Apelin is the endogenous peptide agonist of the apelin receptor APLNR (APJ), a Gi-coupled G-protein-coupled receptor. It is made as a 77-residue preproprotein: a cleaved signal peptide, a propeptide, and a C-terminal tail that is processed into a family of short bioactive peptides named for their length - apelin-36, -31, -28, -17 and -13, the last of which is frequently N-terminally cyclised to pyroglutamyl apelin-13. Furin cleaves the proprotein directly to apelin-13, and apelin-13 and apelin-17 are the predominant endogenous forms in plasma and hypothalamus. The active part of the molecule is extraordinarily conserved: the twelve C-terminal residues are essentially invariant across vertebrates, and human, rat, mouse and bovine apelin-13 and apelin-17 are identical, with divergence confined to the portion of the precursor that is trimmed away. Both ends of the peptide are required for activity - an N-terminal Arg-Pro-Arg-Leu motif for receptor recognition and the C-terminal phenylalanine for activation - and that terminal phenylalanine is also what sets the balance between the receptor's G-protein and beta-arrestin outputs. Binding of apelin to APLNR activates Gi, inhibiting adenylyl cyclase and lowering cAMP, while also activating ERK1/2 and recruiting beta-arrestin, which desensitises and internalises the receptor. Signalling is terminated proteolytically: angiotensin-converting enzyme 2 removes the single C-terminal phenylalanine, and the truncated peptides are much less active, making ACE2 a negative regulator of the whole axis. The peptide is secreted and acts largely in an autocrine or paracrine fashion; it circulates in human plasma only at subnanomolar concentrations, and it is also secreted in large amounts into colostrum and milk. Physiologically the apelin-APLNR axis is best characterised in the cardiovascular system and in fluid balance. Apelin is among the most potent positive inotropes known in the heart; it lowers blood pressure through a nitric-oxide-dependent vasodilator mechanism; and mice lacking apelin, although viable, fertile and outwardly normal, lose cardiac contractility with ageing and pressure overload and show markedly reduced exercise capacity. In the brain, apelin is co-expressed with vasopressin in magnocellular hypothalamic neurons, inhibits their activity, lowers circulating vasopressin and promotes diuresis, and reduces water intake in dehydrated animals - acting as a counter-regulator of vasopressin in body-fluid homeostasis. In the vasculature apelin is induced by hypoxia through HIF-1alpha, marks sprouting endothelium, and in pulmonary artery endothelial cells sustains transcription of miR-424 and miR-503, which restrain FGF2 and FGFR1 and thereby limit endothelial and smooth-muscle proliferation; this axis is lost in pulmonary arterial hypertension. Apelin also improves whole-body glucose utilisation in rodents. The receptor it acts through is shared with a second, structurally unrelated endogenous ligand, ELABELA/Toddler, and the two ligands are separable: apelin-null and APLNR-null animals have different, sometimes opposite, developmental phenotypes.
Definition: Any process that decreases the rate, frequency or extent of the regulated release of vasopressin from a cell.
Justification: GO:0030103 vasopressin secretion exists but has no regulation children, while its parent GO:0090278 negative regulation of peptide hormone secretion already has ten hormone-specific children - calcitonin, somatostatin, corticotropin-releasing hormone, corticotropin, growth hormone, glucagon, substance P, prolactin, thyroid-stimulating hormone and insulin. Vasopressin is conspicuously missing. Apelin is the clearest case needing it: it is co-localised with vasopressin in magnocellular hypothalamic neurons, inhibits their phasic activity, and lowers plasma vasopressin with a corresponding increase in diuresis, and this is its best-characterised central action. The term would also serve the several other neuropeptides and receptors known to modulate vasopressin release. Without it the biology has to be recorded against the generic parent, which loses the identity of the hormone.
Parent term: negative regulation of peptide hormone secretion
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005102 signaling receptor binding | TAS PMID:10525157 Apelin, the natural ligand of the orphan receptor APJ, is ab... | MODIFY | Summary: Legacy ProtInc statement that apelin binds a signalling receptor. True but uninformative: the receptor is known and named, and the specific term is already on the gene. Reason: GO:0031704 apelin receptor binding is a descendant of this term via GO:0001664 G protein-coupled receptor binding (QuickGO ancestors), and the gene already carries GO:0031704 from an IDA in native human left ventricle. The generic parent therefore adds nothing that the specific child does not say better, and 'signaling receptor binding' does not record which receptor. This is a granularity fix, not a disagreement with the curator: the cited paper is precisely about the apelin/APJ pairing. Proposed replacements: apelin receptor binding Supporting Evidence: PMID:10525157 we have recently identified a natural ligand, apelin, for the orphan 7TMR, APJ PMID:9792798 Synthetic peptides derived from the C-terminal amino acid sequence of bovine preproapelin were capable of specifically promoting the acidification rate in the cells expressing the APJ receptor in a range from 10(-7) to 10(-10) M, indicating that apelin is an endogenous ligand for the APJ receptor. |
| GO:0005102 signaling receptor binding | TAS PMID:9792798 Isolation and characterization of a novel endogenous peptide... | MODIFY | Summary: Legacy ProtInc statement from the paper that identified apelin as the APJ ligand. The paper names the receptor, so the annotation can be specific. Reason: GO:0031704 apelin receptor binding is a descendant of this term via GO:0001664 G protein-coupled receptor binding (QuickGO ancestors), and the gene already carries GO:0031704 from an IDA in native human left ventricle. The generic parent therefore adds nothing that the specific child does not say better, and 'signaling receptor binding' does not record which receptor. This is a granularity fix, not a disagreement with the curator: the cited paper is precisely about the apelin/APJ pairing. The cited paper is the deorphanisation of APJ itself, so nothing about the receptor's identity is in doubt. Proposed replacements: apelin receptor binding Supporting Evidence: PMID:9792798 Synthetic peptides derived from the C-terminal amino acid sequence of bovine preproapelin were capable of specifically promoting the acidification rate in the cells expressing the APJ receptor in a range from 10(-7) to 10(-10) M, indicating that apelin is an endogenous ligand for the APJ receptor. PMID:9792798 By monitoring this activity, we isolated an APJ receptor ligand, designated apelin, from bovine stomach extracts. |
| GO:0005179 hormone activity | IDA PMID:22810587 APJ acts as a dual receptor in cardiac hypertrophy. | ACCEPT | Summary: Apelin acting on human APJ expressed in HEK cells inhibits cAMP accumulation in a pertussis-toxin-sensitive manner, raises pERK and recruits beta-arrestin - receptor-ligand activity measured directly on the human receptor. Reason: GO:0005179 is a child of GO:0048018 receptor ligand activity and its definition is explicitly permissive about route - 'carried (sometimes in the bloodstream) to another organ or group of cells' - so a peptide that acts mostly in an autocrine/paracrine mode still satisfies it. This is the core molecular function of the gene product and the assays here are on the human receptor. One caveat belongs on the record rather than on the action: the best human measurement of circulating apelin, in PMID:28137936, concludes the peptides look more like locally released mediators than circulating hormones, so 'hormone' should be read as 'receptor agonist' rather than as a claim about endocrine delivery. The activity belongs to the cleaved peptides (apelin-13/-17), not to the 77-residue precursor, which UniProt records as PRO chains. Supporting Evidence: PMID:22810587 apelin addition decreased cAMP levels in the APJ-HEK cells PMID:22810587 This effect of apelin was partially inhibited by PTX, consistent with the involvement of GΞ±i PMID:22810587 Engineered cells stably expressing human APJ (APJ-HEK) responded to apelin by increasing the content of pERK PMID:22810587 These data agree with previous reports21 and demonstrate that GΞ±i transduces the signal initiated by apelin binding to APJ. file:human/APLN/APLN-uniprot.txt Several active peptides may be produced by proteolytic processing |
| GO:0005179 hormone activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO from IPR026155 'Apelin', a family signature that matches this gene family and essentially nothing else. The mapping is exact. Reason: IPR026155 resolves to InterPro family 'Apelin' with 345 member proteins, i.e. a one-family signature, and the whole family is peptide agonists of the apelin receptor. Unlike a fold-level signature, this one cannot leak the activity onto unrelated proteins. The propagation is sound and the term is at the right depth. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR026155 Β· InterPro family 'Apelin', 345 proteins SUPPORTS TRANSFER Gene-family-level signature, not a fold or domain shared with other activities; every member is an apelin-receptor agonist precursor, so the hormone/receptor-ligand activity cannot be mis-assigned through it. Supporting Evidence: PMID:9792798 Synthetic peptides derived from the C-terminal amino acid sequence of bovine preproapelin were capable of specifically promoting the acidification rate in the cells expressing the APJ receptor in a range from 10(-7) to 10(-10) M, indicating that apelin is an endogenous ligand for the APJ receptor. file:human/APLN/APLN-uniprot.txt Belongs to the apelin family. |
