APELA (ELABELA, Toddler) encodes a small secreted peptide hormone, processed from a signal-peptide precursor to ELA-32 and shorter fragments, that is an endogenous agonist of the apelin receptor APLNR (APJ). ELA binds APJ with sub-nanomolar affinity, competes with apelin, and signals through Gi (cAMP inhibition), ERK1/2 and beta-arrestin, causing receptor internalization. In zebrafish it is essential for endoderm differentiation, mesendodermal cell movement during gastrulation and heart formation. In mice its loss causes cardiovascular and vascular-remodeling defects, and placenta-derived ELA prevents preeclampsia-like disease by supporting placental angiogenesis. In adults ELA circulates in plasma, increases cardiac contractility and vasodilation, induces angiogenesis in endothelial cells, and in rats regulates fluid homeostasis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001570 vasculogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Vasculogenesis (ISS from mouse Apela). Mouse Apela mutants have vascular-remodeling defects, and ELA stimulates angioblast migration during vasculogenesis (shown in zebrafish). The mouse donor evidence is closer to remodeling than to de novo vessel formation; kept as non-core. Reason: [PMID:28854362 "Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos."] [PMID:28890073 "identified early APJ endogenous ligand that promotes endoderm differentiation and stimulates migration of angioblasts during vasculogenesis"] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC4 SUPPORTS TRANSFER Mouse Apela (ortholog); vasculogenesis by IMP in PMID:28663440 and PMID:28854362. Supporting Evidence: PMID:28854362 Three-dimensional micro-computed tomography revealed a higher penetrance of vascular remodeling defects, from which some mutants recover, and identified extraembryonic anomalies as the earliest morphological distinction in Apela mutant embryos. PMID:28890073 identified early APJ endogenous ligand that promotes endoderm differentiation and stimulates migration of angioblasts during vasculogenesis |
| GO:0005179 hormone activity | IDA PMID:35817871 Structural insight into apelin receptor-G protein stoichiome... | ACCEPT | Summary: Hormone activity (IDA). ELABELA is a secreted peptide hormone and an endogenous agonist of the apelin receptor APLNR. Human ELA circulates in plasma, is secreted by the placenta, and drives APLNR signalling at nanomolar potency; core function. Reason: [PMID:24316148 "We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Supporting Evidence: PMID:24316148 We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005179 hormone activity | IMP PMID:25639753 Elabela-apelin receptor signaling pathway is functional in m... | ACCEPT | Summary: Hormone activity (IMP). ELABELA is a secreted peptide hormone and an endogenous agonist of the apelin receptor APLNR. Human ELA circulates in plasma, is secreted by the placenta, and drives APLNR signalling at nanomolar potency; core function. Reason: [PMID:24316148 "We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Supporting Evidence: PMID:24316148 We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005179 hormone activity | IMP PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Hormone activity (IMP). ELABELA is a secreted peptide hormone and an endogenous agonist of the apelin receptor APLNR. Human ELA circulates in plasma, is secreted by the placenta, and drives APLNR signalling at nanomolar potency; core function. Reason: [PMID:24316148 "We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Supporting Evidence: PMID:24316148 We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005179 hormone activity | ISS GO_REF:0000024 | ACCEPT | Summary: Hormone activity (ISS from zebrafish apela). ELABELA is a secreted peptide hormone and an endogenous agonist of the apelin receptor APLNR. Human ELA circulates in plasma, is secreted by the placenta, and drives APLNR signalling at nanomolar potency; core function. Reason: [PMID:24316148 "We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); hormone activity by IMP in PMID:24316148. Supporting Evidence: PMID:24316148 We report here the discovery and characterization of a gene, ELABELA (ELA), encoding a conserved hormone of 32 amino acids. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005576 extracellular region | IDA PMID:24316148 ELABELA: a hormone essential for heart development signals v... | ACCEPT | Summary: Extracellular region (IDA). ELA is a secreted, circulating peptide detected in human plasma; accepted. Reason: [PMID:28137936 "We detected ELA expression in human vascular endothelium and plasma."] