ANGPTL3 is a secreted glycoprotein produced predominantly by the liver that regulates circulating lipoproteins. Its N-terminal region inhibits lipoprotein lipase and endothelial lipase, helping maintain plasma triglyceride, cholesterol and phospholipid levels. Association with ANGPTL8 supports potent inhibition of intravascular lipoprotein lipase, while endothelial lipase inhibition can occur independently of ANGPTL8. Its C-terminal fibrinogen-like domain binds integrin alpha-v/beta-3 and supports endothelial adhesion, migration and angiogenic responses in experimental systems. Proteolytic processing generates fragments with distinct activities but is not obligatory for every inhibitory mechanism. Biallelic loss-of-function variants cause familial combined hypolipidemia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004857 enzyme inhibitor activity | IEA GO_REF:0000107 | MODIFY | Summary: The Ensembl transfer names mouse Angptl3. Reason: The Ensembl transfer names mouse Angptl3. Direct ANGPTL3 assays identify the inhibited enzymes as lipases, including LPL and endothelial lipase. Refine this generic molecular function to lipase inhibitor activity; this is a specificity correction, not rejection of orthology. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Proposed replacements: lipase inhibitor activity Supporting Evidence: |
| GO:0004857 enzyme inhibitor activity | ISS GO_REF:0000024 | MODIFY | Summary: The manually curated mouse ortholog transfer is biologically credible, but direct target evidence permits the more informative lipase inhibitor activity. Reason: The manually curated mouse ortholog transfer is biologically credible, but direct target evidence permits the more informative lipase inhibitor activity. The N-terminal inhibitory activity is distinct from the C-terminal integrin-binding activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Proposed replacements: lipase inhibitor activity Supporting Evidence: |
| GO:0004859 phospholipase inhibitor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Endothelial lipase phospholipase inhibition is experimentally supported for ANGPTL3. Reason: Endothelial lipase phospholipase inhibition is experimentally supported for ANGPTL3. The human protein in WITH/FROM is legitimate descendant evidence contributing to PAINT, not circular support. The original phylogenetic node was not independently reconstructed; target experimental grounding supports the inherited functional assertion. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1353627 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. PANTHER:PTN002709730 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9Y5C1 SUPPORTS TRANSFER Human ANGPTL3 is the target and an experimentally grounded descendant source. Target self-inclusion is appropriate PAINT provenance, not circularity; any term-scope refinement is discussed separately. Supporting Evidence: |
| GO:0004859 phospholipase inhibitor activity | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | ACCEPT | Summary: PMID:17110602 reports direct inhibition of endothelial lipase phospholipase activity through the ANGPTL3 N-terminal region, alongside mouse deficiency/add-back and human plasma correlations. Reason: PMID:17110602 reports direct inhibition of endothelial lipase phospholipase activity through the ANGPTL3 N-terminal region, alongside mouse deficiency/add-back and human plasma correlations. The biochemical inhibitory result supports this molecular function; the abstract does not resolve every recombinant construct species. Supporting Evidence: PMID:17110602 In vitro, ANGPTL3 inhibited the phospholipase activity of endothelial lipase (EL) |
| GO:0004859 phospholipase inhibitor activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic assertion agrees with directly tested endothelial lipase inhibition. Reason: The combined electronic assertion agrees with directly tested endothelial lipase inhibition. The ARBA rule and historical Ensembl donor row were not independently reconstructed, so the target assay corroborates the biological claim without treating the electronic rule as an experiment. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00087834 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: |
| GO:0005178 integrin binding | IPI PMID:11877390 ANGPTL3 stimulates endothelial cell adhesion and migration v... | KEEP AS NON CORE | Summary: The original paper directly tests recombinant human ANGPTL3 binding to alpha-v/beta-3 and human endothelial adhesion. Reason: The original paper directly tests recombinant human ANGPTL3 binding to alpha-v/beta-3 and human endothelial adhesion. P06756 is the alpha-v subunit; the assayed receptor is the heterodimer, not isolated alpha-v. This is a real domain-specific activity, retained outside the compact systemic lipid-regulation core. Supporting Evidence: PMID:11877390 recombinant ANGPTL3 bound to alpha(v)beta(3) |