| GO:0005179 hormone activity | IMP PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Receptor-ligand activity of apelin measured alongside ELABELA in the same assays: competition binding in human left ventricle and full agonism in cells expressing the human apelin receptor. Reason: The paper is titled for ELABELA/Toddler, but pyroglutamyl-apelin-13 is run as a head-to-head comparator in every assay, so there are genuine apelin measurements: competition binding in human left ventricle homogenate, complete inhibition of forskolin-stimulated cAMP, and concentration-dependent beta-arrestin recruitment. The biology is right and the annotation is not ELABELA's biology mis-filed under APLN. What does not fit is the evidence code: IMP implies a mutant phenotype and this paper contains no APLN mutant or knockdown - its apelin data are synthetic peptide pharmacology, which is IDA-grade. Flagged for UniProt rather than acted on, since the term itself is correct and already carried by an IDA row. Supporting Evidence: PMID:28137936 ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. PMID:28137936 completely inhibited forskolin-induced cAMP production in a concentration-dependent manner PMID:28137936 stimulated Ξ²-arrestin recruitment in a concentration-dependent manner PMID:28137936 Experiments were conducted in homogenate of human ventricle or Chinese hamster ovary (CHO)-K1 cells expressing the human apelin receptor. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: The single PAINT assertion for the whole apelin family: the ancestral node PTN001041490, placed at Tetrapoda, is active in the extracellular region. Human APLN is inside that clade and is itself one of the seeds. Reason: The committed PAINT slice resolves this row completely: PTHR15953 carries exactly one node-level annotation, an IBD for GO:0005576 at node PTN001041490, not negated, at taxon:32523 (Tetrapoda per NCBI Taxonomy), seeded by rat Apln, bovine APLN and human APLN. Human is a tetrapod, so the target sits inside the inheriting clade. The seeds are experimentally grounded on two other species - rat Apln has an EXP GO:0005576 from PMID:10525157 and bovine APLN has experimental GO:0005576 from PMID:10525157 and PMID:9792798 - and the target's own accession appearing in the WITH/FROM is the expected, valid case: human APLN's own IDA rows are among the descendant evidences the PAINT curator used to place the node, which is a marker of experimental grounding on the target, not circularity. There is no IRD or IKR anywhere in the family slice and no reason to expect one: the protein has a signal peptide, no transmembrane segment, and is measured in plasma, colostrum and conditioned medium. Note also that this row has three gene-level donors, not four - PANTHER:PTN001041490 is the node, not a donor. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001041490 Β· PTHR15953 (APELIN) IBD node PTN001041490, placed at taxon:32523 Tetrapoda SUPPORTS TRANSFER The ancestral node and the source of the transfer. PTHR15953-paint.tsv: IBD, GO:0005576, aspect C, negated=false, taxon:32523 (Tetrapoda), seeds RGD:620672|UniProtKB:Q9TUI9|UniProtKB:Q9ULZ1. It is the only node-level annotation in the entire family. RGD:620672 Β· Apln (rat) - resolves to exactly one entry, Q9R0R3 APEL_RAT SUPPORTS TRANSFER One of three gene-level donors. Resolves to exactly one UniProt entry, Q9R0R3 APEL_RAT, whose own GO:0005576 is EXP from PMID:10525157. UniProtKB:Q9TUI9 Β· APLN (bovine, Swiss-Prot APEL_BOVIN) SUPPORTS TRANSFER Bovine APLN, the species apelin was first purified from; its own GO:0005576 is experimental from PMID:10525157 and PMID:9792798. UniProtKB:Q9ULZ1 Β· APLN (human, the target itself) SUPPORTS TRANSFER The target's own accession. Expected and valid: human APLN's experimental GO:0005576 annotations are among the descendant evidences behind the IBD, so the gene legitimately appears among the node's seeds. Supporting Evidence: PMID:28137936 ELA and apelin were detectable in healthy human plasma at 0.34Β±0.03 nmol/L and 0.26Β±0.03 nmol/L, respectively PMID:10525157 a large amount of apelin (14-93 pmol/ml) was found to be secreted in the bovine colostrum, and it was still detectable even in commercial bovine milk file:human/APLN/APLN-uniprot.txt SUBCELLULAR LOCATION: Secreted file:human/APLN/APLN-bioinformatics/RESULTS.md Human is inside that clade, so the target inherits. |
| GO:0005576 extracellular region | IDA PMID:22810587 APJ acts as a dual receptor in cardiac hypertrophy. | ACCEPT | Summary: Apelin quantified in mouse blood and in cardiomyocyte conditioned medium. Reason: Direct measurement of the peptide outside cells: circulating apelin rose from 1 to 2 ng/ml after transaortic constriction, and apelin in cardiomyocyte conditioned medium was measured at about 5 ng/ml. Extracellular location is where every apelin function is executed, so this is core. Supporting Evidence: PMID:22810587 endogenous levels of apelin in blood increased after TAC from 1ng/ml to 2ng/ml PMID:22810587 the concentration of apelin in the media remained unchanged (approximately 5ng/ml) with or without stretch |
| GO:0005576 extracellular region | IDA PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Apelin measured in human plasma by enzyme immunoassay at 0.26 nmol/L. Reason: The most direct human evidence for the location: apelin in plasma from 25 healthy donors, quantified by immunoassay. The authors add that the subnanomolar concentration looks more like a locally released mediator than a circulating hormone - which bears on the choice of MF term, not on the cellular component, since either way the peptide is extracellular. Supporting Evidence: PMID:28137936 Levels of ELA and apelin in healthy human plasma (n=25) were measured by using enzyme immunoassays PMID:28137936 ELA and apelin were detectable in healthy human plasma at 0.34Β±0.03 nmol/L and 0.26Β±0.03 nmol/L, respectively PMID:28137936 Both ELA and apelin were detectable in human plasma at subnanomolar levels, more indicative of peptides acting as locally released autocrine/paracrine mediators than as circulating hormones. |
| GO:0005576 extracellular region | IDA PMID:38428423 Structure-based design of non-hypertrophic apelin receptor m... | ACCEPT | Summary: Apelin-13 resolved as an extracellular ligand engaging the APLNR-Gi1 complex in cryo-EM structures. Reason: The structures place the peptide in the extracellular-facing orthosteric pocket of the receptor; UniProt records the modelled chains as residues 65-77 and 66-77 of APLN in PDB 8XZG/8XZH/8XZJ. A ligand bound from outside the cell is extracellular by construction, and this is the same location the IBA and the immunoassay rows assert. Supporting Evidence: PMID:38428423 we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles PMID:38428423 Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. file:human/APLN/APLN-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Mapping of UniProt's own subcellular-location vocabulary ('Secreted', 'Extracellular space') onto GO:0005576. Reason: Both source locations resolve to exactly the concept GO:0005576 names, and the UniProt record carries them with experimental evidence (ECO:0000269 from PMID:22810587 and PMID:38428423) as well as by similarity. A vocabulary mapping is only as good as its source term, and here the source terms are precise. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0112 Β· UniProt subcellular location 'Extracellular space' SUPPORTS TRANSFER Resolves to 'Extracellular space' (rest.uniprot.org/locations), a child concept of GO:0005576 rather than a broader or unrelated one. UniProtKB-SubCell:SL-0243 Β· UniProt subcellular location 'Secreted' SUPPORTS TRANSFER Resolves to 'Secreted'. The APLN record's SUBCELLULAR LOCATION line carries ECO:0000269 from PMID:22810587 and PMID:38428423, so the source assertion is experimentally backed, not inferred. Supporting Evidence: file:human/APLN/APLN-uniprot.txt SUBCELLULAR LOCATION: Secreted PMID:28137936 ELA and apelin were detectable in healthy human plasma at 0.34Β±0.03 nmol/L and 0.26Β±0.03 nmol/L, respectively |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of secretion from bovine APLN, the species apelin was purified from. Reason: The donor is Swiss-Prot bovine APLN (Q9TUI9), whose own GO:0005576 is experimental from PMID:10525157 and PMID:9792798 - the papers that purified apelin from bovine stomach extract and measured it at 14-93 pmol/ml in bovine colostrum. Human and bovine precursors are both 77 residues and their apelin-13 and apelin-17 peptides are identical, so the transfer is about as safe as an ISS gets. The human gene also has three independent IDA rows for the same term, so this row adds provenance rather than new information. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9TUI9 Β· APLN (bovine, Swiss-Prot APEL_BOVIN) SUPPORTS TRANSFER Bovine APLN, Swiss-Prot, 77 aa. Its GO:0005576 is experimental from PMID:10525157 and PMID:9792798 (QuickGO). cterm_conservation.py shows bovine and human apelin-13 and apelin-17 are identical, with only two substitutions across the whole of apelin-36. Supporting Evidence: PMID:10525157 a large amount of apelin (14-93 pmol/ml) was found to be secreted in the bovine colostrum, and it was still detectable even in commercial bovine milk PMID:9792798 By monitoring this activity, we isolated an APJ receptor ligand, designated apelin, from bovine stomach extracts. file:human/APLN/APLN-bioinformatics/RESULTS.md A "rat" or "bovine" apelin-17 in a pharmacology paper is, residue for residue, the human gene product. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-374337 | ACCEPT | Summary: Reactome places apelin extracellularly in its reaction for apelin binding to its receptor. Reason: Reactome's curated human reaction set places apelin in the extracellular compartment as the ligand of the apelin receptor, and exports one GO:0005576 row per reaction in the ligand-binding and Gi-activation cascade. The four rows are a single curatorial assertion projected across four reaction identifiers rather than four independent lines of evidence, but the assertion itself is correct and matches the IDA, IBA and ISS rows. Redundant, not wrong. Supporting Evidence: file:human/APLN/APLN-uniprot.txt SUBCELLULAR LOCATION: Secreted PMID:28137936 ELA and apelin were detectable in healthy human plasma at 0.34Β±0.03 nmol/L and 0.26Β±0.03 nmol/L, respectively |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Reactome places apelin extracellularly in its reaction for the liganded receptor acting as a GEF for Gi. Reason: Reactome's curated human reaction set places apelin in the extracellular compartment as the ligand of the apelin receptor, and exports one GO:0005576 row per reaction in the ligand-binding and Gi-activation cascade. The four rows are a single curatorial assertion projected across four reaction identifiers rather than four independent lines of evidence, but the assertion itself is correct and matches the IDA, IBA and ISS rows. Redundant, not wrong. Supporting Evidence: file:human/APLN/APLN-uniprot.txt SUBCELLULAR LOCATION: Secreted PMID:28137936 ELA and apelin were detectable in healthy human plasma at 0.34Β±0.03 nmol/L and 0.26Β±0.03 nmol/L, respectively |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Reactome places apelin extracellularly in its reaction for dissociation of the ligand:GPCR:Gi complex. Reason: Reactome's curated human reaction set places apelin in the extracellular compartment as the ligand of the apelin receptor, and exports one GO:0005576 row per reaction in the ligand-binding and Gi-activation cascade. The four rows are a single curatorial assertion projected across four reaction identifiers rather than four independent lines of evidence, but the assertion itself is correct and matches the IDA, IBA and ISS rows. Redundant, not wrong. Supporting Evidence: file:human/APLN/APLN-uniprot.txt SUBCELLULAR LOCATION: Secreted PMID:28137936 ELA and apelin were detectable in healthy human plasma at 0.34Β±0.03 nmol/L and 0.26Β±0.03 nmol/L, respectively |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Reactome places apelin extracellularly in its reaction for the liganded receptor binding inactive Gi. Reason: Reactome's curated human reaction set places apelin in the extracellular compartment as the ligand of the apelin receptor, and exports one GO:0005576 row per reaction in the ligand-binding and Gi-activation cascade. The four rows are a single curatorial assertion projected across four reaction identifiers rather than four independent lines of evidence, but the assertion itself is correct and matches the IDA, IBA and ISS rows. Redundant, not wrong. Supporting Evidence: file:human/APLN/APLN-uniprot.txt SUBCELLULAR LOCATION: Secreted PMID:28137936 ELA and apelin were detectable in healthy human plasma at 0.34Β±0.03 nmol/L and 0.26Β±0.03 nmol/L, respectively |