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Supporting Evidence: PMID:28137936 We detected ELA expression in human vascular endothelium and plasma. PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005576 extracellular region | IDA PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Extracellular region (IDA). ELA is a secreted, circulating peptide detected in human plasma; accepted. Reason: [PMID:28137936 "We detected ELA expression in human vascular endothelium and plasma."] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Supporting Evidence: PMID:28137936 We detected ELA expression in human vascular endothelium and plasma. PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005576 extracellular region | IDA PMID:35817871 Structural insight into apelin receptor-G protein stoichiome... | ACCEPT | Summary: Extracellular region (IDA). ELA is a secreted, circulating peptide detected in human plasma; accepted. Reason: [PMID:28137936 "We detected ELA expression in human vascular endothelium and plasma."] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Supporting Evidence: PMID:28137936 We detected ELA expression in human vascular endothelium and plasma. PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Extracellular region (IEA). ELA is a secreted, circulating peptide detected in human plasma; accepted. Reason: [PMID:28137936 "We detected ELA expression in human vascular endothelium and plasma."] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Supporting Evidence: PMID:28137936 We detected ELA expression in human vascular endothelium and plasma. PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Extracellular region (ISS from mouse Apela). ELA is a secreted, circulating peptide detected in human plasma; accepted. Reason: [PMID:28137936 "We detected ELA expression in human vascular endothelium and plasma."] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P0DMC4 SUPPORTS TRANSFER Mouse Apela (ortholog); extracellular region by IDA in PMID:28663440. Supporting Evidence: PMID:28137936 We detected ELA expression in human vascular endothelium and plasma. PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:35817871 Structural insight into apelin receptor-G protein stoichiome... | MODIFY | Summary: G protein-coupled receptor signaling pathway (IDA, cryo-EM of APJ-G protein complexes with ELA). Correct, but the receptor is known, so the precise term is apelin receptor signaling pathway; modified. Reason: [PMID:25995451 "Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] The cryo-EM study resolves ELA bound to the apelin receptor-G protein complex. Proposed replacements: apelin receptor signaling pathway Supporting Evidence: PMID:25995451 Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin PMID:35817871 Protein preparations, in the presence of the endogenous peptide ligand ELA or a synthetic small molecule, both demonstrate these mixed stoichiometric states. |
| GO:0007492 endoderm development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endoderm development (ISS from zebrafish apela). Zebrafish ela null embryos have impaired endoderm differentiation; kept as a non-core developmental role. Reason: [PMID:24316148 "ela null embryos have impaired endoderm differentiation potential marked by reduced gata5 and sox17 expression."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); endoderm development by IMP in PMID:24316148. Supporting Evidence: PMID:24316148 ela null embryos have impaired endoderm differentiation potential marked by reduced gata5 and sox17 expression. |
| GO:0007507 heart development | IEA GO_REF:0000002 | ACCEPT | Summary: Heart development (IEA). Zebrafish ela mutants form a rudimentary heart or none, phenocopying aplnr loss, and mouse Apela loss causes cardiovascular defects. This is the best-established developmental role of the hormone; accepted. Reason: [PMID:24316148 "Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor."] [PMID:28854362 "We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation."] Supporting Evidence: PMID:24316148 Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor. PMID:28854362 We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. |
| GO:0007507 heart development | ISS GO_REF:0000024 | ACCEPT | Summary: Heart development (ISS from zebrafish apela). Zebrafish ela mutants form a rudimentary heart or none, phenocopying aplnr loss, and mouse Apela loss causes cardiovascular defects. This is the best-established developmental role of the hormone; accepted. Reason: [PMID:24316148 "Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor."] [PMID:28854362 "We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); heart development by IMP in PMID:24316148. Supporting Evidence: PMID:24316148 Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor. PMID:28854362 We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. |