| GO:0005576 extracellular region | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | ACCEPT | Summary: The source identifies a circulating hepatic factor and measures human plasma ANGPTL3. Reason: The source identifies a circulating hepatic factor and measures human plasma ANGPTL3. Extracellular action on endothelial lipase is consistent with the secreted mature protein and is the functional compartment for the lipid-regulatory core. Supporting Evidence: |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: The secretion mapping agrees with the native signal peptide, secreted protein and plasma measurements. Reason: The secretion mapping agrees with the native signal peptide, secreted protein and plasma measurements. SL-0243 supports the extracellular location; the exact historical ARBA rule was not separately inspected. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027128 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB-SubCell:SL-0243 SUPPORTS TRANSFER The UniProt secreted-location mapping agrees with the signal peptide and directly measured circulating protein. Supporting Evidence: |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8856525 | ACCEPT | Summary: The curated reaction places ANGPTL3 with ANGPTL8 extracellularly, consistent with the co-immunoprecipitated circulating complex in PMID:23150577. Reason: The curated reaction places ANGPTL3 with ANGPTL8 extracellularly, consistent with the co-immunoprecipitated circulating complex in PMID:23150577. Retain the compartment without treating the reaction summary as proof that proteolytic cleavage is obligatory for every inhibitory activity. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9657775 | ACCEPT | Summary: The Reactome record describes production of a secreted hepatic protein under nuclear-receptor control. Reason: The Reactome record describes production of a secreted hepatic protein under nuclear-receptor control. The resulting extracellular ANGPTL3 location is supported; being transcriptionally regulated does not make ANGPTL3 a transcription factor. Supporting Evidence: Reactome:R-HSA-9657775 |
| GO:0005769 early endosome | IEA GO_REF:0000107 | UNDECIDED | Summary: Mouse ortholog transfer for early-endosomal/Golgi pool needs the actual donor experiment; secretion alone neither establishes nor excludes these specific pools. Reason: The mouse/Ensembl transfer is preserved, but the exact early-endosomal donor experiment was not recovered. PMID:37634084 reports tagged ANGPTL3 with late-endosome Rab7 markers, which does not establish early-endosome localization. Secretion neither proves nor excludes an early-endosomal pool. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Tagged ANGPTL3 has a Golgi-associated secretory-pathway pool in human cells. Reason: PMID:37634084 reports tagged ANGPTL3 colocalization with the Golgi marker YFP-GalT in HEK293T cells. The human ANGPTL3 construct series in Figure 5 and human-sequence knockdown of the expression plasmid support interpreting the shared expression constructs as human. This resolves the biological location at the scope of transient tagged expression; it does not establish endogenous Golgi residence. Retain this secretory-pathway location as non-core. The original mouse/Ensembl donor chain remains unreconstructed and its source-specific caveats are preserved. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: UniProt:Q9Y5C1 PMID:37634084 ANGPTL3 and IL1R1 co-localized with markers of ER, Golgi apparatus, late endosome, and MVB |
| GO:0006071 glycerol metabolic process | IDA PMID:12565906 Angiopoietin-like protein 3, a hepatic secretory factor, act... | MODIFY | Summary: The cited study reports ANGPTL3-induced glycerol release from adipocytes. Reason: The cited study reports ANGPTL3-induced glycerol release from adipocytes. This demonstrates regulation of lipolysis, not a glycerol-converting reaction performed by ANGPTL3. Refine to the already represented positive regulation of lipid catabolic process; this context is separate from inhibition of intravascular LPL. Proposed replacements: positive regulation of lipid catabolic process Supporting Evidence: |
| GO:0006631 fatty acid metabolic process | IDA PMID:12565906 Angiopoietin-like protein 3, a hepatic secretory factor, act... | MODIFY | Summary: The cited study reports free-fatty-acid release following ANGPTL3 treatment and binding to adipose cells. Reason: The cited study reports free-fatty-acid release following ANGPTL3 treatment and binding to adipose cells. The supported role is stimulation of adipocyte lipolysis, not direct fatty-acid chemistry. Use the already represented positive regulation of lipid catabolic process. Proposed replacements: positive regulation of lipid catabolic process Supporting Evidence: |
