vascular EDN1 expression as a direct role in response to activity. Reason: Orthology projection (GO_REF:0000107) reflects changes in tissue or plasma Edn1 expression in response to physical activity rather than EDN1 directly mediating the physiological activity response pathway. |
| GO:0014824 artery smooth muscle contraction | IDA PMID:8982507 Characterization of endothelin receptors in the human umbili... | ACCEPT | Summary: Core physiological function of mature endothelin-1 in evoking sustained arterial smooth muscle contraction. Reason: Mature ET-1 acts directly on vascular smooth muscle EDNRA (and EDNRB) receptors to trigger potent, long-lasting contraction of isolated human and mammalian arteries (PMID:8982507, PMID:1725334). |
| GO:0014824 artery smooth muscle contraction | IEA GO_REF:0000107 | ACCEPT | Summary: Core physiological function of mature endothelin-1 in evoking sustained arterial smooth muscle contraction. Reason: Mature ET-1 acts directly on vascular smooth muscle EDNRA (and EDNRB) receptors to trigger potent, long-lasting contraction of isolated human and mammalian arteries (PMID:8982507, PMID:1725334). |
| GO:0014824 artery smooth muscle contraction | TAS PMID:1725334 Functional and autoradiographic studies of endothelin-1 and ... | ACCEPT | Summary: Core physiological function of mature endothelin-1 in evoking sustained arterial smooth muscle contraction. Reason: Mature ET-1 acts directly on vascular smooth muscle EDNRA (and EDNRB) receptors to trigger potent, long-lasting contraction of isolated human and mammalian arteries (PMID:8982507, PMID:1725334). |
| GO:0014826 vein smooth muscle contraction | IBA GO_REF:0000033 | ACCEPT | Summary: Core physiological function of mature endothelin-1 in evoking venous smooth muscle contraction. Reason: Mature ET-1 potently contracts isolated human saphenous and internal mammary veins via smooth muscle endothelin receptors (PMID:9422810, GO_REF:0000033). |
| GO:0014826 vein smooth muscle contraction | IDA PMID:9422810 Endothelin converting enzyme (ECE) activity in human vascula... | ACCEPT | Summary: Core physiological function of mature endothelin-1 in evoking venous smooth muscle contraction. Reason: Mature ET-1 potently contracts isolated human saphenous and internal mammary veins via smooth muscle endothelin receptors (PMID:9422810, GO_REF:0000033). |
| GO:0019229 regulation of vasoconstriction | IEA GO_REF:0000002 | MODIFY | Summary: InterPro domain mapping to regulation of vasoconstriction refined to direct vasoconstriction and blood pressure regulation. Reason: InterPro2GO (GO_REF:0000002) maps the conserved endothelin/sarafotoxin domain to generic GO:0019229 (regulation of vasoconstriction), whereas mature ET-1 is a direct vasoconstrictor agonist that executes vasoconstriction (GO:0042310) and regulates systemic arterial blood pressure by endothelin (GO:0003100). Proposed replacements: regulation of systemic arterial blood pressure by endothelin vasoconstriction |
| GO:0019722 calcium-mediated signaling | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | MODIFY | Summary: Calcium signaling/homeostasis annotation (calcium-mediated signaling) that should be refined to positive regulation of cytosolic calcium ion concentration. Reason: ET-1 acts as an extracellular GPCR agonist that triggers acute IP3-dependent Ca2+ release and Ca2+ influx to elevate cytosolic Ca2+ (GO:0007204 positive regulation of cytosolic calcium ion concentration, already present on EDN1) rather than functioning as a calcium channel or basal homeostasis regulator (PMID:10770212). Proposed replacements: positive regulation of cytosolic calcium ion concentration |
| GO:0023019 signal transduction involved in regulation of gene expression | IDA PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | MODIFY | Summary: Precomposed signal transduction involved in regulation of gene expression term that should be refined to endothelin receptor signaling pathway. Reason: GO:0023019 (signal transduction involved in regulation of gene expression) is a precomposed term; in PMID:16820593, ET-1 initiates the endothelin receptor signaling pathway (GO:0086100) and phospholipase C/PKC cascade (GO:0160135), which downstream represses eNOS expression. Proposed replacements: endothelin receptor signaling pathway phospholipase C-activating endothelin receptor signaling pathway Context of precomposed term: module endothelin_receptor_signaling |
| GO:0030072 peptide hormone secretion | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | MODIFY | Summary: Role of endothelin-1 in stimulating GnRH hormone release behaves as positive regulation rather than executing exocytosis. Reason: In PMID:10770212, exogenous ET-1 stimulates GnRH release from FNC-B4 neurons via endothelin receptors; as an extracellular ligand, EDN1 positively regulates hormone secretion (GO:0046887) rather than forming the exocytic machinery. Proposed replacements: positive regulation of hormone secretion |
| GO:0030133 transport vesicle | TAS Reactome:R-HSA-8877620 | KEEP AS NON CORE | Summary: Intracellular trafficking localization of big ET-1 and mature ET-1 within constitutive secretory transport vesicles. Reason: Following furin-mediated cleavage of preproendothelin-1 in the trans-Golgi network, big ET-1 and ECE-1 co-localize in constitutive secretory transport vesicles en route to the plasma membrane (Reactome:R-HSA-8877620); retained as a non-core biosynthetic trafficking compartment. |
| GO:0030185 nitric oxide transport | IDA PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | MARK AS OVER ANNOTATED | Summary: Indirect downstream or background pathway annotation (nitric oxide transport) from PMID:16820593. Reason: PMID:16820593 showed that ET-1 activates PKCdelta to repress eNOS (NOS3) expression and reduce endothelial NO levels; GO:0030185 (nitric oxide transport) is an indirect or background physiological process rather than a direct function of EDN1. |
| GO:0030195 negative regulation of blood coagulation | TAS PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | MARK AS OVER ANNOTATED | Summary: Indirect downstream or background pathway annotation (negative regulation of blood coagulation) from PMID:16820593. Reason: PMID:16820593 showed that ET-1 activates PKCdelta to repress eNOS (NOS3) expression and reduce endothelial NO levels; GO:0030195 (negative regulation of blood coagulation) is an indirect or background physiological process rather than a direct function of EDN1. |
| GO:0030335 positive regulation of cell migration | IDA PMID:9696419 The involvement of protein kinase G in stimulation of neutro... | KEEP AS NON CORE | Summary: Downstream stimulation of cell migration in target leukocytes, endothelial cells, and smooth muscle cells. Reason: In PMID:9696419, exogenous ET-1 stimulates human neutrophil migration (chemokinesis) via endothelin receptor activation; retained as a non-core downstream cellular response. |