| GO:0007509 mesoderm migration involved in gastrulation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mesoderm migration involved in gastrulation (ISS from zebrafish apela). In zebrafish, Toddler acts as a motogen for mesendodermal cells during gastrulation through APJ. In mouse, Apela loss affects early Aplnr-expressing mesoderm, but the mouse papers reviewed here do not report a mesendoderm migration defect; kept as non-core. Reason: [PMID:24407481 "Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation."] [PMID:24407481 "These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals."] [PMID:29117894 "These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling."] [PMID:28854362 "Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin"] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); mesoderm migration by IMP in PMID:29117894. Supporting Evidence: PMID:24407481 Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation. PMID:24407481 These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals. PMID:29117894 These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling. PMID:28854362 Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin |
| GO:0007512 adult heart development | ISS GO_REF:0000024 | REMOVE | Summary: Adult heart development (ISS). The similarity source is Q9WV08, mouse Aplnr, the receptor, which is not an APELA homolog, so the transfer has no valid basis. The adult cardiac data for ELA concern acute contractility, not heart development; removed. Reason: The GOA row's WITH/FROM is the receptor: [file:human/APELA/APELA-goa.tsv "GO:0007512 adult heart development biological_process ECO:0000250 ISS GO_REF:0000024 UniProtKB:Q9WV08"] UniProt lists the row as ISS: [file:human/APELA/APELA-uniprot.txt "DR GO; GO:0007512; P:adult heart development; ISS:UniProtKB."] Adult heart work with ELA measures inotropy, not development: [PMID:26611206 "Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level."] Propagation Review Root cause: PROPAGATION BAD Sources checked: UniProtKB:Q9WV08 NOT RELEVANT Mouse Aplnr, the apelin receptor (QuickGO: its GO:0007512 row is an IMP from PMID:28663440). A receptor is not a homolog of its peptide ligand, so it is not a valid ISS donor whatever its own annotation's merit. Supporting Evidence: file:human/APELA/APELA-uniprot.txt DR GO; GO:0007512; P:adult heart development; ISS:UniProtKB. PMID:26611206 Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level. |
| GO:0031704 apelin receptor binding | IDA PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Apelin receptor binding (IDA). ELA binds APJ directly with sub-nanomolar affinity and competes with apelin for binding in human heart; core function. Reason: [PMID:25995451 "Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding."] [PMID:28137936 "ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling."] Supporting Evidence: PMID:25995451 Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding. PMID:28137936 ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. |
| GO:0031704 apelin receptor binding | IEA GO_REF:0000002 | ACCEPT | Summary: Apelin receptor binding (IEA). ELA binds APJ directly with sub-nanomolar affinity and competes with apelin for binding in human heart; core function. Reason: [PMID:25995451 "Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding."] [PMID:28137936 "ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling."] Supporting Evidence: PMID:25995451 Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding. PMID:28137936 ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. |
| GO:0031704 apelin receptor binding | ISS GO_REF:0000024 | ACCEPT | Summary: Apelin receptor binding (ISS from zebrafish apela). ELA binds APJ directly with sub-nanomolar affinity and competes with apelin for binding in human heart; core function. Reason: [PMID:25995451 "Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding."] [PMID:28137936 "ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling."] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); apelin receptor binding by IDA in PMID:24316148 and PMID:24407481. Supporting Evidence: PMID:25995451 Using a chimeric apela ligand, we showed direct binding of apela to APJ with high affinity (Kd = 0.51 nm) and the ability of apelin, the known peptide ligand for APJ, to compete for apela binding. PMID:28137936 ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. |