| GO:0006644 phospholipid metabolic process | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | MODIFY | Summary: The observed molecular step is inhibition of endothelial lipase phospholipase activity. Reason: The observed molecular step is inhibition of endothelial lipase phospholipase activity. ANGPTL3 regulates phospholipid breakdown rather than hydrolyzing phospholipids itself. Use regulation of phospholipid catabolic process, with inhibition stated in the rationale; the same replacement is used for the catabolism rows to avoid overlapping authored coverage. GO:0060696 is direction-neutral; the negative effect is retained in prose because no generic negative phospholipid-catabolism child was found in the checked ontology. Proposed replacements: regulation of phospholipid catabolic process Supporting Evidence: |
| GO:0007160 cell-matrix adhesion | IPI PMID:11877390 ANGPTL3 stimulates endothelial cell adhesion and migration v... | KEEP AS NON CORE | Summary: Recombinant human ANGPTL3 immobilized on culture surfaces supported human endothelial adhesion through alpha-v/beta-3. Reason: Recombinant human ANGPTL3 immobilized on culture surfaces supported human endothelial adhesion through alpha-v/beta-3. This is direct contextual adhesion evidence, retained as non-core; an immobilized-ligand assay does not establish ubiquitous structural membership of native extracellular matrix. Supporting Evidence: |
| GO:0007165 signal transduction | IDA PMID:11877390 ANGPTL3 stimulates endothelial cell adhesion and migration v... | MODIFY | Summary: The paper tests alpha-v/beta-3-dependent adhesion/migration and associated FAK, MAPK and Akt phosphorylation. Reason: The paper tests alpha-v/beta-3-dependent adhesion/migration and associated FAK, MAPK and Akt phosphorylation. The existing integrin-mediated signaling pathway term is more informative than generic signal transduction. The discussion leaves open whether every signaling response is exclusively mediated by that integrin. Proposed replacements: integrin-mediated signaling pathway Supporting Evidence: |
| GO:0007229 integrin-mediated signaling pathway | NAS PMID:11877390 ANGPTL3 stimulates endothelial cell adhesion and migration v... | KEEP AS NON CORE | Summary: The original paper supports integrin-associated signaling in endothelial cells through binding, inhibition of adhesion/migration by blocking antibody, and downstream phosphorylation. Reason: The original paper supports integrin-associated signaling in endothelial cells through binding, inhibition of adhesion/migration by blocking antibody, and downstream phosphorylation. Keep this contextual activity distinct from the systemic lipase-inhibitory core and do not infer exclusivity of every signaling response. Supporting Evidence: |
| GO:0008083 growth factor activity | IDA PMID:11877390 ANGPTL3 stimulates endothelial cell adhesion and migration v... | MODIFY | Summary: GO:0008083 requires stimulation of cell growth or proliferation. Reason: GO:0008083 requires stimulation of cell growth or proliferation. The original paper reports a negative endothelial proliferation result under the tested conditions, alongside positive direct integrin binding, adhesion and migration. Refine this source-specific claim to integrin binding, already represented among the existing annotations. The original Results passage and assay context are linked and excerpted in the notes; the normal cache contains only the abstract. This conclusion does not follow from abstract silence and does not exclude growth-related effects in other tissues. Proposed replacements: integrin binding Supporting Evidence: PMID:11877390 recombinant ANGPTL3 bound to alpha(v)beta(3) file:human/ANGPTL3/ANGPTL3-notes.md The original endothelial proliferation result is negative under the stated culture conditions, while direct integrin binding is positive. |
| GO:0008203 cholesterol metabolic process | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | MODIFY | Summary: PMID:17110602 links inhibition of endothelial lipase to maintenance of HDL cholesterol and phospholipids, with mouse perturbation and human plasma correlations. Reason: PMID:17110602 links inhibition of endothelial lipase to maintenance of HDL cholesterol and phospholipids, with mouse perturbation and human plasma correlations. Cholesterol homeostasis, already present with this citation, states the supported regulatory role more precisely than suggesting ANGPTL3 performs sterol chemistry. Proposed replacements: cholesterol homeostasis Supporting Evidence: |