| GO:0030593 neutrophil chemotaxis | IDA NOT PMID:9696419 The involvement of protein kinase G in stimulation of neutro... | KEEP AS NON CORE | Summary: Context-specific negative annotation on directional neutrophil chemotaxis from PMID:9696419. Reason: PMID:9696419 examined endothelin-stimulated human neutrophil migration (chemokinesis vs. chemotaxis); retained as non-core experimental context alongside GO:0030335 (positive regulation of cell migration). |
| GO:0030878 thyroid gland development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of pharyngeal arch endothelin-1 signaling in thyroid gland morphogenesis. Reason: Loss of Edn1 in mouse embryos impairs pharyngeal arch patterning and secondary morphogenesis of the developing thyroid gland (projected via GO_REF:0000107); retained as a non-core developmental phenotype. |
| GO:0031175 neuron projection development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of paracrine endothelin-1 in promoting sympathetic and peripheral neuron projection development. Reason: Vascular-derived ET-1 promotes neurite outgrowth and projection development of innervating sympathetic neurons in vertebrate development (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0031394 positive regulation of prostaglandin biosynthetic process | IDA PMID:9492062 Prostaglandin endoperoxide synthase-2 contributes to the end... | KEEP AS NON CORE | Summary: Downstream stimulation of arachidonic acid release and prostaglandin biosynthesis via endothelin receptor activation. Reason: In PMID:9492062, ET-1 binding to endothelin receptors activates phospholipase A2 and cyclooxygenase-dependent prostaglandin synthesis in target cells; retained as a non-core downstream signaling effect. |
| GO:0031707 endothelin A receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a high-affinity orthosteric agonist of the endothelin A receptor (EDNRA). Reason: Mature ET-1 binds human EDNRA with sub-nanomolar affinity to activate Gq/11-coupled vascular smooth muscle contraction and mitogenic signaling (PMID:10770212, PMID:8982507). Supporting Evidence: PMID:10770212 Experiments with radiolabeled ET-1 and ET-3 strongly indicated the presence of two classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies, using selective analogs, indicated that these two classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression. |
| GO:0031707 endothelin A receptor binding | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a high-affinity orthosteric agonist of the endothelin A receptor (EDNRA). Reason: Mature ET-1 binds human EDNRA with sub-nanomolar affinity to activate Gq/11-coupled vascular smooth muscle contraction and mitogenic signaling (PMID:10770212, PMID:8982507). Supporting Evidence: PMID:10770212 Experiments with radiolabeled ET-1 and ET-3 strongly indicated the presence of two classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies, using selective analogs, indicated that these two classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression. |
| GO:0031707 endothelin A receptor binding | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a high-affinity orthosteric agonist of the endothelin A receptor (EDNRA). Reason: Mature ET-1 binds human EDNRA with sub-nanomolar affinity to activate Gq/11-coupled vascular smooth muscle contraction and mitogenic signaling (PMID:10770212, PMID:8982507). Supporting Evidence: PMID:10770212 Experiments with radiolabeled ET-1 and ET-3 strongly indicated the presence of two classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies, using selective analogs, indicated that these two classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44ERK1 expression. |
| GO:0031708 endothelin B receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a high-affinity orthosteric agonist of the endothelin B receptor (EDNRB). Reason: Mature ET-1 binds human EDNRB with sub-nanomolar affinity equipotent to ET-2 and ET-3, triggering intracellular Ca2+ mobilization (PMID:1713452, PMID:10770212). Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. |
| GO:0031708 endothelin B receptor binding | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a high-affinity orthosteric agonist of the endothelin B receptor (EDNRB). Reason: Mature ET-1 binds human EDNRB with sub-nanomolar affinity equipotent to ET-2 and ET-3, triggering intracellular Ca2+ mobilization (PMID:1713452, PMID:10770212). Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. |
| GO:0031708 endothelin B receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a high-affinity orthosteric agonist of the endothelin B receptor (EDNRB). Reason: Mature ET-1 binds human EDNRB with sub-nanomolar affinity equipotent to ET-2 and ET-3, triggering intracellular Ca2+ mobilization (PMID:1713452, PMID:10770212). Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. |
| GO:0031708 endothelin B receptor binding | IPI PMID:1713452 Cloning and functional expression of human cDNA for the ETB ... | ACCEPT | Summary: Core molecular function of mature endothelin-1 as a high-affinity orthosteric agonist of the endothelin B receptor (EDNRB). Reason: Mature ET-1 binds human EDNRB with sub-nanomolar affinity equipotent to ET-2 and ET-3, triggering intracellular Ca2+ mobilization (PMID:1713452, PMID:10770212). Supporting Evidence: PMID:1713452 COS cells transiently transfected with the cloned cDNA expressed specific, high-affinity binding sites for endothelin isopeptides and responded to the peptides with a transient increase of [Ca2+]i; endothelin-1 and endothelin-3 exhibited approximately equal potencies both in displacing 125I-labeled endothelin-1 binding and in eliciting [Ca2+]i transients. |
| GO:0032308 positive regulation of prostaglandin secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream stimulation of prostaglandin release from vascular and renal target cells following endothelin receptor activation. Reason: ET-1 receptor activation triggers Ca2+- and PLA2-dependent synthesis and secretion of prostaglandins (such as PGI2 and PGE2) in mammalian tissues (projected via GO_REF:0000107); retained as a non-core downstream paracrine response. |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of lipopolysaccharide-induced endothelial EDN1 expression as a direct role in response to lipopolysaccharide. Reason: Orthology projection (GO_REF:0000107) reflects endotoxin/LPS-stimulated transcriptional upregulation and release of Edn1 from endothelial cells and macrophages during sepsis rather than EDN1 acting as an LPS receptor or innate immune sensor. |
| GO:0033093 Weibel-Palade body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulated endothelial storage granule localization of endothelin-1 within Weibel-Palade bodies. Reason: In vascular endothelial cells, mature ET-1 and big ET-1 are packaged alongside von Willebrand factor into Weibel-Palade bodies for regulated exocytosis upon mechanical or agonist stimulation; retained as a non-core storage compartment upstream of extracellular hormone function. |