| GO:0006955 immune response | TAS PMID:10525157 Apelin, the natural ligand of the orphan receptor APJ, is ab... | MODIFY | Summary: Legacy ProtInc row resting on one ex vivo observation: apelin partially suppressed cytokine production by mouse spleen cells after TCR/CD3 cross-linking. Reason: GO:0006955 is 'any immune system process that functions in the calibrated response of an organism to a potential internal or invasive threat'. Apelin is not mounting a response here; the single experiment behind the row shows it damping cytokine output, which is the opposite direction and a different kind of process. GO:0001818 negative regulation of cytokine production says what was actually measured. The underlying evidence is weak - one ex vivo assay on mouse splenocytes, described as partial, with the authors' own conclusion hedged to 'might therefore modulate immune responses in neonates' - so the replacement should be read as the most this observation can support, not as a well-established role. Proposed replacements: negative regulation of cytokine production Supporting Evidence: PMID:10525157 Since apelin partially suppressed cytokine production by mouse spleen cells in response to T cell receptor/CD3 cross-linking, the oral intake of apelin in the colostrum and milk might modulate immune responses in neonates. PMID:10525157 a large amount of apelin (14-93 pmol/ml) was found to be secreted in the bovine colostrum, and it was still detectable even in commercial bovine milk |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO maps the gene-family signature IPR026155 'Apelin' to the generic signal transduction term. Reason: GO:0060183 apelin receptor signaling pathway exists, is exactly this gene's pathway, and is already on the record from three IDA rows and an IMP. Annotating the root-level GO:0007165 alongside it loses everything specific. This is a granularity fix. The source signature makes the case stronger, not weaker: IPR026155 is a single-family signature covering 345 apelin precursors and nothing else, so it can safely carry the family-exact term. A fold-level signature would have to stay generic; this one need not. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR026155 Β· InterPro family 'Apelin', 345 proteins SUPPORTS SOURCE BUT NOT TARGET The signature is right and family-exact ('Apelin', 345 proteins); it is the interpro2go target term that is too shallow. Every protein matching this signature signals through the apelin receptor, so the mapping could point at GO:0060183 without risk of over-reach. Proposed replacements: apelin receptor signaling pathway Supporting Evidence: PMID:9792798 Synthetic peptides derived from the C-terminal amino acid sequence of bovine preproapelin were capable of specifically promoting the acidification rate in the cells expressing the APJ receptor in a range from 10(-7) to 10(-10) M, indicating that apelin is an endogenous ligand for the APJ receptor. PMID:22810587 These data agree with previous reports21 and demonstrate that GΞ±i transduces the signal initiated by apelin binding to APJ. |
| GO:0007165 signal transduction | TAS PMID:9792798 Isolation and characterization of a novel endogenous peptide... | MODIFY | Summary: Legacy ProtInc row from the deorphanisation paper, recorded before the apelin-specific pathway term existed. Reason: GO:0060183 apelin receptor signaling pathway exists, is exactly this gene's pathway, and is already on the record from three IDA rows and an IMP. Annotating the root-level GO:0007165 alongside it loses everything specific. This is a granularity fix. The cited paper's content is specifically apelin-receptor signalling - synthetic C-terminal peptides raising the extracellular acidification rate of APJ-expressing cells at 0.1-100 nM - so the specific term is what the statement actually supports. Proposed replacements: apelin receptor signaling pathway Supporting Evidence: PMID:9792798 Synthetic peptides derived from the C-terminal amino acid sequence of bovine preproapelin were capable of specifically promoting the acidification rate in the cells expressing the APJ receptor in a range from 10(-7) to 10(-10) M, indicating that apelin is an endogenous ligand for the APJ receptor. PMID:9792798 The preproproteins consisted of 77 amino acid residues, and the apelin sequence was encoded in the C-terminal regions. |
| GO:0007595 lactation | TAS PMID:10525157 Apelin, the natural ligand of the orphan receptor APJ, is ab... | REMOVE | Summary: Legacy ProtInc row inferred from apelin being abundant in mammary gland and secreted into colostrum and milk. That is expression and localisation, not participation in milk release. Reason: GO:0007595 is defined as 'the regulated release of milk from the mammary glands and the period of time that a mother lactates to feed her young'. What the cited paper reports is abundance: apelin mRNA highest in the mammary gland of pregnant rats, rising through pregnancy and lactation to a peak around parturition, and 14-93 pmol/ml of peptide in bovine colostrum. Apelin is therefore a constituent of milk - a localisation fact the gene already carries on ten other rows as GO:0005576 - and the paper contains no perturbation of apelin with a milk-release or milk-yield readout. Inferring a biological process from an expression profile is precisely the inference GO asks curators not to make, and nothing published since supplies the missing experiment: targeted PubMed searches pairing apelin with lactation, milk ejection and oxytocin return no study that perturbs apelin and measures milk release. The nearby real biology runs the other way - apelin acts centrally on vasopressin neurons and was studied in lactating rats for that reason (PMID:15231996) - which is a body-fluid role, not a lactation role, and is proposed separately here as GO:0050878. Supporting Evidence: PMID:10525157 Although apelin mRNA was widely detected in a variety of tissues, the highest expression of apelin mRNA was detected in the mammary gland of pregnant rats. PMID:10525157 In the mammary gland, biologically active apelin and its mRNA considerably increased during pregnancy and lactation, and reached a maximal level around parturition. PMID:10525157 a large amount of apelin (14-93 pmol/ml) was found to be secreted in the bovine colostrum, and it was still detectable even in commercial bovine milk |
| GO:0010629 negative regulation of gene expression | IGI PMID:23263626 An endothelial apelin-FGF link mediated by miR-424 and miR-5... | KEEP AS NON CORE | Summary: APLN knockdown in human pulmonary artery endothelial cells raises FGF2 and FGFR1; overexpressing miR-424 and miR-503 abolishes the rise. The two WITH/FROM identifiers resolve to exactly those miRNAs. Reason: The experiment is sound and human: siRNA against APLN and lentiviral APLN overexpression in patient-derived and control PAECs, with both perturbation directions reported. The genetic-interaction partners are correctly identified - URS00000F0F49_9606 resolves to hsa-miR-424-5p and URS00000F6E49_9606 to hsa-miR-503-5p, which are the two miRNAs the paper is about. The term itself is near the top of the regulation hierarchy and says nothing about which gene, but it is not wrong and no obviously better child exists for 'reduces FGF2 and FGFR1 message'. Non-core: apelin is a secreted ligand, and this is a transcriptional consequence two steps downstream of receptor engagement, confined to pulmonary endothelium. Supporting Evidence: PMID:23263626 Lastly, we found that APLN knockdown resulted in robust increases of FGF2 and FGFR1, that were abrogated with concurrent overexpression of miR-424 and miR-503 (Fig. PMID:23263626 We confirmed this relationship by demonstrating a robust increase in FGF2 expression with APLN knockdown, and reciprocally decreased FGF2 levels with APLN overexpression (Fig. |
| GO:0031704 apelin receptor binding | IDA PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Radioligand competition binding in homogenates of human left ventricle and in CHO-K1 cells expressing the human apelin receptor. Reason: This is the gene's most informative molecular-function annotation and it is measured in native human tissue rather than only in a heterologous system. The paper's subject is ELABELA, but apelin is the competitor the ELA peptides are measured against, so the apelin affinity is a real datum from this paper and not ELABELA's biology transferred onto APLN. Core function. Supporting Evidence: PMID:28137936 ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. PMID:28137936 Experiments were conducted in homogenate of human ventricle or Chinese hamster ovary (CHO)-K1 cells expressing the human apelin receptor. PMID:38428423 we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles |
| GO:0031704 apelin receptor binding | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automatic pipeline: rat Apln ortholog plus the apelin family signature, both pointing at the same, correct, family-exact term. Reason: Two independent supports converge. Rat Apln (Q9R0R3) carries GO:0031704 as an IDA from PMID:26611206, and IPR026155 is a single-family signature covering apelin precursors only. Human and rat apelin-13 and apelin-17 are identical residue for residue, so orthology transfer here is not an approximation. The human gene also has its own IDA in human left ventricle, so the row is redundant but correct, and it is the right depth. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln. Its own GO:0031704 is IDA from PMID:26611206, a paper whose subject is apela/ELABELA but which reports apelin-receptor binding in heart with apelin as the benchmark ligand. Cached abstract only, so the apelin binding panel itself is not visible here; the curator read the full text. ensembl:ENSRNOP00000100018 Β· rat Apln protein - resolves to Q9R0R3, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R3, the same rat entity already listed on this row - two identifiers, one donor. InterPro:IPR026155 Β· InterPro family 'Apelin', 345 proteins SUPPORTS TRANSFER Independent of the ortholog arm: a family signature matching 345 apelin precursors and nothing else. Supporting Evidence: PMID:26611206 We also provide evidence that apela binds to apelin receptors in the heart. PMID:26611206 just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level PMID:28137936 ELA competed for binding of apelin in human heart with overlap for the 2 peptides indicated by in silico modeling. file:human/APLN/APLN-bioinformatics/RESULTS.md A "rat" or "bovine" apelin-17 in a pharmacology paper is, residue for residue, the human gene product. |