| GO:0009395 phospholipid catabolic process | IBA GO_REF:0000033 | MODIFY | Summary: The human descendant evidence supports suppression of endothelial lipase-mediated phospholipid breakdown. Reason: The human descendant evidence supports suppression of endothelial lipase-mediated phospholipid breakdown. The target acts as an inhibitor, not the phospholipid-cleaving enzyme, so refine the process to regulation of phospholipid catabolic process. This challenges term scope rather than donor count or target self-inclusion; the ancestral PAINT placement remains unverified. GO:0060696 is direction-neutral; the negative effect is retained in prose because no generic negative phospholipid-catabolism child was found in the checked ontology. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN002709730 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9Y5C1 SUPPORTS TRANSFER Human ANGPTL3 is the target and an experimentally grounded descendant source. Target self-inclusion is appropriate PAINT provenance, not circularity; any term-scope refinement is discussed separately. Proposed replacements: regulation of phospholipid catabolic process Supporting Evidence: |
| GO:0009395 phospholipid catabolic process | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | MODIFY | Summary: The cited experiment establishes inhibition of endothelial lipase phospholipase activity. Reason: The cited experiment establishes inhibition of endothelial lipase phospholipase activity. Refine direct phospholipid catabolism to its regulation, with inhibition stated in the rationale, because endothelial lipase performs the hydrolysis and ANGPTL3 reduces that activity. GO:0060696 is direction-neutral; the negative effect is retained in prose because no generic negative phospholipid-catabolism child was found in the checked ontology. Proposed replacements: regulation of phospholipid catabolic process Supporting Evidence: |
| GO:0009725 response to hormone | IEA GO_REF:0000107 | UNDECIDED | Summary: Exact rat source-chain experiment not inspected; hormone regulation of ANGPTL3 abundance alone does not prove ANGPTL3 performs the response. Reason: This electronic transfer names rat F7FHP0 and an Ensembl rat protein, but its original hormone-response experiment was not recovered. Hormone-dependent changes in ANGPTL3 expression alone do not settle participation by the protein in a response process. Preserve the assertion as unresolved rather than reject it from an incomplete source chain. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:F7FHP0 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSRNOP00000011486 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: UniProt:Q9Y5C1 |
| GO:0009986 cell surface | IDA PMID:12565906 Angiopoietin-like protein 3, a hepatic secretory factor, act... | KEEP AS NON CORE | Summary: The original abstract reports fluorescent and radiolabeled ANGPTL3 binding to adipose cells. Reason: The original abstract reports fluorescent and radiolabeled ANGPTL3 binding to adipose cells. Retain a contextual surface-associated pool, without implying membrane insertion or constitutive residence on all cell types. Full cell and construct details were not available. Supporting Evidence: PMID:12565906 Specific bindings of ANGPTL3 to adipose cells were shown |
| GO:0009986 cell surface | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The combined mouse-derived electronic assertion is biologically supported by target adipose-cell binding. Reason: The combined mouse-derived electronic assertion is biologically supported by target adipose-cell binding. This is an extracellular protein bound at a cell surface, retained as non-core; the exact historical ARBA and Ensembl source experiments were not independently reconstructed. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00027349 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: |
| GO:0010903 negative regulation of very-low-density lipoprotein particle remodeling | IDA PMID:19542565 GPIHBP1 stabilizes lipoprotein lipase and prevents its inhib... | ACCEPT | Summary: ANGPTL3 inhibition of LPL provides a mechanistic basis for reduced lipolytic remodeling of VLDL. Reason: ANGPTL3 inhibition of LPL provides a mechanistic basis for reduced lipolytic remodeling of VLDL. The original abstract establishes biochemical LPL inhibition and mouse serum-triglyceride responses; the later human kinetic study independently supports physiological triglyceride-rich lipoprotein regulation. Retain the established regulatory function without describing the earlier enzyme assay as a direct human VLDL-particle experiment. Supporting Evidence: PMID:19542565 ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. |
| GO:0010903 negative regulation of very-low-density lipoprotein particle remodeling | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion agrees with the lipase-inhibitory mechanism controlling triglyceride-rich lipoprotein remodeling. Reason: The electronic assertion agrees with the lipase-inhibitory mechanism controlling triglyceride-rich lipoprotein remodeling. Target corroboration supports the functional term; the precise ARBA rule and historical mouse/Ensembl source rows were not independently audited. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00093686 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: |