| GO:0033574 response to testosterone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of androgen-regulated EDN1 expression as a direct role in response to testosterone. Reason: Orthology projection (GO_REF:0000107) reflects changes in endothelial or gonadal Edn1 transcript/peptide levels following testosterone treatment rather than EDN1 directly mediating androgen receptor signaling. |
| GO:0034392 negative regulation of smooth muscle cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream anti-apoptotic survival signaling of endothelin-1 in vascular smooth muscle cells. Reason: ET-1 activation of EDNRA/EDNRB stimulates PI3K/Akt and MAPK survival pathways that inhibit apoptosis in vascular smooth muscle cells (projected via GO_REF:0000107); retained as a non-core downstream cellular effect. |
| GO:0034696 response to prostaglandin F | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of prostaglandin F2alpha-induced luteal EDN1 expression as a direct role in response to prostaglandin F. Reason: Orthology projection (GO_REF:0000107) reflects transcriptional induction of ovarian/luteal Edn1 by prostaglandin F2alpha during luteolysis rather than EDN1 functioning as a prostaglandin receptor or direct transducer. |
| GO:0035050 embryonic heart tube development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of paracrine endothelin-1 signaling in embryonic heart tube and pharyngeal arch patterning. Reason: Endocardial and pharyngeal epithelial ET-1 signaling via EDNRA contributes to cardiogenic mesoderm and neural crest patterning during embryonic heart tube development in mouse models (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0035094 response to nicotine | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of nicotine-induced endothelial EDN1 upregulation as a direct role in response to nicotine. Reason: Orthology projection (GO_REF:0000107) reflects elevated endothelial Edn1 mRNA expression and plasma ET-1 levels following nicotine exposure rather than EDN1 acting as a nicotinic receptor component. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000107 | MODIFY | Summary: Broad intracellular signal transduction annotation that should be refined to endothelin receptor signaling pathway. Reason: GO:0035556 (intracellular signal transduction) is true but less specific than GO:0086100 (endothelin receptor signaling pathway) and GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway), which are directly supported for EDN1. |
| GO:0035994 response to muscle stretch | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of stretch-induced endothelial and cardiac EDN1 transcription as a direct role in response to muscle stretch. Reason: Orthology projection (GO_REF:0000107) reflects mechanical stretch-induced transcription and release of Edn1 from endothelial cells and cardiomyocytes rather than EDN1 acting as a primary mechanosensor. |
| GO:0042045 epithelial fluid transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream paracrine modulation of renal and pulmonary epithelial fluid and electrolyte transport. Reason: Locally secreted ET-1 acts on EDNRB in renal collecting duct and epithelial cells to inhibit water and sodium reabsorption and modulate epithelial fluid transport (projected via GO_REF:0000107); retained as a non-core physiological role. |
| GO:0042310 vasoconstriction | IDA PMID:11410113 Effect of adrenomedullin on the production of endothelin-1 a... | ACCEPT | Summary: Core physiological function of mature endothelin-1 as a potent endogenous vasoconstrictor peptide. Reason: Mature ET-1 is one of the most potent known endogenous vasoconstrictors, acting directly on vascular smooth muscle EDNRA and EDNRB receptors to constrict resistance and conduit blood vessels in vivo and ex vivo (PMID:2649896, PMID:11410113). |
| GO:0042310 vasoconstriction | IDA PMID:2649896 The human endothelin family: three structurally and pharmaco... | ACCEPT | Summary: Core physiological function of mature endothelin-1 as a potent endogenous vasoconstrictor peptide. Reason: Mature ET-1 is one of the most potent known endogenous vasoconstrictors, acting directly on vascular smooth muscle EDNRA and EDNRB receptors to constrict resistance and conduit blood vessels in vivo and ex vivo (PMID:2649896, PMID:11410113). |
| GO:0042310 vasoconstriction | IEA GO_REF:0000107 | ACCEPT | Summary: Core physiological function of mature endothelin-1 as a potent endogenous vasoconstrictor peptide. Reason: Mature ET-1 is one of the most potent known endogenous vasoconstrictors, acting directly on vascular smooth muscle EDNRA and EDNRB receptors to constrict resistance and conduit blood vessels in vivo and ex vivo (PMID:2649896, PMID:11410113). |
| GO:0042482 positive regulation of odontogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of pharyngeal arch endothelin-1 signaling in promoting tooth morphogenesis (odontogenesis). Reason: Paracrine ET-1/EDNRA signaling in first pharyngeal arch ectomesenchyme promotes odontogenesis during craniofacial development in rodent models (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0042554 superoxide anion generation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream stimulation of NADPH oxidase-dependent superoxide anion generation in vascular cells following endothelin receptor activation. Reason: Chronic ET-1 stimulation of vascular smooth muscle and endothelial cells activates NADPH oxidases to increase superoxide production in vascular disease models (projected via GO_REF:0000107); retained as a non-core downstream signaling effect. |
| GO:0043200 response to amino acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of amino acid-modulated EDN1 expression as a direct role in response to amino acid. Reason: Orthology projection (GO_REF:0000107) reflects altered endothelial or renal Edn1 expression in response to dietary amino acid or homocysteine levels rather than EDN1 functioning as an amino acid sensor. |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | ACCEPT | Summary: Downstream activation of the ERK1/2 MAPK cascade following endothelin receptor stimulation. Reason: Binding of mature ET-1 to EDNRA and EDNRB activates PKC- and Ras/Raf-dependent phosphorylation of ERK1/2 MAPKs in human target cells (PMID:10770212). |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | ACCEPT | Summary: Downstream activation of the ERK1/2 MAPK cascade following endothelin receptor stimulation. Reason: Binding of mature ET-1 to EDNRA and EDNRB activates PKC- and Ras/Raf-dependent phosphorylation of ERK1/2 MAPKs in human target cells (PMID:12847114). |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | IDA PMID:17078114 Mechanisms of endothelin 1-stimulated proliferation in color... | KEEP AS NON CORE | Summary: Downstream activation of the PI3K/Akt signaling cascade by endothelin-1 receptor stimulation. Reason: In PMID:17078114, ET-1 stimulation of endothelin receptors activates phosphatidylinositol 3-kinase (PI3K) and Akt/PKB phosphorylation to promote cell survival and proliferation; retained as a non-core downstream intracellular cascade. |