| GO:0035050 embryonic heart tube development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Embryonic heart tube development (ISS from mouse Apela). Mouse Apela loss causes low-penetrance cardiovascular defects, lethal cardiac defects in some embryos, and affects early Aplnr-expressing mesoderm, matching the zebrafish requirement for heart formation. Kept as non-core. Reason: [PMID:28854362 "We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation."] [PMID:28854362 "leading to lethal cardiac defects in some Apela null embryos."] [PMID:24316148 "Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC4 SUPPORTS TRANSFER Mouse Apela (ortholog); embryonic heart tube development by IMP in PMID:28663440 and PMID:28854362. Supporting Evidence: PMID:28854362 We found that loss of Apela results in low-penetrance cardiovascular defects that manifest after the onset of circulation. PMID:28854362 leading to lethal cardiac defects in some Apela null embryos. PMID:24316148 Loss of Ela causes embryos to develop with a rudimentary heart or no heart at all, surprisingly phenocopying the loss of the apelin receptor (aplnr), which we show serves as Ela's cognate G protein-coupled receptor. |
| GO:0045766 positive regulation of angiogenesis | IMP PMID:25639753 Elabela-apelin receptor signaling pathway is functional in m... | KEEP AS NON CORE | Summary: Positive regulation of angiogenesis (IMP). ELA induces angiogenesis in human umbilical vein endothelial cells; kept as non-core. Reason: [PMID:25639753 "we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin."] Supporting Evidence: PMID:25639753 we tested ELA biological function in human umbilical vascular endothelial cells and showed that ELA induces angiogenesis and relaxes mouse aortic blood vessel in a dose-dependent manner through a mechanism different from apelin. |
| GO:0045823 positive regulation of heart contraction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of heart contraction (ISS from rat Apela). In isolated adult rat hearts, apela increases contractility at nanomolar doses, and ELA raises cardiac output in rats in vivo; kept as a non-core physiological effect. Reason: [PMID:26611206 "Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DP76 SUPPORTS TRANSFER Rat Apela (ortholog); positive regulation of heart contraction by IMP in PMID:26611206. Supporting Evidence: PMID:26611206 Using isolated adult rat hearts, we demonstrate, that just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level. |
| GO:0060183 apelin receptor signaling pathway | IDA PMID:25639753 Elabela-apelin receptor signaling pathway is functional in m... | ACCEPT | Summary: Apelin receptor signaling pathway (IDA). Through APJ, ELA inhibits cAMP via Gi, stimulates ERK1/2, and engages beta-arrestin; core process. Reason: [PMID:25639753 "In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization."] [PMID:25995451 "Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] Supporting Evidence: PMID:25639753 In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. PMID:25995451 Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin |
| GO:0060183 apelin receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: Apelin receptor signaling pathway (IEA). Through APJ, ELA inhibits cAMP via Gi, stimulates ERK1/2, and engages beta-arrestin; core process. Reason: [PMID:25639753 "In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization."] [PMID:25995451 "Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] Supporting Evidence: PMID:25639753 In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. PMID:25995451 Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin |
| GO:0060183 apelin receptor signaling pathway | IMP PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Apelin receptor signaling pathway (IMP). Through APJ, ELA inhibits cAMP via Gi, stimulates ERK1/2, and engages beta-arrestin; core process. Reason: [PMID:25639753 "In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization."] [PMID:25995451 "Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] Supporting Evidence: PMID:25639753 In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. PMID:25995451 Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin |
| GO:0060183 apelin receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Apelin receptor signaling pathway (ISS from zebrafish apela). Through APJ, ELA inhibits cAMP via Gi, stimulates ERK1/2, and engages beta-arrestin; core process. Reason: [PMID:25639753 "In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization."] [PMID:25995451 "Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation."] [PMID:28137936 "These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin"] Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); apelin receptor signaling by IMP/IDA in PMID:24316148 and PMID:24407481. Supporting Evidence: PMID:25639753 In Chinese hamster ovarian (CHO) cells over-expressing human APJ, ELA suppresses cAMP production with EC50 of 11.1 nM, stimulates ERK1/2 phosphorylation with EC50 of 14.3 nM and weakly induces intracellular calcium mobilization. PMID:25995451 Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. PMID:28137936 These results show that ELA is an endogenous agonist of the human apelin receptor, exhibits a cardiovascular profile comparable to apelin |