| GO:0019915 lipid storage | IDA PMID:12565906 Angiopoietin-like protein 3, a hepatic secretory factor, act... | UNDECIDED | Summary: The accessible source demonstrates lipid mobilization; its full lipid-storage assay scope remains unexamined. Do not reject the experimental row from the abstract alone. Reason: The available PMID:12565906 abstract reports mobilization of fatty acids and glycerol, but does not expose the experiment underlying the storage annotation. GO:0019915 concerns accumulation and maintenance of lipids. Mobilization does not by itself refute a storage-related physiological role, so retain the original experimental assertion as unresolved pending full text. Supporting Evidence: |
| GO:0030027 lamellipodium | IEA GO_REF:0000044 | UNDECIDED | Summary: UniProt mapping explicitly transfers mouse podocyte/lamellipodial colocalization. The detailed source and human applicability still require checking; do not infer contradiction from the secreted pool. Reason: The UniProt subcellular-location statement is explicitly transferred from mouse Q9R182 and describes podocyte colocalization with HSPG2 and activated ITGB3. The exact donor imaging experiment and human transfer context were not recovered. Secreted ANGPTL3 could be surface-associated; a secretory signal is not evidence against this location. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB-SubCell:SL-0291 UNRESOLVED The human UniProt lamellipodium statement is explicitly transferred from mouse Q9R182. The exact podocyte donor imaging experiment was not recovered. Supporting Evidence: UniProt:Q9Y5C1 |
| GO:0030335 positive regulation of cell migration | IDA PMID:11877390 ANGPTL3 stimulates endothelial cell adhesion and migration v... | KEEP AS NON CORE | Summary: The original paper demonstrates alpha-v/beta-3-dependent haptotactic migration of human endothelial cells on recombinant ANGPTL3. Reason: The original paper demonstrates alpha-v/beta-3-dependent haptotactic migration of human endothelial cells on recombinant ANGPTL3. Retain the experimentally tested positive regulation as a contextual non-core process, without generalizing to all migratory cells. Supporting Evidence: |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | UNDECIDED | Summary: Exact PAINT matrix-localization node placement and source context remain unresolved; donor count and fibrinogen-domain architecture are not sufficient objections. Reason: This PAINT assertion may reflect a genuine inherited extracellular-matrix association, but the actual ancestral node, donor experiments and target tissue context were not recovered. A shared fibrinogen-like domain or an immobilized adhesion substrate is not enough to decide native matrix incorporation. Donor number or evolutionary distance alone is not a propagation failure. Circulating HDL association does not exclude a tissue-specific matrix pool. Different ancestral identifiers alone do not establish relative node depth or refute placement without the tree and ancestral evidence. Propagation Review Root cause: UNRESOLVED Sources checked: MGI:MGI:2665790 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. MGI:MGI:99516 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. PANTHER:PTN000441162 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. RGD:3886 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:P55083 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:P55918 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9UQP3 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: UniProt:Q9Y5C1 |
| GO:0035473 lipase binding | IPI PMID:19542565 GPIHBP1 stabilizes lipoprotein lipase and prevents its inhib... | ACCEPT | Summary: Binding to the inhibited lipase is consistent with ANGPTL3 inhibitory function and later target-protein biophysical studies. Reason: Binding to the inhibited lipase is consistent with ANGPTL3 inhibitory function and later target-protein biophysical studies. The original Figure1 assay measures GPIHBP1 binding to LPL, as documented with a public section locator in the notes; it is not used as direct evidence of the ANGPTL3 interface. Retain the curator-supported functional interaction and the later mechanistic corroboration without inventing a direct-binding assay in the original paper. PMID:40112106 independently maps an LPL-binding interface in the proximal N-terminal helix of human ANGPTL3 and ANGPTL3/8 by HDX-MS, using bovine LPL in the interface experiments; separate activity assays use human furin-resistant R297A LPL. These later experiments corroborate lipase binding without changing the original source assertion. Supporting Evidence: PMID:40112106 the proximal Ξ±-helix of ANGPTL3 participates in the LPL binding interface file:human/ANGPTL3/ANGPTL3-notes.md The original Figure1 binding assay tests GPIHBP1 with LPL; the later PMID:40112106 experiments independently establish an ANGPTL3βLPL interface. |