| GO:0044321 response to leptin | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of leptin-induced endothelial EDN1 expression as a direct role in response to leptin. Reason: Orthology projection (GO_REF:0000107) reflects leptin-stimulated transcription and release of Edn1 in vascular endothelial cells rather than EDN1 functioning as a component of the leptin receptor signaling pathway. |
| GO:0044751 cellular response to human chorionic gonadotropin stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of hCG-induced ovarian EDN1 expression as a direct role in cellular response to human chorionic gonadotropin stimulus. Reason: Orthology projection (GO_REF:0000107) reflects gonadotropin (hCG)-induced Edn1 mRNA expression in periovulatory ovarian follicles rather than EDN1 directly transducing LHCGR receptor signaling. |
| GO:0045178 basal part of cell | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Polarized basolateral localization of endothelin-1 secretion in vascular endothelial and epithelial cells. Reason: Endothelial and polarized epithelial cells preferentially secrete mature ET-1 across the basal/abluminal plasma membrane toward underlying vascular smooth muscle cells (projected via GO_REF:0000107); retained as a non-core subcellular trafficking localization. |
| GO:0045321 leukocyte activation | TAS PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | MARK AS OVER ANNOTATED | Summary: Indirect downstream or background pathway annotation (leukocyte activation) from PMID:16820593. Reason: PMID:16820593 showed that ET-1 activates PKCdelta to repress eNOS (NOS3) expression and reduce endothelial NO levels; GO:0045321 (leukocyte activation) is an indirect or background physiological process rather than a direct function of EDN1. |
| GO:0045429 positive regulation of nitric oxide biosynthetic process | TAS PMID:8999856 Permissive role of nitric oxide in endothelin-induced migrat... | KEEP AS NON CORE | Summary: Endothelial EDNRB-mediated stimulation of nitric oxide synthase activity and nitric oxide production. Reason: Binding of mature ET-1 to endothelial EDNRB receptors triggers Ca2+/calmodulin- and Akt-dependent activation of endothelial nitric oxide synthase (eNOS/NOS3) to produce vasodilatory nitric oxide (PMID:8999856); retained as a non-core counter-regulatory vascular pathway. |
| GO:0045793 positive regulation of cell size | IDA PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | KEEP AS NON CORE | Summary: Downstream trophic induction of cardiomyocyte cell enlargement (hypertrophy) by endothelin-1. Reason: In PMID:12847114, ET-1 receptor stimulation increases cardiomyocyte surface area and protein content via MAPK/JNK activation; retained as a non-core cellular growth outcome. |
| GO:0045840 positive regulation of mitotic nuclear division | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | MODIFY | Summary: Over-specific mitotic nuclear division annotation from a thymidine-incorporation cell proliferation assay. Reason: PMID:10770212 measured [3H]thymidine incorporation (DNA synthesis and cell population proliferation) in FNC-B4 cells rather than mitotic nuclear division specifically; GO:0008284 (positive regulation of cell population proliferation) accurately captures this finding. Proposed replacements: positive regulation of cell population proliferation |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:24117217 The miR-19a/b family positively regulates cardiomyocyte hype... | KEEP AS NON CORE | Summary: Downstream transcriptional activation of RNA polymerase II-transcribed target genes following endothelin receptor signaling. Reason: ET-1 binding to cell-surface EDNRA/EDNRB activates Ca2+, PKC, and MAPK cascades that stimulate transcription factors (such as GATA4, NFAT, and AP-1) to upregulate RNA polymerase II target genes (PMID:24117217); retained as a non-core downstream signaling effect. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream transcriptional activation of RNA polymerase II-transcribed target genes following endothelin receptor signaling. Reason: ET-1 binding to cell-surface EDNRA/EDNRB activates Ca2+, PKC, and MAPK cascades that stimulate transcription factors (such as GATA4, NFAT, and AP-1) to upregulate RNA polymerase II target genes (PMID:24117217); retained as a non-core downstream signaling effect. |
| GO:0045987 positive regulation of smooth muscle contraction | IBA GO_REF:0000033 | ACCEPT | Summary: Core physiological role of mature endothelin-1 in positively regulating vascular and non-vascular smooth muscle contraction. Reason: Mature ET-1 activates Gq/11-coupled EDNRA and EDNRB on smooth muscle cells to elevate cytosolic Ca2+ and activate RhoA/ROCK calcium sensitization, potently stimulating smooth muscle contraction (GO_REF:0000033, PMID:8982507). |
| GO:0045987 positive regulation of smooth muscle contraction | IEA GO_REF:0000107 | ACCEPT | Summary: Core physiological role of mature endothelin-1 in positively regulating vascular and non-vascular smooth muscle contraction. Reason: Mature ET-1 activates Gq/11-coupled EDNRA and EDNRB on smooth muscle cells to elevate cytosolic Ca2+ and activate RhoA/ROCK calcium sensitization, potently stimulating smooth muscle contraction (GO_REF:0000033, PMID:8982507). |
| GO:0046330 positive regulation of JNK cascade | IDA PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | KEEP AS NON CORE | Summary: Downstream activation of the stress-activated JNK MAPK cascade in endothelin-1-stimulated cardiomyocytes. Reason: In PMID:12847114, ET-1 stimulation of cardiomyocytes activates c-Jun N-terminal kinase (JNK) phosphorylation downstream of endothelin receptors; retained as a non-core intracellular effector branch. |
| GO:0046887 positive regulation of hormone secretion | IDA PMID:10770212 Expression and biological effects of endothelin-1 in human g... | KEEP AS NON CORE | Summary: Paracrine/neuroendocrine stimulation of peptide hormone (GnRH) secretion by endothelin-1. Reason: In PMID:10770212, exogenous ET-1 acts on endothelin receptors in human FNC-B4 GnRH-secreting neuroblasts to stimulate gonadotropin-releasing hormone secretion; retained as a non-core neuroendocrine regulatory role. |
| GO:0046888 negative regulation of hormone secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Paracrine inhibition of hormone (such as renin or prolactin) secretion via endothelin receptor signaling. Reason: ET-1 acts on juxtaglomerular and pituitary target cells to inhibit renin or prolactin secretion in mammalian physiological models (projected via GO_REF:0000107); retained as a non-core endocrine regulatory effect. |
| GO:0048018 receptor ligand activity | IEA GO_REF:0000107 | MODIFY | Summary: Broad or imprecise receptor ligand activity annotation that should be refined to hormone activity and specific endothelin A/B receptor binding. Reason: GO:0048018 (receptor ligand activity) is less precise than GO:0005179 (hormone activity), GO:0031707 (endothelin A receptor binding), and GO:0031708 (endothelin B receptor binding), which are directly supported for EDN1. |