| GO:0040037 negative regulation of fibroblast growth factor receptor signaling pathway | IGI PMID:23263626 An endothelial apelin-FGF link mediated by miR-424 and miR-5... | KEEP AS NON CORE | Summary: Loss of APLN in human pulmonary artery endothelial cells de-represses FGF2 and FGFR1 and increases downstream proliferation; restoring miR-424/miR-503 reverses it. Reason: A well-formed IGI: the interacting entities really are hsa-miR-424-5p and hsa-miR-503-5p, and the epistasis runs in both directions (knockdown raises FGF2/FGFR1; miRNA overexpression abolishes the rise; FGF2 knockdown abolishes the downstream smooth-muscle phenotype). The term is more specific and more useful than its GO:0010629 sibling row. It remains non-core: apelin does not touch the FGF pathway directly - the chain is apelin, apelin receptor, miR-424/503 transcription, FGF2/FGFR1 message - and the whole axis is characterised only in pulmonary endothelium in the context of pulmonary arterial hypertension. Supporting Evidence: PMID:23263626 Lastly, we found that APLN knockdown resulted in robust increases of FGF2 and FGFR1, that were abrogated with concurrent overexpression of miR-424 and miR-503 (Fig. PMID:23263626 Moreover, the hyperproliferative response of PASMCs to CM from PAEC subjected to APLN knockdown was abrogated by concurrent knockdown of FGF2 (Fig. PMID:23263626 Rather, an emerging role of APLN signaling in mature vessels appears to be to preserve a differentiated, quiescent, and homeostatic endothelial layer. |
| GO:0042756 drinking behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Central injection of pyroglutamyl-apelin-13 reduced water intake in dehydrated rats; the human rows are ortholog transfers of that rat IMP. Automatic Ensembl Compara transfer. Reason: The donor annotation is sound and the transfer is safe at the level of the ligand: rat Apln carries GO:0042756 as an IMP from PMID:11359874, whose abstract states that central pE13F significantly decreased water intake in dehydrated normotensive rats, and the rat and human apelin-13 and apelin-17 peptides are identical. The wider picture supports it - apelin inhibits vasopressin neuron activity and vasopressin release, and acts as a diuretic counteracting vasopressin (PMID:15231996). Two qualifications keep it out of core. It is an organismal behaviour several steps downstream of receptor activation, and the rat evidence is peptide infusion into the brain rather than a genetic loss of Apln, so 'IMP' overstates the perturbation: Apln-null mice have normal water intake (PMID:17673668). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln, GO:0042756 IMP from PMID:11359874. The cited abstract does support this term - it is the same sentence that fails to support the rat blood-pressure annotation. ensembl:ENSRNOP00000100018 Β· rat Apln protein - resolves to Q9R0R3, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R3: the same donor under a second identifier, so this row has one gene-level donor, not two. Supporting Evidence: PMID:11359874 central injection of pE13F significantly decreased water intake in dehydrated normotensive rats but did not affect blood pressure PMID:11359874 Together, these results suggest that neuronal apelin plays an important role in the central control of body fluid homeostasis. PMID:15231996 Altogether, these data demonstrate that apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release. PMID:17673668 Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. |
| GO:0042756 drinking behavior | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Central injection of pyroglutamyl-apelin-13 reduced water intake in dehydrated rats; the human rows are ortholog transfers of that rat IMP. Curator sequence-similarity transfer. Reason: The donor annotation is sound and the transfer is safe at the level of the ligand: rat Apln carries GO:0042756 as an IMP from PMID:11359874, whose abstract states that central pE13F significantly decreased water intake in dehydrated normotensive rats, and the rat and human apelin-13 and apelin-17 peptides are identical. The wider picture supports it - apelin inhibits vasopressin neuron activity and vasopressin release, and acts as a diuretic counteracting vasopressin (PMID:15231996). Two qualifications keep it out of core. It is an organismal behaviour several steps downstream of receptor activation, and the rat evidence is peptide infusion into the brain rather than a genetic loss of Apln, so 'IMP' overstates the perturbation: Apln-null mice have normal water intake (PMID:17673668). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln, GO:0042756 IMP from PMID:11359874. Sequence similarity is not an approximation here: rat and human apelin-13 and apelin-17 are identical, so the peptide injected into rat brain is the human gene product. Supporting Evidence: PMID:11359874 central injection of pE13F significantly decreased water intake in dehydrated normotensive rats but did not affect blood pressure PMID:11359874 Together, these results suggest that neuronal apelin plays an important role in the central control of body fluid homeostasis. PMID:15231996 Altogether, these data demonstrate that apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release. PMID:17673668 Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. |
| GO:0045776 negative regulation of blood pressure | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Apelin is a vasodepressor. The human rows transfer a rat IMP whose cited paper reports no blood-pressure effect; the biology is nonetheless well established from other work. Automatic Ensembl Compara transfer. Reason: Two things have to be separated here. The claim is true: apelin-12, -13 and -36 lower mean arterial pressure in anaesthetised rats in a nitric-oxide-dependent way (PMID:11384769), apelin infusion lowers systolic blood pressure in wild-type but not APJ-null mice (PMID:22810587), and ACE2 knockout potentiates the hypotensive action of the apelin peptides (PMID:27217402). The propagation chain, however, is weak: the only donor is rat Apln, whose GO:0045776 is an IMP citing PMID:11359874, and that paper's abstract reports the opposite result for its own blood-pressure readout - central pE13F decreased water intake but did not affect blood pressure. The cache is abstract-only so a peripheral-route experiment in the full text cannot be excluded, and the curator read what we cannot; but on the accessible record the cited evidence does not establish this term, and the same sentence is what legitimately supports the drinking-behaviour row. Kept, because the function is real and supported elsewhere, but non-core: it is an organismal haemodynamic readout of receptor activation, not a second activity of the gene product. Raised as a question for UniProt. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SOURCE WEAK OR INFERRED Rat Apln, GO:0045776 IMP from PMID:11359874 (verified on the rat record via the GO API). That paper's abstract states central pE13F 'did not affect blood pressure'. The vasodepressor effect of apelin is real but comes from PMID:11384769 and PMID:22810587, neither of which is cited by the donor annotation. ensembl:ENSRNOP00000100018 Β· rat Apln protein - resolves to Q9R0R3, the same entity as the UniProtKB donor on this row SOURCE WEAK OR INFERRED Resolves to Q9R0R3: one donor under two identifiers, so the weakness is not offset by a second, independent source. Supporting Evidence: PMID:11359874 central injection of pE13F significantly decreased water intake in dehydrated normotensive rats but did not affect blood pressure PMID:11384769 mean arterial pressure after the administration of apelin-12, apelin-13, and apelin-36 at a dose of 10 nmol/kg in anaesthetized rats was reduced by 26+/-5, 11+/-4, and 5+/-4 mm Hg, respectively PMID:11384769 In the presence of a nitric oxide (NO) synthase inhibitor, the effect of apelin-12 on blood pressure was abolished. PMID:22810587 Apelin infusion significantly decreased systolic blood pressure in WT animals but not in APJ-KO mice PMID:27217402 In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated |
| GO:0045776 negative regulation of blood pressure | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Apelin is a vasodepressor. The human rows transfer a rat IMP whose cited paper reports no blood-pressure effect; the biology is nonetheless well established from other work. Curator sequence-similarity transfer. Reason: Two things have to be separated here. The claim is true: apelin-12, -13 and -36 lower mean arterial pressure in anaesthetised rats in a nitric-oxide-dependent way (PMID:11384769), apelin infusion lowers systolic blood pressure in wild-type but not APJ-null mice (PMID:22810587), and ACE2 knockout potentiates the hypotensive action of the apelin peptides (PMID:27217402). The propagation chain, however, is weak: the only donor is rat Apln, whose GO:0045776 is an IMP citing PMID:11359874, and that paper's abstract reports the opposite result for its own blood-pressure readout - central pE13F decreased water intake but did not affect blood pressure. The cache is abstract-only so a peripheral-route experiment in the full text cannot be excluded, and the curator read what we cannot; but on the accessible record the cited evidence does not establish this term, and the same sentence is what legitimately supports the drinking-behaviour row. Kept, because the function is real and supported elsewhere, but non-core: it is an organismal haemodynamic readout of receptor activation, not a second activity of the gene product. Raised as a question for UniProt. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SOURCE WEAK OR INFERRED The sole donor. Sequence similarity is not the problem - rat and human apelin-13/-17 are identical - the problem is that the donor's own IMP cites PMID:11359874, whose stated blood-pressure result is negative. A re-citation to PMID:11384769 on the rat record would repair the chain without changing any term. Supporting Evidence: PMID:11359874 central injection of pE13F significantly decreased water intake in dehydrated normotensive rats but did not affect blood pressure PMID:11384769 mean arterial pressure after the administration of apelin-12, apelin-13, and apelin-36 at a dose of 10 nmol/kg in anaesthetized rats was reduced by 26+/-5, 11+/-4, and 5+/-4 mm Hg, respectively PMID:11384769 In the presence of a nitric oxide (NO) synthase inhibitor, the effect of apelin-12 on blood pressure was abolished. PMID:22810587 Apelin infusion significantly decreased systolic blood pressure in WT animals but not in APJ-KO mice PMID:27217402 In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated |
| GO:0045823 positive regulation of heart contraction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Apelin is a potent positive inotrope. The human rows transfer a rat IMP, with independent genetic support from Apln-null mice. Automatic Ensembl Compara transfer. Reason: This is the best-supported of the organismal terms on the gene. Apelin is described as the most potent inotrope in the heart in vitro (PMID:28137936), and unlike the other physiological rows it has genuine loss-of-function backing: aged Apln-knockout mice develop progressive impairment of cardiac contractility and systolic dysfunction (PMID:17673668), and both apelin-null and APJ-null mice show basal contractile decrements and striking loss of exercise capacity (PMID:19767528). The donor chain is thinner than the biology: rat Apln's GO:0045823 is an IMP from PMID:26611206, a paper whose subject is apela/ELABELA and in which apelin appears as the comparator agonist, and which contains no Apln mutant. Kept as non-core because it is an organ-level readout of apelin receptor signalling rather than a second molecular function of the gene product. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln, GO:0045823 IMP from PMID:26611206. The paper is about apela, with apelin as the benchmark agonist in isolated adult rat hearts; the cache is abstract-only so the apelin inotropy panel is not visible here. The term is independently supported by Apln-null mouse data (PMID:17673668, PMID:19767528) that the donor does not cite. ensembl:ENSRNOP00000100018 Β· rat Apln protein - resolves to Q9R0R3, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R3 - the same rat donor under a second identifier. Supporting Evidence: PMID:26611206 just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level PMID:28137936 In heart, apelin is reportedly the most potent inotrope in vitro PMID:17673668 aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities PMID:17673668 These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging. PMID:19767528 Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. |
| GO:0045823 positive regulation of heart contraction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Apelin is a potent positive inotrope. The human rows transfer a rat IMP, with independent genetic support from Apln-null mice. Curator sequence-similarity transfer. Reason: This is the best-supported of the organismal terms on the gene. Apelin is described as the most potent inotrope in the heart in vitro (PMID:28137936), and unlike the other physiological rows it has genuine loss-of-function backing: aged Apln-knockout mice develop progressive impairment of cardiac contractility and systolic dysfunction (PMID:17673668), and both apelin-null and APJ-null mice show basal contractile decrements and striking loss of exercise capacity (PMID:19767528). The donor chain is thinner than the biology: rat Apln's GO:0045823 is an IMP from PMID:26611206, a paper whose subject is apela/ELABELA and in which apelin appears as the comparator agonist, and which contains no Apln mutant. Kept as non-core because it is an organ-level readout of apelin receptor signalling rather than a second molecular function of the gene product. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln, GO:0045823 IMP from PMID:26611206. Sequence similarity is exact at the level of the mature peptide, so the transfer risk is in the physiology, not the ligand. Mouse Apln-null phenotypes make the same point genetically. Supporting Evidence: PMID:26611206 just like the fellow receptor agonist apelin, apela increases cardiac contractility and induces coronary vasodilation already in the nanomolar level PMID:28137936 In heart, apelin is reportedly the most potent inotrope in vitro PMID:17673668 aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities PMID:17673668 These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging. PMID:19767528 Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. |
| GO:0060183 apelin receptor signaling pathway | IDA PMID:11359874 Physiological role of a novel neuropeptide, apelin, and its ... | ACCEPT | Summary: Apelin-17 and pyroglutamyl-apelin-13 inhibit forskolin-stimulated cAMP and drive receptor internalisation in cells expressing the apelin receptor; N-terminally truncated fragments are inactive. Reason: A clean pharmacological demonstration of the pathway, with an internal specificity control: K17F and pE13F are active while R10F and G5F are not, so the response depends on the intact peptide and is not a non-specific effect. The receptor is rat and the cells are CHO, but the peptides are the human ones - human, rat, mouse and bovine apelin-13 and apelin-17 are identical residue for residue - so this is the human gene product engaging its receptor. Core function. Supporting Evidence: PMID:11359874 Stimulation of this receptor by the apelin fragments K17F (Lys1-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and pE13F (pGlu5-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) resulted in a dose-dependent inhibition of forskolin-induced cAMP production and promoted its internalization. PMID:11359874 In contrast, the apelin fragments R10F (Arg8-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and G5F (Gly13-Pro-Met-Pro-Phe17) were inactive. PMID:11359874 We established a stable Chinese hamster ovary (CHO) cell line expressing a gene encoding the rat apelin receptor fused to the enhanced green fluorescent protein, to investigate internalization and the pharmacological profile of the apelin receptor. file:human/APLN/APLN-bioinformatics/RESULTS.md A "rat" or "bovine" apelin-17 in a pharmacology paper is, residue for residue, the human gene product. |
| GO:0060183 apelin receptor signaling pathway | IDA PMID:22810587 APJ acts as a dual receptor in cardiac hypertrophy. | ACCEPT | Summary: Apelin acting on human APJ inhibits adenylyl cyclase through Gi, raises pERK, generates inositol phosphates and recruits beta-arrestin. Reason: The most complete single description of the pathway on the human receptor: cAMP inhibition that is pertussis-toxin sensitive, dose-dependent IP1 accumulation via the promiscuous Galpha16 reporter, ERK phosphorylation, and beta-arrestin recruitment. The paper's headline is that APJ also signals independently of apelin in response to stretch; that is a receptor property and is correctly not annotated to APLN. Core function. Supporting Evidence: PMID:22810587 apelin addition decreased cAMP levels in the APJ-HEK cells PMID:22810587 These data agree with previous reports21 and demonstrate that GΞ±i transduces the signal initiated by apelin binding to APJ. PMID:22810587 Stretch did not increase IP1 production whereas apelin did so in a dose-responsive manner PMID:22810587 Using a Ξ²-arrestin/APJ complementation assay, apelin was found to induce a dose-dependent increase in Ξ²-arrestin signaling, as expected PMID:22810587 In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. |
| GO:0060183 apelin receptor signaling pathway | IDA PMID:38428423 Structure-based design of non-hypertrophic apelin receptor m... | ACCEPT | Summary: Cryo-EM structures of apelin-bound APLNR-Gi1 complexes, with the residues controlling G-protein versus beta-arrestin bias identified. Reason: Structural evidence for the pathway at its first step: the peptide occupies the orthosteric site of APLNR in complex with Gi1, and structure-guided redesign produced biased agonists, which only makes sense if the native ligand engages both arms. UniProt records two APLN residues from this work - SITE 75 and SITE 77, 'Important for the balance between G(i) and beta-arrestin pathways induced by apelin-13-APLNR system' - so the paper assigns pathway-determining roles to positions in this gene product, not only to the receptor. Core function. Supporting Evidence: PMID:38428423 we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles PMID:38428423 in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561 PMID:38428423 However, adverse effects through the Ξ²-arrestin pathway limit its pharmacological use. PMID:38428423 Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. |
| GO:0060183 apelin receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automatic pipeline transferring the pathway from the rat and mouse orthologs, each of which carries it from PMID:11359874. Reason: Both donors carry GO:0060183 as an IDA from PMID:11359874, and the human gene has three independent IDA rows of its own, so the propagation agrees with direct human evidence rather than substituting for it. The transfer is exact at the level of the ligand: cterm_conservation.py shows the C-terminal 12 residues R66-F77 are 97-98.5% invariant across all 333 UniProt members of PTHR15953, and rat, mouse, bovine and human apelin-13 and apelin-17 are identical. The terminal Phe77 that human apelin retains is both the determinant of signalling bias recorded by UniProt and the single residue ACE2 removes to terminate the signal, so retention of that residue is what makes the orthologs' pathway the target's pathway. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln, GO:0060183 IDA from PMID:11359874 (cAMP inhibition and receptor internalisation). ensembl:ENSRNOP00000100018 Β· rat Apln protein - resolves to Q9R0R3, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R3; one donor, two identifiers. UniProtKB:Q9R0R4 Β· Apln (mouse, Swiss-Prot APEL_MOUSE) SUPPORTS TRANSFER Mouse Apln, GO:0060183 IDA from PMID:11359874, confirmed on the mouse record via the GO API. ensembl:ENSMUSP00000046012 Β· mouse Apln protein - resolves to Q9R0R4, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R4; one donor, two identifiers. Supporting Evidence: PMID:11359874 Stimulation of this receptor by the apelin fragments K17F (Lys1-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and pE13F (pGlu5-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) resulted in a dose-dependent inhibition of forskolin-induced cAMP production and promoted its internalization. file:human/APLN/APLN-bioinformatics/RESULTS.md A "rat" or "bovine" apelin-17 in a pharmacology paper is, residue for residue, the human gene product. PMID:11815627 in each case, the proteolytic activity resulted in removal of the C-terminal residue only PMID:11815627 An alignment of the ACE2 peptide substrates reveals a consensus sequence of: Pro-X((1-3 residues))-Pro-Hydrophobic, where hydrolysis occurs between proline and the hydrophobic amino acid. |
| GO:0060183 apelin receptor signaling pathway | IMP PMID:28137936 Elabela/Toddler Is an Endogenous Agonist of the Apelin APJ R... | ACCEPT | Summary: Apelin activating the human apelin receptor in cell-based assays, run alongside ELABELA: cAMP inhibition and beta-arrestin recruitment, both blocked by the antagonist ML221. Reason: The pathway readouts for apelin in this paper are real and the antagonist control makes them receptor-dependent. As with the GO:0005179 row from the same paper, the evidence code is the questionable part: IMP implies a mutant phenotype, and the apelin arm of this study is synthetic peptide pharmacology in CHO-K1 cells expressing the human apelin receptor, which is IDA-grade. The term is correct, is already carried by three IDA rows, and is core. Supporting Evidence: PMID:28137936 completely inhibited forskolin-induced cAMP production in a concentration-dependent manner PMID:28137936 stimulated Ξ²-arrestin recruitment in a concentration-dependent manner PMID:28137936 Experiments were conducted in homogenate of human ventricle or Chinese hamster ovary (CHO)-K1 cells expressing the human apelin receptor. PMID:28137936 apelin and ELA-32 increased levels of ERK1/2 phosphorylation, and in PAECs there was also a significant increase in phosphorylation of endothelial nitric oxide synthase |