| GO:0042632 cholesterol homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Endothelial lipase inhibition, the mouse deficiency/add-back phenotype and human plasma association support the cholesterol-homeostatic role. Reason: Endothelial lipase inhibition, the mouse deficiency/add-back phenotype and human plasma association support the cholesterol-homeostatic role. Human ANGPTL3 is valid descendant evidence for PAINT; its occurrence in WITH/FROM is not circular. The exact ancestral placement was not independently inspected. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1353627 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. PANTHER:PTN002709730 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9Y5C1 SUPPORTS TRANSFER Human ANGPTL3 is the target and an experimentally grounded descendant source. Target self-inclusion is appropriate PAINT provenance, not circularity; any term-scope refinement is discussed separately. Supporting Evidence: |
| GO:0042632 cholesterol homeostasis | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | ACCEPT | Summary: The source separates low HDL cholesterol in deficient mice and restoration by ANGPTL3 from the correlation of human plasma ANGPTL3 with HDL cholesterol. Reason: The source separates low HDL cholesterol in deficient mice and restoration by ANGPTL3 from the correlation of human plasma ANGPTL3 with HDL cholesterol. Together with direct endothelial lipase inhibition these support the homeostatic role; the human observations alone are not an intervention experiment. Supporting Evidence: |
| GO:0042632 cholesterol homeostasis | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic cholesterol-homeostasis assertion agrees with target biochemical and physiological evidence. Reason: The combined electronic cholesterol-homeostasis assertion agrees with target biochemical and physiological evidence. Exact historical rule execution and donor peptide versions remain unverified, without undermining the experimentally grounded biological role. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00086791 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: |
| GO:0045766 positive regulation of angiogenesis | IDA PMID:11877390 ANGPTL3 stimulates endothelial cell adhesion and migration v... | KEEP AS NON CORE | Summary: The original paper tests human and mouse recombinant ANGPTL3 in rat corneal pellets and finds vessel growth. Reason: The original paper tests human and mouse recombinant ANGPTL3 in rat corneal pellets and finds vessel growth. The FBN construct includes an oligomerizing leucine zipper. Keep this contextual angiogenic activity as non-core; it is not an endogenous human arterial-development experiment. Supporting Evidence: |
| GO:0048844 artery morphogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: The specific artery-morphogenesis donor experiment is not yet recovered. The human endothelial/rat corneal evidence establishes broader angiogenic effects, not this artery-specific developmental outcome. Reason: The exact mouse experiment supporting artery morphogenesis was not recovered. General rat corneal angiogenesis after recombinant protein application does not specifically establish artery morphogenesis. Retain the transfer as unresolved rather than infer that the donor curator was wrong. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: UniProt:Q9Y5C1 |
| GO:0048844 artery morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: The specific artery-morphogenesis donor experiment is not yet recovered. The human endothelial/rat corneal evidence establishes broader angiogenic effects, not this artery-specific developmental outcome. Reason: The manually curated mouse ortholog transfer is preserved, but the artery-specific source experiment remains unavailable. The independently read angiogenesis study does not settle this more specific developmental process. Orthology itself is not the reason for uncertainty. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: UniProt:Q9Y5C1 |
| GO:0050996 positive regulation of lipid catabolic process | IDA PMID:12565906 Angiopoietin-like protein 3, a hepatic secretory factor, act... | KEEP AS NON CORE | Summary: The cited study directly reports ANGPTL3-stimulated fatty-acid and glycerol release from adipocytes. Reason: The cited study directly reports ANGPTL3-stimulated fatty-acid and glycerol release from adipocytes. Retain this positive lipolytic effect as a contextual non-core role. It occurs in a different cellular setting from the inhibition of vascular LPL and is not contradicted merely by that inhibitory core. Supporting Evidence: |