| GO:0048237 rough endoplasmic reticulum lumen | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Biosynthetic localization of nascent preproendothelin-1 in the rough endoplasmic reticulum lumen. Reason: Newly synthesized preproendothelin-1 carries an N-terminal signal peptide (residues 1-17) that directs cotranslational translocation into the rough endoplasmic reticulum lumen prior to proteolytic processing; retained as a non-core biosynthetic compartment. |
| GO:0048661 positive regulation of smooth muscle cell proliferation | IDA PMID:10393673 Endothelin-1 potentiates human smooth muscle cell growth to ... | ACCEPT | Summary: Downstream mitogenic role of endothelin-1 in stimulating vascular smooth muscle cell proliferation. Reason: In PMID:10393673, mature ET-1 stimulates proliferation of human vascular smooth muscle cells via EDNRA/EDNRB activation, a well-established trophic action of ET-1 in vascular remodeling. |
| GO:0048675 axon extension | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of vascular-derived endothelin-1 in promoting sympathetic axon extension. Reason: Vascular smooth muscle- and endothelial-derived ET-1 promotes axon extension of sympathetic neurons innervating blood vessels during development (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0050850 positive regulation of calcium-mediated signaling | IDA PMID:1917960 Effects of endothelins on signal transduction and proliferat... | MODIFY | Summary: Calcium signaling/homeostasis annotation (positive regulation of calcium-mediated signaling) that should be refined to positive regulation of cytosolic calcium ion concentration. Reason: ET-1 acts as an extracellular GPCR agonist that triggers acute IP3-dependent Ca2+ release and Ca2+ influx to elevate cytosolic Ca2+ (GO:0007204 positive regulation of cytosolic calcium ion concentration, already present on EDN1) rather than functioning as a calcium channel or basal homeostasis regulator (PMID:1917960). Proposed replacements: positive regulation of cytosolic calcium ion concentration |
| GO:0051248 negative regulation of protein metabolic process | IDA PMID:19767294 Krüppel-like factor 15 regulates BMPER in endothelial cells. | KEEP AS NON CORE | Summary: Downstream negative regulation of target protein levels in endothelin-1-treated cells. Reason: In PMID:19767294, ET-1 receptor signaling reduces abundance of specific target proteins in endothelial cells; retained as a non-core downstream cellular consequence. |
| GO:0051899 membrane depolarization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream plasma membrane depolarization evoked by endothelin receptor activation in vascular smooth muscle cells. Reason: ET-1 binding to smooth muscle EDNRA activates Ca2+-activated chloride channels and non-selective cation channels while inhibiting K+ channels, producing membrane depolarization that opens voltage-gated L-type Ca2+ channels (projected via GO_REF:0000107); retained as a non-core downstream electrophysiological effect. |
| GO:0060070 canonical Wnt signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of indirect downstream transcriptional cross-talk as a direct role of endothelin-1 in the canonical Wnt signaling pathway. Reason: Mature ET-1 is an orthosteric agonist of class A GPCRs (EDNRA/EDNRB), not a Frizzled/LRP5/6 ligand or core component of the canonical Wnt/beta-catenin signaling pathway; secondary cross-talk or Wnt-regulated Edn1 expression in rodent models (projected via GO_REF:0000107) represents an indirect over-annotation. |
| GO:0060137 maternal process involved in parturition | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Physiological role of uteroplacental endothelin-1 in myometrial contraction during parturition. Reason: Uterine and amniotic ET-1 levels rise at term and stimulate myometrial smooth muscle contraction during parturition in rodent models (projected via GO_REF:0000107); retained as a non-core reproductive physiological role. |
| GO:0060298 positive regulation of sarcomere organization | IMP PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | KEEP AS NON CORE | Summary: Downstream trophic promotion of sarcomere assembly in endothelin-1-stimulated cardiomyocytes. Reason: In PMID:12847114, ET-1 stimulation of cardiomyocytes induces myofibrillar and sarcomeric organization via ERK/JNK signaling during cardiomyocyte hypertrophy; retained as a non-core downstream cellular response. |
| GO:0060385 axonogenesis involved in innervation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of vascular endothelin-1 as a tropic cue for sympathetic axonogenesis involved in target organ innervation. Reason: ET-1 secreted by developing arteries directs sympathetic axonogenesis from the superior cervical ganglion to innervate target organs in mouse embryos (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0061051 positive regulation of cell growth involved in cardiac muscle cell development | IDA PMID:24117217 The miR-19a/b family positively regulates cardiomyocyte hype... | KEEP AS NON CORE | Summary: Downstream trophic stimulation of cardiomyocyte growth during cardiac muscle development and hypertrophy. Reason: In PMID:24117217, ET-1 receptor signaling activates hypertrophic transcription factors and promotes cardiomyocyte cell growth; retained as a non-core downstream trophic response. |
| GO:0061051 positive regulation of cell growth involved in cardiac muscle cell development | IGI PMID:24117217 The miR-19a/b family positively regulates cardiomyocyte hype... | KEEP AS NON CORE | Summary: Downstream trophic stimulation of cardiomyocyte growth during cardiac muscle development and hypertrophy. Reason: In PMID:24117217, ET-1 receptor signaling activates hypertrophic transcription factors and promotes cardiomyocyte cell growth; retained as a non-core downstream trophic response. |
| GO:0061626 pharyngeal arch artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of pharyngeal arch endothelin-1 signaling in pharyngeal arch artery morphogenesis. Reason: Paracrine ET-1/EDNRA signaling between pharyngeal arch epithelium and cardiac neural crest mesenchyme is required for normal remodeling of the pharyngeal arch arteries into the aortic arch and great vessels in mouse embryos (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0070101 positive regulation of chemokine-mediated signaling pathway | IDA PMID:17178876 Endothelins induce CCR7 expression by breast tumor cells via... | KEEP AS NON CORE | Summary: Downstream amplification of chemokine-mediated signaling and leukocyte recruitment by endothelin-1. Reason: In PMID:17178876, ET-1 stimulation upregulates chemokine expression and potentiates chemokine-mediated signaling in target cells; retained as a non-core downstream inflammatory effect. |