| GO:0060976 coronary vasculature development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred from a mouse Apln IMP whose underlying paper reports that Apelin-null hearts have the opposite coronary phenotype to Apj-null hearts. The unsigned term survives; any directional reading does not. Automatic Ensembl Compara transfer. Reason: Traced to its origin, this row means something different from what it looks like. The mouse donor's GO:0060976 is an IMP from PMID:28890073, a paper whose thesis is that the ELABELA-APJ axis, not apelin, is what sinus-venosus-derived coronary progenitors require. Its apelin data are a measured negative plus an opposite-sign phenotype: Apelin-knockout animals did not phenocopy the Apj-knockout coronary defect, and Apelin-deficient hearts showed increased coronary growth with earlier full coverage than wild type. Since GO:0060976 is an unsigned developmental process used with involved_in, an Apln-null with accelerated coronary coverage is still involvement, so the term itself transfers correctly and should not be removed. What does not transfer is the gloss UniProt places on the same evidence, 'Plays a role in early coronary blood vessels formation (By similarity)', which reads as a positive requirement. GO offers no regulation-of-coronary-vasculature-development child to move to, so the honest action is to keep the term as non-core with the direction recorded here. This is also the one row where the ELABELA/apelin confound genuinely reaches APLN, and the wider literature agrees the two ligands are separable: apelin-null mice develop normally while APJ-null mice do not (PMID:19767528, PMID:22810587). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R0R4 Β· Apln (mouse, Swiss-Prot APEL_MOUSE) SUPPORTS TRANSFER Mouse Apln, GO:0060976 IMP from PMID:28890073 (confirmed on the mouse record via the GO API). The paper is an ELABELA/Apj study; its Apln data are 'Apelin KO animals did not phenocopy the coronary defect seen in Apj KOs' and an opposite-direction phenotype of increased coronary growth. The unsigned term transfers; a positive reading of it does not. ensembl:ENSMUSP00000046012 Β· mouse Apln protein - resolves to Q9R0R4, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R4 - the same mouse donor under a second identifier, so there is one donor behind this row. Supporting Evidence: PMID:28890073 but Apelin KO animals did not phenocopy the coronary defect seen in Apj KOs PMID:28890073 In fact, Apelin-deficient hearts displayed a phenotype opposite to that in Apj mutants with an increase in coronary growth so that the heart was fully covered at developmental time points earlier than wild-type controls PMID:28890073 The opposing phenotypes in Apln and Ela KOs indicate that these two ligands may have opposing functions vis-a-vis APJ in the context of coronary vessel formation. PMID:19767528 Apelin-deficient mice were viable, fertile, and showed normal development. PMID:19767528 differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ |
| GO:0060976 coronary vasculature development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from a mouse Apln IMP whose underlying paper reports that Apelin-null hearts have the opposite coronary phenotype to Apj-null hearts. The unsigned term survives; any directional reading does not. Curator sequence-similarity transfer. Reason: Traced to its origin, this row means something different from what it looks like. The mouse donor's GO:0060976 is an IMP from PMID:28890073, a paper whose thesis is that the ELABELA-APJ axis, not apelin, is what sinus-venosus-derived coronary progenitors require. Its apelin data are a measured negative plus an opposite-sign phenotype: Apelin-knockout animals did not phenocopy the Apj-knockout coronary defect, and Apelin-deficient hearts showed increased coronary growth with earlier full coverage than wild type. Since GO:0060976 is an unsigned developmental process used with involved_in, an Apln-null with accelerated coronary coverage is still involvement, so the term itself transfers correctly and should not be removed. What does not transfer is the gloss UniProt places on the same evidence, 'Plays a role in early coronary blood vessels formation (By similarity)', which reads as a positive requirement. GO offers no regulation-of-coronary-vasculature-development child to move to, so the honest action is to keep the term as non-core with the direction recorded here. This is also the one row where the ELABELA/apelin confound genuinely reaches APLN, and the wider literature agrees the two ligands are separable: apelin-null mice develop normally while APJ-null mice do not (PMID:19767528, PMID:22810587). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R0R4 Β· Apln (mouse, Swiss-Prot APEL_MOUSE) SUPPORTS TRANSFER The sole donor. Mouse and human apelin-13/-17 are identical, so orthology is not in question; the issue is that the donor phenotype is an increase in coronary growth on loss of Apln, which an unsigned developmental term cannot express. Supporting Evidence: PMID:28890073 but Apelin KO animals did not phenocopy the coronary defect seen in Apj KOs PMID:28890073 In fact, Apelin-deficient hearts displayed a phenotype opposite to that in Apj mutants with an increase in coronary growth so that the heart was fully covered at developmental time points earlier than wild-type controls PMID:28890073 The opposing phenotypes in Apln and Ela KOs indicate that these two ligands may have opposing functions vis-a-vis APJ in the context of coronary vessel formation. PMID:19767528 Apelin-deficient mice were viable, fertile, and showed normal development. PMID:19767528 differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ |
| GO:1902895 positive regulation of miRNA transcription | IDA PMID:23263626 An endothelial apelin-FGF link mediated by miR-424 and miR-5... | KEEP AS NON CORE | Summary: APLN overexpression induces a miR-424/503 promoter-reporter in human pulmonary artery endothelial cells and APLN knockdown lowers both the primary and the mature miRNAs. Reason: Both perturbation directions are present and the paper distinguishes transcription from processing, which is what the term requires: the pri- and mature forms fall together on knockdown, and a promoter-reporter responds to overexpression. Apelin is obviously not acting at the promoter - it is a secreted ligand and the effect is downstream of the apelin receptor - but 'involved_in' a regulation term tolerates that indirection. Non-core: this is one transcriptional output of apelin receptor signalling in one cell type, not an activity of the gene product. The evidence is also overexpression-and-knockdown, i.e. IMP-grade rather than IDA-grade, whatever the code says. Supporting Evidence: PMID:23263626 We generated a putative miR-424/503 promoter based luciferase reporter construct, which was robustly induced by APLN overexpression in PAECs (Fig. PMID:23263626 We confirmed via real-time quantitative PCR that both the pri-form and the mature form of miR-424 and miR-503 are significantly downregulated with APLN knockdown (Fig. PMID:23263626 suggesting that the transcription of these miRNAs, rather than their post-transcriptional maturation, appears to be regulated by APLN signaling. |
| GO:1904022 positive regulation of G protein-coupled receptor internalization | IDA PMID:11359874 Physiological role of a novel neuropeptide, apelin, and its ... | ACCEPT | Summary: Apelin-17 and pyroglutamyl-apelin-13 drive internalisation of a GFP-tagged apelin receptor; inactive fragments do not. Reason: Agonist-driven receptor internalisation is part of what apelin does to its receptor, not a distant consequence: it is the desensitisation arm whose balance against Gi signalling is set by apelin residues 75 and 77 (UniProt SITE, from PMID:38428423) and whose over-activation is the adverse-effect problem that motivated the design of G-protein-biased agonists. The assay has its own specificity control in the inactive truncated fragments. One precision worth recording rather than glossing: apelin drives beta-arrestin recruitment and it drives internalisation, but these are not the same step - pyroglutamyl-apelin-13 internalises APJ through clathrin-coated vesicles in a GRK2-dependent, EPS15- and dynamin-dependent but beta-arrestin1-independent manner (PMID:27492965). Core. Supporting Evidence: PMID:11359874 Stimulation of this receptor by the apelin fragments K17F (Lys1-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and pE13F (pGlu5-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) resulted in a dose-dependent inhibition of forskolin-induced cAMP production and promoted its internalization. PMID:11359874 In contrast, the apelin fragments R10F (Arg8-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and G5F (Gly13-Pro-Met-Pro-Phe17) were inactive. PMID:27492965 stimulation caused internalization of mAPJ via clathrin coated vesicles (CCVs) and also caused a rapid reduction in cell surface and whole cell HA-mAPJ PMID:27492965 Our data suggest that upon continuous agonist exposure GRK2-mediated phosphorylation targets APJ to CCVs that are internalized from the cell surface in a Ξ²-arrestin1-independent, EPS15- and dynamin-dependent manner. PMID:38428423 However, adverse effects through the Ξ²-arrestin pathway limit its pharmacological use. |
| GO:1904022 positive regulation of G protein-coupled receptor internalization | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automatic pipeline transferring receptor internalisation from the rat and mouse orthologs, both of which carry it from PMID:11359874. Reason: Both donors hold GO:1904022 as an IDA from the same paper the human IDA row cites, and the human gene already carries the term directly, so this is a redundant but correct restatement. Transfer risk is negligible because the peptides are identical across the three species; the receptor in the donors' experiment is rat, but pyroglutamyl-apelin-13 was subsequently run in a receptor-internalisation assay against the human apelin receptor in CHO-K1 cells (PMID:28137936), and the mechanism - clathrin-coated vesicles, GRK2-, EPS15- and dynamin-dependent, beta-arrestin1-independent - has been worked out separately (PMID:27492965). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln, GO:1904022 IDA from PMID:11359874. ensembl:ENSRNOP00000100018 Β· rat Apln protein - resolves to Q9R0R3, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R3; one donor, two identifiers. UniProtKB:Q9R0R4 Β· Apln (mouse, Swiss-Prot APEL_MOUSE) SUPPORTS TRANSFER Mouse Apln, GO:1904022 IDA from PMID:11359874, confirmed on the mouse record via the GO API. ensembl:ENSMUSP00000046012 Β· mouse Apln protein - resolves to Q9R0R4, the same entity as the UniProtKB donor on this row SUPPORTS TRANSFER Resolves to Q9R0R4; one donor, two identifiers. Supporting Evidence: PMID:11359874 Stimulation of this receptor by the apelin fragments K17F (Lys1-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and pE13F (pGlu5-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) resulted in a dose-dependent inhibition of forskolin-induced cAMP production and promoted its internalization. PMID:28137936 Potency (pD2) and Efficacy (EMAX) of ...apelin-13, ELA-32, ELA-21, and ELA-11 in cAMP Inhibition, Ξ²-Arrestin Recruitment, and Receptor Internalization Assays PMID:28137936 Experiments were conducted in homogenate of human ventricle or Chinese hamster ovary (CHO)-K1 cells expressing the human apelin receptor. PMID:27492965 Our data suggest that upon continuous agonist exposure GRK2-mediated phosphorylation targets APJ to CCVs that are internalized from the cell surface in a Ξ²-arrestin1-independent, EPS15- and dynamin-dependent manner. file:human/APLN/APLN-bioinformatics/RESULTS.md A "rat" or "bovine" apelin-17 in a pharmacology paper is, residue for residue, the human gene product. |
| GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation | IMP PMID:23263626 An endothelial apelin-FGF link mediated by miR-424 and miR-5... | KEEP AS NON CORE | Summary: Conditioned medium from APLN-knockdown endothelial cells makes pulmonary artery smooth muscle cells proliferate; restoring miR-424/503 in the endothelium, or knocking down FGF2, abolishes the effect. Reason: The perturbation is of APLN and the phenotype is a genuine increase in smooth muscle proliferation, so the annotation is well founded. It is doubly indirect, however: apelin acts on the endothelial cell, changes miR-424/503 and hence FGF2, and the smooth muscle cell responds to secreted FGF2 - the paper demonstrates exactly this chain by abolishing the phenotype with FGF2 knockdown. That places the term well downstream of anything the gene product does, and confines it to the pulmonary circulation in a disease model. Non-core. Supporting Evidence: PMID:23263626 we found that CM from normal PAECs subjected to APLN knockdown induced a significant increase in PASMC proliferation, which was reduced to baseline by concurrent overexpression of miR-424/503 in PAECs (Fig. PMID:23263626 Moreover, the hyperproliferative response of PASMCs to CM from PAEC subjected to APLN knockdown was abrogated by concurrent knockdown of FGF2 (Fig. |
| GO:1905564 positive regulation of vascular endothelial cell proliferation | IDA PMID:23263626 An endothelial apelin-FGF link mediated by miR-424 and miR-5... | KEEP AS NON CORE | Summary: Augmenting APLN signalling increases proliferation of control pulmonary artery endothelial cells - but has the reverse effect in cells from patients with pulmonary arterial hypertension, and the authors flag the effect as small and contested. Reason: The positive direction is observed in the paper and independently: knockdown of apelin blocks hypoxia-induced endothelial proliferation (PMID:18617693). But the sign is context-dependent in the very same experiment - augmenting APLN signalling inhibited proliferation in PAH-derived endothelial cells - and the authors explicitly discount the literature the term rests on, calling the effects modest at best and noting that others have refuted them. Their own conclusion is that apelin's role in mature vessels is to preserve a quiescent, homeostatic endothelium, which is not a proliferative role. Kept, because the measurement in control cells is real, but firmly non-core and with the context-dependence recorded rather than smoothed over. Supporting Evidence: PMID:23263626 We also found that whereas augmentation of APLN signaling in normal PAECs led to an increase in PAEC proliferation as previously described,9 augmentation of APLN signaling in PAH PAECs had a reverse effect of inhibiting proliferation (Supp. PMID:23263626 Nevertheless, these effects have been modest at best, and others have refuted such findings,23 suggesting a strong context-dependence for APLNβs effects on the endothelium. PMID:23263626 Rather, an emerging role of APLN signaling in mature vessels appears to be to preserve a differentiated, quiescent, and homeostatic endothelial layer. PMID:18617693 microinterfering RNA-mediated apelin or APJ receptor knockdown inhibits both hypoxia-induced endothelial cell proliferation in vitro and hypoxia-induced vessel regeneration in the caudal fin regeneration of Fli-1 transgenic zebrafish |
| GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway | IDA PMID:22810587 APJ acts as a dual receptor in cardiac hypertrophy. | NEW | Summary: Apelin engaging the human apelin receptor inhibits adenylyl cyclase through Gi and lowers intracellular cAMP - the mechanistic identity of the apelin receptor signalling pathway, which the record currently states only in the ligand-specific term. Reason: GO:0060183 says which ligand starts the pathway; it does not say how the signal is transduced. Every primary description of apelin action reports the same mechanism - inhibition of adenylyl cyclase and a fall in cAMP through a pertussis-toxin-sensitive Gi protein - and this is measured directly on the human receptor: apelin lowers isoproterenol-stimulated cAMP in HEK cells stably expressing human APJ, an effect PTX inhibits and which is absent in untransfected controls, and apelin completely inhibits forskolin-stimulated cAMP in CHO-K1 cells expressing the human apelin receptor. The cryo-EM structures of APLNR-Gi1 complexes with apelin bound make the coupling explicit. GO:0007193 is the mechanism-level sibling of GO:0060183 and both belong on a Gi-coupled receptor's ligand; adding it is what makes the record say that apelin is an inhibitory-Gi agonist rather than merely that it has its own named pathway. Supporting Evidence: PMID:22810587 apelin addition decreased cAMP levels in the APJ-HEK cells PMID:22810587 This effect of apelin was partially inhibited by PTX, consistent with the involvement of GΞ±i PMID:22810587 These data agree with previous reports21 and demonstrate that GΞ±i transduces the signal initiated by apelin binding to APJ. PMID:28137936 completely inhibited forskolin-induced cAMP production in a concentration-dependent manner PMID:38428423 we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles |
| GO:0090278 negative regulation of peptide hormone secretion | ISS PMID:15231996 Apelin, a potent diuretic neuropeptide counteracting vasopre... | NEW | Summary: Apelin is a diuretic neuropeptide that opposes vasopressin: it inhibits vasopressin neuron activity, lowers plasma vasopressin and increases diuresis. The human record captures only the drinking half of this biology. Reason: GO:0042756 drinking behavior is already annotated by ISS from rat, and it records the intake side of apelin's role in fluid balance. The output side is at least as well documented and is missing entirely. Apelin is co-localised with vasopressin in magnocellular supraoptic neurons, inhibits their phasic electrical activity, reduces plasma vasopressin and increases diuresis in vivo; water deprivation moves apelin and vasopressin in opposite directions, which is the signature of a counter-regulatory pair rather than a pharmacological artefact. The same laboratory's earlier work, which is the source of the existing drinking-behaviour annotation, already reported decreased vasopressin release after central apelin injection. Vasopressin is a peptide hormone, so GO:0090278 applies directly and is more informative than its broad alternative GO:0050878 regulation of body fluid levels; the ideal term, negative regulation of vasopressin secretion, does not exist, although ten sibling peptide hormones have one, and is proposed separately. Coded ISS rather than IMP because the perturbations are in rat and mouse; the transfer is unusually safe because rat and human apelin-13 and apelin-17 are identical residue for residue, so the peptide injected is the human gene product. Non-core, like the other organismal terms on this gene. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R0R3 Β· Apln (rat, Swiss-Prot APEL_RAT) SUPPORTS TRANSFER Rat Apln. The rat and mouse experiments in PMID:15231996 are the primary evidence; rat Apln already carries the sibling term GO:0042756 as an IMP from the companion study PMID:11359874. Rat and human apelin-13/-17 are identical, so sequence similarity is exact at the level of the active peptide. Supporting Evidence: PMID:15231996 Altogether, these data demonstrate that apelin acts as a potent diuretic neuropeptide counteracting AVP actions through inhibition of AVP neuron activity and AVP release. PMID:15231996 In lactating mice, intracerebroventricular administration of apelin 17 reduced plasma AVP levels and increased diuresis. PMID:15231996 Moreover, water deprivation, which increases systemic AVP release and causes depletion of hypothalamic AVP stores, decreased plasma apelin concentrations and induced hypothalamic accumulation of the peptide, indicating that AVP and apelin are conversely regulated to facilitate systemic AVP release and suppress diuresis. PMID:11359874 a decrease in vasopressin release following intracerebroventricular injection of K17F, or pE13F, but not R10F PMID:11359874 Together, these results suggest that neuronal apelin plays an important role in the central control of body fluid homeostasis. file:human/APLN/APLN-bioinformatics/RESULTS.md A "rat" or "bovine" apelin-17 in a pharmacology paper is, residue for residue, the human gene product. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: For the PAINT curators of PTHR15953: the family carries exactly one node-level annotation, an IBD for GO:0005576 at PTN001041490. Apelin receptor binding (GO:0031704) and the apelin receptor signalling pathway (GO:0060183) are experimentally annotated in human, rat, mouse and zebrafish, and the peptide's C-terminal twelve residues are 97-98.5% invariant across all 333 members. Is there a reason these were not placed at the same node, or is this simply unfinished?
Q: For UniProt: rat Apln carries GO:0045776 negative regulation of blood pressure as an IMP from PMID:11359874, and that paper's abstract reports that central pE13F 'did not affect blood pressure'. The same sentence is what supports the drinking-behaviour annotation from the same paper. Apelin's vasodepressor action is well established, but from PMID:11384769 and PMID:22810587. What supports the blood-pressure annotation as cited? This row reaches human APLN twice, by ISS and by Ensembl Compara IEA.
Q: For UniProt: the mouse Apln GO:0060976 coronary vasculature development IMP cites PMID:28890073, which reports that Apelin-knockout animals did not phenocopy the Apj-knockout coronary defect and that Apelin-deficient hearts showed increased coronary growth - the opposite direction. The unsigned GO term still applies, but the FUNCTION line transferred to human APLN reads 'Plays a role in early coronary blood vessels formation', which implies the opposite sign. Should that comment be reworded?
Q: For UniProt: four APLN rows cite PMID:28137936 and two of them are coded IMP (GO:0005179, GO:0060183). That paper contains no APLN mutant or knockdown; its apelin data are synthetic-peptide pharmacology run as a comparator to ELABELA. Should these be IDA? The same question applies to rat Apln GO:0045823 IMP from PMID:26611206, which is an apela paper.
Q: For GOA and UniProt jointly: UniProt defines four PRO chain identifiers for this entry (PRO_0000001760 to PRO_0000001763) and almost every annotation on the gene is really about apelin-13 or apelin-17 rather than about the 77-residue precursor. Would annotations against those chain identifiers be accepted, as they already are for some orthologs?