| GO:0060674 placenta blood vessel development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Placenta blood vessel development (ISS from mouse Apela). Elabela-deficient pregnant mice show defective placental angiogenesis with preeclampsia-like symptoms; kept as non-core. Reason: [PMID:28663440 "Elabela but not Apelin knockout pregnant mice exhibit PE-like symptoms, including proteinuria and elevated blood pressure due to defective placental angiogenesis."] [PMID:28663440 "Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC4 SUPPORTS TRANSFER Mouse Apela (ortholog); placenta blood vessel development by IMP in PMID:28663440. Supporting Evidence: PMID:28663440 Elabela but not Apelin knockout pregnant mice exhibit PE-like symptoms, including proteinuria and elevated blood pressure due to defective placental angiogenesis. PMID:28663440 Here, we show that ELABELA (ELA), an endogenous ligand of the apelin receptor (APLNR, or APJ), is a circulating hormone secreted by the placenta. |
| GO:0060976 coronary vasculature development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Coronary vasculature development (ISS from mouse Apela). In mouse, heterozygous and homozygous Ela or Apj deletion impairs coronary vessel development: migration of sinus-venosus-derived endothelial cells onto the heart is stunted, though endocardial progenitors later compensate. Kept as a non-core developmental role. Reason: [PMID:28890073 "Both heterozygous and homozygous deletions of Apj and Ela cause significant defects in coronary vessel development due to deficiencies in the migration of Apj-expressing SV-derived endothelial cells beneath the Ela-expressing epicardium."] [PMID:28890073 "In both Apj- and Ela-deficient mouse hearts, blood vessel migration onto regions of the heart populated by the SV is stunted, whereas regions derived from the endocardium are not."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC4 SUPPORTS TRANSFER Mouse Apela (ortholog); coronary vasculature development by IMP in PMID:28890073. Supporting Evidence: PMID:28890073 Both heterozygous and homozygous deletions of Apj and Ela cause significant defects in coronary vessel development due to deficiencies in the migration of Apj-expressing SV-derived endothelial cells beneath the Ela-expressing epicardium. PMID:28890073 In both Apj- and Ela-deficient mouse hearts, blood vessel migration onto regions of the heart populated by the SV is stunted, whereas regions derived from the endocardium are not. |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of ERK1 and ERK2 cascade (ISS from rat Apela). ERK1/2 phosphorylation is a downstream output of ELA-activated APJ; kept as non-core. Reason: [PMID:26611206 "The inotropic effect, as revealed by Western blot analysis, is accompanied by a significant increase in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation."] [PMID:25995451 "Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation."] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DP76 SUPPORTS TRANSFER Rat Apela (ortholog); ERK1/2 cascade from PMID:26611206. Supporting Evidence: PMID:26611206 The inotropic effect, as revealed by Western blot analysis, is accompanied by a significant increase in extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. PMID:25995451 Apela, similar to apelin, acts through the inhibitory G protein pathway by inhibiting forskolin-stimulated cAMP production and by inducing ERK1/2 phosphorylation. |
| GO:0090133 mesendoderm migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mesendoderm migration (ISS from zebrafish apela). In zebrafish, Toddler acts as a motogen for mesendodermal cells during gastrulation through APJ. In mouse, Apela loss affects early Aplnr-expressing mesoderm, but the mouse papers reviewed here do not report a mesendoderm migration defect; kept as non-core. Reason: [PMID:24407481 "Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation."] [PMID:24407481 "These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals."] [PMID:29117894 "These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling."] [PMID:28854362 "Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin"] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); mesendoderm migration by IMP in PMID:24407481. Supporting Evidence: PMID:24407481 Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation. PMID:24407481 These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals. PMID:29117894 These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling. PMID:28854362 Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin |
| GO:0090134 cell migration involved in mesendoderm migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cell migration involved in mesendoderm migration (ISS from zebrafish apela). In zebrafish, Toddler acts as a motogen for mesendodermal cells during gastrulation through APJ. In mouse, Apela loss affects early Aplnr-expressing mesoderm, but the mouse papers reviewed here do not report a mesendoderm migration defect; kept as non-core. Reason: [PMID:24407481 "Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation."] [PMID:24407481 "These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals."] [PMID:29117894 "These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling."] [PMID:28854362 "Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin"] Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P0DMC2 SUPPORTS TRANSFER Zebrafish apela (ortholog); cell migration in mesendoderm migration by IMP/IDA in PMID:24407481. Supporting Evidence: PMID:24407481 Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation. PMID:24407481 These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals. PMID:29117894 These results suggest that Toddler signaling regulates mesodermal cell migration downstream of Nodal signaling and indirectly affects endodermal cell migration via Cxcr4a-signaling. PMID:28854362 Double-mutant analyses showed that loss of Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin |
| GO:1901165 positive regulation of trophoblast cell migration | IMP PMID:28663440 ELABELA deficiency promotes preeclampsia and cardiovascular ... | KEEP AS NON CORE | Summary: Positive regulation of trophoblast cell migration (IMP). ELA increases the invasiveness of trophoblast-like cells; kept as non-core. Reason: [PMID:28663440 "ELA, which is abundant in human placentas, increases the invasiveness of trophoblast-like cells, suggesting that it enhances placental development to prevent PE."] Supporting Evidence: PMID:28663440 ELA, which is abundant in human placentas, increases the invasiveness of trophoblast-like cells, suggesting that it enhances placental development to prevent PE. |
| GO:1903589 positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis (ISS from mouse Apela). The donor paper shows that ELA-APJ is needed for migration of sinus-venosus-derived coronary endothelial cells, not their proliferation; its cached full text reports no proliferation measurement. Marked as over-annotated. Reason: [PMID:28890073 "Both heterozygous and homozygous deletions of Apj and Ela cause significant defects in coronary vessel development due to deficiencies in the migration of Apj-expressing SV-derived endothelial cells beneath the Ela-expressing epicardium."] [PMID:28890073 "In both Apj- and Ela-deficient mouse hearts, blood vessel migration onto regions of the heart populated by the SV is stunted, whereas regions derived from the endocardium are not."] Propagation Review Root cause: SOURCE BAD Sources checked: UniProtKB:P0DMC4 SOURCE BAD Mouse Apela; donor IMP from PMID:28890073, whose full text attributes the coronary defect to stunted migration of sinus-venosus-derived endothelial cells and reports no proliferation measurement. Supporting Evidence: PMID:28890073 Both heterozygous and homozygous deletions of Apj and Ela cause significant defects in coronary vessel development due to deficiencies in the migration of Apj-expressing SV-derived endothelial cells beneath the Ela-expressing epicardium. PMID:28890073 In both Apj- and Ela-deficient mouse hearts, blood vessel migration onto regions of the heart populated by the SV is stunted, whereas regions derived from the endocardium are not. |
| GO:1904022 positive regulation of G protein-coupled receptor internalization | IMP PMID:25639753 Elabela-apelin receptor signaling pathway is functional in m... | KEEP AS NON CORE | Summary: Positive regulation of G protein-coupled receptor internalization (IMP). ELA addition causes rapid internalization of APJ, an agonist-induced consequence of receptor activation; kept as non-core. Reason: [PMID:25639753 "Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor."] Supporting Evidence: PMID:25639753 Addition of ELA to HEK293 cells over-expressing GFP-AJP fusion protein resulted in rapid internalization of the fusion receptor. |
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Download this section (compressed HTML)Q: Which processed forms of the ELA precursor (ELA-32, ELA-11 and other furin or plasma fragments) carry hormone activity in vivo?
Q: Does the APELA locus act through its RNA as well as its peptide? The affinage record cites a mouse ES-cell study reporting an RNA-level role in p53 regulation.
Q: Does ELA act during mammalian gastrulation as Toddler does in zebrafish, or is its mouse role confined to later cardiovascular and extraembryonic development?
Experiment: Compare ELA-32 and ELA-11 for Gi versus beta-arrestin bias at human APLNR in cardiomyocytes and endothelial cells.
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