| GO:0070294 renal sodium ion absorption | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Paracrine regulation of renal tubular sodium ion absorption by intrarenal endothelin-1. Reason: Renal medullary ET-1 acts via tubular EDNRB receptors to regulate epithelial sodium channel (ENaC) and Na+/K+-ATPase activity, modulating renal sodium absorption and natriuresis (projected via GO_REF:0000107); retained as a non-core renal physiological role. |
| GO:0070301 cellular response to hydrogen peroxide | IDA PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati... | MARK AS OVER ANNOTATED | Summary: Over-annotation of oxidative stress-induced EDN1 expression or co-treatment in PMID:30990108 as a direct role in cellular response to hydrogen peroxide. Reason: In PMID:30990108, hydrogen peroxide/oxidative stress alters cellular signaling and EDN1 levels, but mature ET-1 is a vasoactive GPCR hormone rather than a direct mediator of the cellular response to hydrogen peroxide. |
| GO:0070371 ERK1 and ERK2 cascade | IEA GO_REF:0000107 | MODIFY | Summary: Broad ERK1 and ERK2 cascade annotation that should be refined to positive regulation of MAPK cascade. Reason: As an extracellular GPCR ligand, ET-1 positively regulates the MAPK/ERK cascade (GO:0043410, already present on EDN1 via IDA in PMID:10770212 and PMID:12847114) rather than acting as an intracellular kinase component. Proposed replacements: positive regulation of MAPK cascade |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000107 | MODIFY | Summary: Calcium signaling/homeostasis annotation (calcium ion transmembrane transport) that should be refined to positive regulation of cytosolic calcium ion concentration. Reason: ET-1 acts as an extracellular GPCR agonist that triggers acute IP3-dependent Ca2+ release and Ca2+ influx to elevate cytosolic Ca2+ (GO:0007204 positive regulation of cytosolic calcium ion concentration, already present on EDN1) rather than functioning as a calcium channel or basal homeostasis regulator (GO_REF:0000107). Proposed replacements: positive regulation of cytosolic calcium ion concentration |
| GO:0071277 cellular response to calcium ion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of calcium-modulated endothelial EDN1 release as a direct role in cellular response to calcium ion. Reason: Orthology projection (GO_REF:0000107) conflates Ca2+-dependent regulated exocytosis of ET-1 or downstream GPCR-evoked Ca2+ mobilization (GO:0007204) with EDN1 functioning as a direct calcium-sensing effector. |
| GO:0071346 cellular response to type II interferon | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of interferon-gamma-stimulated endothelial EDN1 expression as a direct role in cellular response to type II interferon. Reason: Orthology projection (GO_REF:0000107) reflects transcriptional upregulation of endothelial Edn1 by interferon-gamma (commonly in synergy with TNF-alpha) rather than EDN1 acting as a component of the IFNGR/JAK-STAT pathway. |
| GO:0071347 cellular response to interleukin-1 | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of interleukin-1-induced endothelial EDN1 transcription as a direct role in cellular response to interleukin-1. Reason: Orthology projection (GO_REF:0000107) reflects pro-inflammatory IL-1-stimulated transcription and secretion of Edn1 in vascular endothelial cells rather than EDN1 directly transducing IL-1 receptor signaling. |
| GO:0071356 cellular response to tumor necrosis factor | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of TNF-alpha-induced endothelial EDN1 expression as a direct role in cellular response to tumor necrosis factor. Reason: Orthology projection (GO_REF:0000107) reflects TNF-alpha-stimulated transcription and release of Edn1 from vascular endothelium rather than EDN1 acting as a direct transducer of TNFR signaling. |
| GO:0071372 cellular response to follicle-stimulating hormone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of FSH-regulated ovarian EDN1 expression as a direct role in cellular response to follicle-stimulating hormone stimulus. Reason: Orthology projection (GO_REF:0000107) reflects gonadotropin (FSH)-regulated Edn1 mRNA expression in ovarian granulosa cells rather than EDN1 directly mediating FSHR signaling. |
| GO:0071373 cellular response to luteinizing hormone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of LH-induced ovarian EDN1 expression as a direct role in cellular response to luteinizing hormone stimulus. Reason: Orthology projection (GO_REF:0000107) reflects ovulatory LH surge-induced Edn1 transcription in ovarian follicles rather than EDN1 acting as an intracellular transducer of LHCGR signaling. |
| GO:0071375 cellular response to peptide hormone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of peptide hormone-induced EDN1 expression (such as angiotensin II or insulin) as a direct role in cellular response to peptide hormone stimulus. Reason: Orthology projection (GO_REF:0000107) reflects transcriptional induction of endothelial Edn1 by upstream peptide hormones (such as angiotensin II or vasopressin) rather than EDN1 acting as an intracellular effector of those hormone receptors. |
| GO:0071385 cellular response to glucocorticoid stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of glucocorticoid-induced EDN1 expression as a direct role in cellular response to glucocorticoid stimulus. Reason: Orthology projection (GO_REF:0000107) reflects glucocorticoid-regulated transcription of Edn1 in vascular and renal tissues rather than EDN1 mediating glucocorticoid receptor signaling. |
| GO:0071389 cellular response to mineralocorticoid stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of aldosterone/mineralocorticoid-induced EDN1 transcription as a direct role in cellular response to mineralocorticoid stimulus. Reason: Orthology projection (GO_REF:0000107) reflects mineralocorticoid receptor-dependent induction of vascular and renal Edn1 expression by aldosterone rather than EDN1 directly transducing mineralocorticoid signaling. |
| GO:0071398 cellular response to fatty acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of free fatty acid-modulated endothelial EDN1 expression as a direct role in cellular response to fatty acid. Reason: Orthology projection (GO_REF:0000107) reflects altered endothelial Edn1 mRNA/peptide levels upon exposure to free fatty acids rather than EDN1 functioning as a fatty acid sensor or metabolic enzyme. |
| GO:0071456 cellular response to hypoxia | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of hypoxia-induced endothelial EDN1 expression as a direct role in cellular response to hypoxia. Reason: Orthology projection (GO_REF:0000107) reflects HIF-1-mediated transcriptional induction of the Edn1 promoter under low oxygen tension rather than EDN1 acting as an intracellular hypoxia sensor. |