Q: For UniProt: apelin-17 has no PEPTIDE feature on this entry, although it is one of the two predominant endogenous forms (PMID:15231996), is the form used in most central work as K17F, and is one of the two peptides whose ACE2 cleavage was characterised (PMID:27217402). Should it be added alongside apelin-36, -31, -28 and -13?
Q: For GO: apelin is annotated to GO:0005179 hormone activity three times, yet the best human measurement of the circulating peptide concludes it looks 'more indicative of peptides acting as locally released autocrine/paracrine mediators than as circulating hormones'. Does GO intend GO:0005179 to carry a claim about route of delivery, given its definition says 'sometimes in the bloodstream' and its comment points to GO:0048018?
Experiment: Raise or commission form-specific immunoassays that discriminate apelin-36, apelin-17, apelin-13 and pyroglutamyl-apelin-13, validated against synthetic standards and against ACE2-cleaved products, and map their absolute concentrations across plasma, heart, hypothalamus, adipose tissue and colostrum. Then repeat the three defining physiological readouts - inotropy in an isolated heart, blood pressure in vivo, and central vasopressin release - with each form at matched receptor occupancy rather than matched mass dose. The prediction from the processing data is that apelin-13 dominates everywhere and that apelin-36's reported effects are largely a slow-off-rate artefact of high dosing.
Hypothesis: The physiological roles currently attributed to apelin are carried by different processed forms in different tissues, and the precursor-level record conflates them.
Type: quantitative peptidomics plus matched-occupancy pharmacology
Experiment: Measure the arteriovenous gradient of each apelin form across a defined vascular bed in vivo, together with interstitial concentration by microdialysis in heart and skeletal muscle, and compare local concentration with the receptor's measured affinity in human tissue (pKi about 8.85 for pyroglutamyl-apelin-13 in human left ventricle). A hormone should reach receptor-saturating concentrations at the target from the circulation; a paracrine mediator should show local concentrations far above plasma and a net release gradient at the site of production.
Hypothesis: Apelin is a paracrine mediator rather than a circulating hormone, so its molecular-function annotation should be a receptor agonist term and not a hormone term.
Type: in vivo arteriovenous sampling and microdialysis
Experiment: Phenotype apelin-null mice, which are viable, fertile and outwardly normal, with a hyperinsulinaemic-euglycaemic clamp and tissue-specific 2-deoxyglucose uptake on chow and on high-fat diet, alongside wild-type littermates and alongside wild-type animals receiving an ACE2-resistant apelin analogue. This is the loss-of-function control the field has never published, and it is the experiment that decides whether any metabolic GO annotation on this gene is warranted.
Hypothesis: Loss of endogenous apelin, as opposed to infusion of exogenous peptide, does not impair glucose handling - meaning the metabolic literature describes pharmacology rather than physiology.
Type: mouse metabolic phenotyping of a knockout
Experiment: In sinus-venosus-derived coronary progenitors, compare apelin and ELABELA head to head for Gi activation, beta-arrestin recruitment and receptor internalisation at matched occupancy, then test whether a G-protein-biased apelin analogue such as WN561 and a beta-arrestin-biased one reproduce the Apln-null and Apela-null coronary phenotypes respectively when delivered to the developing heart. A bias explanation predicts that the two knockouts can be phenocopied pharmacologically in wild-type embryos; a dosage explanation predicts they cannot.
Hypothesis: The opposite coronary phenotypes of Apln-null and Apela-null mice reflect the two ligands driving different APLNR output arms rather than different amounts of the same signal.
Type: biased-agonist pharmacology in a developmental model
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Which processed apelin peptide does what, in which tissue, is unresolved - and the gene record cannot express the difference, because every annotation is made against the 77-residue precursor rather than against the chains UniProt already defines.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: Firmly established: the precursor yields apelin-36, -31, -28, -17 and -13; furin cleaves proapelin directly to apelin-13 with no longer intermediates; apelin-13 and, less abundantly, apelin-17 are the predominant endogenous forms in plasma and hypothalamus; the peptides differ in receptor residence time, in their G-protein versus beta-arrestin bias, and in susceptibility to ACE2; and UniProt carries PRO chain identifiers PRO_0000001760 to PRO_0000001763 for four of them. Equally established: not one GO annotation on this gene is made against a chain identifier.
Significance: Apelin analogues are being developed as cardiovascular drugs precisely because the forms differ in bias and stability. A record that treats them as one entity cannot support that distinction, and cannot say which form a given physiological claim rests on. It also makes the gene look like a protein with a dozen activities rather than a precursor for a small set of peptides.
What would resolve it: Two separable steps. Biologically: measure the tissue distribution of each processed form with form-specific assays, and repeat the key physiological perturbations with each. Curationally: annotate against the existing PRO chain identifiers. Half the machinery is already in place - mouse and bovine Apln carry GO:0005179, GO:0005576 and GO:0060183 ISS rows whose WITH/FROM is UniProtKB:Q9ULZ1-PRO_0000001763, i.e. the human apelin-13 chain is already used as a similarity donor - but a QuickGO query on that identifier returns zero annotations, so nothing is annotated to the chain itself.
Provenance (the field's own admissions):
Gap: Whether apelin should be treated as a hormone or as a locally released autocrine/paracrine mediator is unsettled, and the ontology forces a choice that the data do not support.
OPEN BIOLOGYONTOLOGY MF_DARK
What is known: Established: apelin is detectable in human plasma, at 0.26 nmol/L, and the authors of that measurement conclude the concentration is more consistent with local release than with circulating hormone action. Also established: apelin is secreted in very large amounts into colostrum, at 14 to 93 pmol/ml, which is an exocrine route entirely. GO:0005179 hormone activity is defined permissively enough to cover both, because it says 'sometimes in the bloodstream', and its own comment points to GO:0048018 receptor agonist activity as an alternative.
Significance: The choice determines what a reader infers about where apelin acts and over what distance, and it propagates: three rows on this gene assert hormone activity, and the term is transferred to the rodent and bovine orthologs by ISS and IEA. If apelin is mostly paracrine, every one of those rows is conveying something slightly false about the route.
What would resolve it: Biologically, a measurement of the arteriovenous gradient of each apelin form across a vascular bed, and of local interstitial concentration, would show whether circulating apelin is a signal or a spillover. Ontologically, the question is whether GO wants GO:0005179 to be about the route of delivery or only about the agonist relationship; if the former, apelin belongs under GO:0048018 instead.
Provenance (the field's own admissions):
Gap: Apelin's role in angiogenesis is absent from the human GO record entirely, although it is one of the two things the protein is best known for.
OPEN CURATION BP_DARK
What is known: Established: apelin is induced by hypoxia through HIF-1alpha binding an intronic hypoxia-responsive element, and knockdown of apelin blocks hypoxia-induced endothelial proliferation in vitro and vessel regeneration in vivo. Zebrafish apln carries GO:0002040 sprouting angiogenesis by IGI, and UniProt keeps 'Angiogenesis' as a keyword on the human entry. Equally established: the human GOA record contains no angiogenesis term of any kind. The closest rows, GO:1905564 and GO:1904706, are about proliferation of the two cell types, not about vessel formation.
Significance: Angiogenesis is the context in which apelin is most often studied and targeted therapeutically, in tumours and in retinopathy. Its absence means a search of GO for angiogenic ligands does not return apelin, and it leaves the review unable to record the function without inventing an ISS donor that does not carry the term.
What would resolve it: A curator with access to the mouse Apln-CreER sprouting-endothelium and retinal-angiogenesis literature could make a mouse experimental annotation, from which an ISS to human would follow. No NEW row is proposed here for exactly that reason: no rodent ortholog currently holds an angiogenesis term, so there is nothing to transfer from, and the human experiments in hand measure endothelial proliferation rather than vessel formation.
Provenance (the field's own admissions):
Gap: The phylogenetic annotation of the apelin family propagates a localisation and nothing else, although the family's function is known and conserved.
OPEN CURATION RESIDUAL_SUBGAP
What is known: Established from the committed PAINT slice: PTHR15953 carries exactly one node-level annotation, an IBD for GO:0005576 at PTN001041490, and UniProt's own cross-reference records 'PAN-GO; Q9ULZ1; 1 GO annotation based on evolutionary models'. Equally established: apelin receptor binding and the apelin receptor signalling pathway are experimentally annotated in human, rat, mouse and zebrafish, and the C-terminal twelve residues of the peptide are 97 to 98.5 per cent invariant across all 333 UniProt members of the family.
Significance: This is an IBA-incompleteness case of the cleanest possible kind: a small, single-function family with an invariant active site and experimental support in four species, whose evolutionary annotation says only that the product leaves the cell. Any downstream analysis that uses IBA as a proxy for conserved function will miss apelin's actual function completely.
What would resolve it: IBD assertions for GO:0031704 and GO:0060183 at or near PTN001041490, seeded from the existing experimental annotations in human, rat, mouse and zebrafish.
Provenance (the field's own admissions):
Gap: Whether apelin regulates glucose metabolism in humans is unknown; the entire case rests on acute peptide infusion into rodents.
OPEN BIOLOGY BP_DARK
What is known: Established in mouse: intravenous apelin lowers blood glucose and increases glucose utilisation in skeletal muscle and adipose tissue, through eNOS, AMPK and Akt, and restores glucose tolerance in obese insulin-resistant animals. Not established: any human perturbation, any effect of losing endogenous apelin on glucose handling, and any GO annotation on any species' APLN for a metabolic process.
Significance: Apelin is repeatedly proposed as a target in insulin resistance on the strength of this work. The distinction between a pharmacological effect of an infused agonist and a physiological role for the endogenous peptide is exactly the distinction GO evidence codes are meant to preserve, and here it has not been tested.
What would resolve it: Glucose tolerance and hyperinsulinaemic-euglycaemic clamp phenotyping of apelin-null mice, which have not been reported for this readout, and a controlled apelin infusion study with a clamp in humans.
Provenance (the field's own admissions):
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)