| GO:0071466 cellular response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of xenobiotic-induced EDN1 expression as a direct role in cellular response to xenobiotic stimulus. Reason: Orthology projection (GO_REF:0000107) reflects changes in endothelial or hepatic Edn1 expression following xenobiotic exposure rather than EDN1 participating in xenobiotic sensing or metabolism. |
| GO:0071526 semaphorin-plexin signaling pathway | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of neural crest/vascular developmental cross-talk as a direct role of endothelin-1 in the semaphorin-plexin signaling pathway. Reason: Mature ET-1 is an orthosteric peptide ligand for the GPCRs EDNRA and EDNRB and does not bind Plexin or Neuropilin receptors; genetic interaction or parallel cardiac neural crest patterning defects with semaphorin-plexin mutants in mouse models (projected via GO_REF:0000107) do not make EDN1 a component of the semaphorin-plexin signaling pathway. |
| GO:0071548 response to dexamethasone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of dexamethasone-induced EDN1 expression as a direct role in response to dexamethasone. Reason: Orthology projection (GO_REF:0000107) reflects synthetic glucocorticoid (dexamethasone)-stimulated Edn1 transcription in vascular or renal cells rather than EDN1 mediating glucocorticoid pharmacology. |
| GO:0071559 response to transforming growth factor beta | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of TGF-beta-induced endothelial EDN1 transcription as a direct role in response to transforming growth factor beta. Reason: Orthology projection (GO_REF:0000107) reflects Smad/AP-1-dependent transcriptional upregulation of Edn1 by TGF-beta1 in endothelial and fibrotic tissues rather than EDN1 acting as a component of the TGF-beta receptor pathway. |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of TGF-beta-induced endothelial EDN1 transcription as a direct role in cellular response to transforming growth factor beta stimulus. Reason: Orthology projection (GO_REF:0000107) reflects Smad/AP-1-dependent transcriptional upregulation of Edn1 by TGF-beta1 in endothelial and fibrotic tissues rather than EDN1 directly transducing TGF-beta receptor signaling. |
| GO:0072011 glomerular endothelium development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental and paracrine role of intrarenal endothelin-1 in glomerular endothelium development. Reason: Paracrine cross-talk between podocytes, mesangial cells, and glomerular endothelial cells via ET-1/EDNRA/EDNRB supports glomerular capillary development and maintenance in rodent models (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0072112 podocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Paracrine role of intrarenal endothelin-1 signaling in renal podocyte differentiation. Reason: Glomerular ET-1 signaling modulates podocyte differentiation and cytoskeletal architecture during nephrogenesis in rodent models (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0086100 endothelin receptor signaling pathway | IDA PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | ACCEPT | Summary: Core biological process of mature endothelin-1 in initiating the endothelin receptor signaling pathway. Reason: Mature ET-1 is the canonical endogenous agonist of EDNRA and EDNRB, directly initiating endothelin receptor signaling across vascular, cardiac, renal, and neural crest target cells (PMID:16820593, PMID:9492062, PMID:19086031). Supporting Evidence: PMID:16820593 Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. |
| GO:0086100 endothelin receptor signaling pathway | IDA PMID:9492062 Prostaglandin endoperoxide synthase-2 contributes to the end... | ACCEPT | Summary: Core biological process of mature endothelin-1 in initiating the endothelin receptor signaling pathway. Reason: Mature ET-1 is the canonical endogenous agonist of EDNRA and EDNRB, directly initiating endothelin receptor signaling across vascular, cardiac, renal, and neural crest target cells (PMID:16820593, PMID:9492062, PMID:19086031). Supporting Evidence: PMID:16820593 Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. |
| GO:0086100 endothelin receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Core biological process of mature endothelin-1 in initiating the endothelin receptor signaling pathway. Reason: Mature ET-1 is the canonical endogenous agonist of EDNRA and EDNRB, directly initiating endothelin receptor signaling across vascular, cardiac, renal, and neural crest target cells (PMID:16820593, PMID:9492062, PMID:19086031). Supporting Evidence: PMID:16820593 Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. |
| GO:0086100 endothelin receptor signaling pathway | IMP PMID:19086031 Pyk2 mediates endothelin-1 signaling via p130Cas/BCAR3 casca... | ACCEPT | Summary: Core biological process of mature endothelin-1 in initiating the endothelin receptor signaling pathway. Reason: Mature ET-1 is the canonical endogenous agonist of EDNRA and EDNRB, directly initiating endothelin receptor signaling across vascular, cardiac, renal, and neural crest target cells (PMID:16820593, PMID:9492062, PMID:19086031). Supporting Evidence: PMID:16820593 Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. |
| GO:0090023 positive regulation of neutrophil chemotaxis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream pro-inflammatory role of endothelin-1 in promoting neutrophil chemotaxis. Reason: ET-1 stimulates neutrophil recruitment and chemotaxis either directly via leukocyte endothelin receptors or by inducing endothelial adhesion molecules and chemokines (projected via GO_REF:0000107, see also PMID:9696419); retained as a non-core inflammatory response. |
| GO:0097237 cellular response to toxic substance | IDA PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati... | MARK AS OVER ANNOTATED | Summary: Over-annotation of toxin-induced EDN1 upregulation as a direct role in cellular response to toxic substance. Reason: Annotation (PMID:30990108) reflects transcriptional upregulation or altered release of endothelial/cardiac EDN1 following exposure to cardiotoxic or cytotoxic agents rather than EDN1 acting as a detoxification enzyme or xenobiotic sensor. |
| GO:0097237 cellular response to toxic substance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of toxin-induced EDN1 upregulation as a direct role in cellular response to toxic substance. Reason: Annotation (GO_REF:0000107) reflects transcriptional upregulation or altered release of endothelial/cardiac EDN1 following exposure to cardiotoxic or cytotoxic agents rather than EDN1 acting as a detoxification enzyme or xenobiotic sensor. |
| GO:0097492 sympathetic neuron axon guidance | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of arterial endothelin-1 as a guidance cue for sympathetic neuron axons. Reason: Venous and arterial endothelial/smooth muscle ET-1 signals through EDNRA on sympathetic postganglionic neurons to guide sympathetic axons along vascular beds to target organs in mouse embryos (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:0141156 cAMP/PKA signal transduction | IDA PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati... | KEEP AS NON CORE | Summary: Downstream modulation of cAMP/PKA signaling in endothelin-1-stimulated target cells. Reason: In PMID:30990108, ET-1 receptor activation engages secondary cAMP/PKA signaling cross-talk in cardiac/vascular cells; retained as a non-core secondary intracellular signaling branch. |
| GO:0160195 negative regulation of phospholipase C/protein kinase C signal transduction | IDA PMID:16820593 Elevated endothelin-1 levels impair nitric oxide homeostasis... | MODIFY | Summary: Incorrectly signed negative regulation of phospholipase C/protein kinase C signal transduction annotation. Reason: In PMID:16820593, ET-1 activates (does not inhibit) PKCdelta downstream of endothelin receptors, and activated PKCdelta then inhibits eNOS (NOS3) transcription ('high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression'). The correct pathway terms for EDN1 are GO:0086100 (endothelin receptor signaling pathway) and GO:0160135 (phospholipase C-activating endothelin receptor signaling pathway). Proposed replacements: endothelin receptor signaling pathway phospholipase C-activating endothelin receptor signaling pathway Supporting Evidence: PMID:16820593 Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. |
| GO:1900182 positive regulation of protein localization to nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream promotion of transcription factor nuclear translocation following endothelin receptor activation. Reason: ET-1 receptor signaling triggers calcineurin- and kinase-dependent nuclear import of transcription factors (such as NFAT and beta-catenin/FoxO) in target cells (GO_REF:0000107); retained as a non-core downstream signaling event. |
| GO:1900182 positive regulation of protein localization to nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Downstream promotion of transcription factor nuclear translocation following endothelin receptor activation. Reason: ET-1 receptor signaling triggers calcineurin- and kinase-dependent nuclear import of transcription factors (such as NFAT and beta-catenin/FoxO) in target cells (GO_REF:0000024); retained as a non-core downstream signaling event. |
| GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream activation of non-canonical NF-kappaB signaling by endothelin-1 in inflammatory and vascular cells. Reason: ET-1 receptor stimulation activates NF-kappaB transcriptional pathways to promote pro-inflammatory and fibrotic gene expression in mammalian tissues (projected via GO_REF:0000107); retained as a non-core downstream signaling branch. |
| GO:1902074 response to salt | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Over-annotation of high-salt diet-induced renal and vascular EDN1 expression as a direct role in response to salt. Reason: Orthology projection (GO_REF:0000107) reflects increased renal medullary and endothelial Edn1 transcription in response to dietary salt loading rather than EDN1 functioning as a direct osmosensor or sodium channel. |
| GO:1903537 meiotic cell cycle process involved in oocyte maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Paracrine role of follicular endothelin-1 in regulating oocyte meiotic maturation in the ovary. Reason: Granulosa cell-derived ET-1 acts paracrinally within the preovulatory follicle to regulate resumption of meiosis and oocyte maturation downstream of the LH surge in rodent models (projected via GO_REF:0000107); retained as a non-core reproductive role. |
| GO:1904707 positive regulation of vascular associated smooth muscle cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Downstream mitogenic stimulation of vascular smooth muscle cell proliferation by endothelin-1. Reason: Mature ET-1 acts via vascular smooth muscle EDNRA/EDNRB receptors and downstream ERK1/2 signaling to stimulate vascular smooth muscle cell proliferation (projected via GO_REF:0000107, and directly shown in human VSMCs under parent term GO:0048661 in PMID:10393673); retained as a non-core downstream trophic response. |
| GO:1905653 positive regulation of artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role of paracrine endothelin-1 signaling in promoting pharyngeal arch and systemic artery morphogenesis. Reason: Endothelial and pharyngeal epithelial ET-1 signaling via EDNRA on neural crest-derived smooth muscle progenitors promotes arterial wall morphogenesis during vertebrate vascular development (projected via GO_REF:0000107); retained as a non-core developmental role. |
| GO:2001259 positive regulation of cation channel activity | IDA PMID:30990108 ET(A)R and protein kinase A pathway mediate ET-1 sensitizati... | KEEP AS NON CORE | Summary: Downstream activation of plasma membrane cation channels following endothelin receptor stimulation. Reason: In PMID:30990108, ET-1 binding to cell-surface endothelin receptors positively regulates cation channel opening and inward cation currents via PLC/PKC signaling; retained as a non-core downstream electrophysiological effect. |
| GO:0160135 phospholipase C-activating endothelin receptor signaling pathway | IC PMID:1917960 Effects of endothelins on signal transduction and proliferat... | NEW | Summary: Mature endothelin-1 directly activates the Gq/11-coupled phospholipase C-activating endothelin receptor signaling pathway via EDNRA and EDNRB. Reason: Mature ET-1 binding to human EDNRA and EDNRB potently stimulates Gq/11-coupled phospholipase C, generating inositol phosphates (EC50 1-4 nM) and mobilizing Ca2+ from intracellular stores (PMID:1917960, PMID:1713452, PMID:10770212). Inferred from GO:0031707 (endothelin A receptor binding), GO:0031708 (endothelin B receptor binding), and GO:0086100 (endothelin receptor signaling pathway). Supporting Evidence: PMID:1917960 Upon incubation with cultured cells, the mass contents of inositol 1,4,5-trisphosphate and intracellular calcium level were substantially increased by 10 nM ET-1, ET-2, and ET-3, but not by big-ET with maximal response at 80-130-s postincubation. |
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Download this section (compressed HTML)Q: What structural determinants of the ET-1-EDNRA complex account for its quasi-irreversible dissociation kinetics compared with ET-3, and how do clinically approved dual endothelin receptor antagonists (bosentan, macitentan) allosterically accelerate complex dissociation?
Suggested experts: Masashi Yanagisawa, Anthony P. Davenport, Osamu Nureki
Experiment: Use live-cell super-resolution imaging and compartment-specific ECE-1 proximity labeling in primary human arterial endothelial cells under laminar vs. disturbed shear stress.
Hypothesis: Polarized sorting of big ET-1 into endothelial Weibel-Palade bodies vs. constitutive secretory vesicles controls the ratio of abluminal EDNRA vasoconstriction to luminal EDNRB nitric oxide release.
Type: Super-resolution microscopy and proximity proteomics
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