| GO:0055088 lipid homeostasis | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | ACCEPT | Summary: ANGPTL3 controls extracellular lipid handling through inhibition of LPL and endothelial lipase. Reason: ANGPTL3 controls extracellular lipid handling through inhibition of LPL and endothelial lipase. The cited paper supports plasma HDL cholesterol/phospholipid regulation. Retain this existing ancestor only as the umbrella for the same core mechanism; it adds no separate functional claim and is omitted from the synthesized core in favor of the specific lipid-homeostasis terms. Supporting Evidence: |
| GO:0055090 acylglycerol homeostasis | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | ACCEPT | Summary: ANGPTL3 controls triglyceride-rich lipoprotein turnover through LPL inhibition. Reason: ANGPTL3 controls triglyceride-rich lipoprotein turnover through LPL inhibition. PMID:17110602 principally tests endothelial lipase and HDL, so its title and abstract alone do not establish a separate acylglycerol experiment; direct LPL studies and ANGPTL3/8 mouse coexpression independently support the known acylglycerol-homeostatic function. |
| GO:0055090 acylglycerol homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse-derived Ensembl transfer agrees with LPL inhibition and ANGPTL3/8-dependent plasma triglyceride regulation. Reason: The mouse-derived Ensembl transfer agrees with LPL inhibition and ANGPTL3/8-dependent plasma triglyceride regulation. Retain the broader acylglycerol-homeostasis term as core; the synthetic core uses the more specific triglyceride-homeostasis term without duplicating both levels. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. |
| GO:0055091 phospholipid homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Direct endothelial lipase inhibition and plasma phospholipid effects support the conserved homeostatic assertion. Reason: Direct endothelial lipase inhibition and plasma phospholipid effects support the conserved homeostatic assertion. Target self-inclusion supplies legitimate experimental descendant grounding for PAINT, not circularity; exact ancestral placement was not reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1353627 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. PANTHER:PTN002709730 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9Y5C1 SUPPORTS TRANSFER Human ANGPTL3 is the target and an experimentally grounded descendant source. Target self-inclusion is appropriate PAINT provenance, not circularity; any term-scope refinement is discussed separately. Supporting Evidence: |
| GO:0055091 phospholipid homeostasis | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | ACCEPT | Summary: PMID:17110602 measures reduced HDL phospholipid in deficient mice, restoration by ANGPTL3 supplementation, increased phospholipase activity in knockout plasma, and a human plasma correlation. Reason: PMID:17110602 measures reduced HDL phospholipid in deficient mice, restoration by ANGPTL3 supplementation, increased phospholipase activity in knockout plasma, and a human plasma correlation. Direct endothelial lipase inhibition connects these observations to phospholipid homeostasis. Supporting Evidence: |
| GO:0055091 phospholipid homeostasis | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion agrees with direct target inhibition of endothelial lipase and plasma phospholipid regulation. Reason: The electronic assertion agrees with direct target inhibition of endothelial lipase and plasma phospholipid regulation. It is retained on biological grounds without claiming that the complete historical rule and donor-source chain were re-executed. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00084814 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: |
| GO:0055102 lipase inhibitor activity | IDA PMID:17110602 Angiopoietin-like protein3 regulates plasma HDL cholesterol ... | ACCEPT | Summary: The paper directly demonstrates inhibition of endothelial lipase phospholipase activity; phospholipase inhibitor activity is a descendant of lipase inhibitor activity. Reason: The paper directly demonstrates inhibition of endothelial lipase phospholipase activity; phospholipase inhibitor activity is a descendant of lipase inhibitor activity. This broad molecular-function assertion is therefore sound, although its more specific phospholipase row retains the same evidence. Supporting Evidence: |
| GO:0055102 lipase inhibitor activity | IDA PMID:19542565 GPIHBP1 stabilizes lipoprotein lipase and prevents its inhib... | ACCEPT | Summary: The cited study directly demonstrates ANGPTL3 inhibition of LPL, modified by the stabilizing environment. Reason: The normal abstract explicitly reports inhibition of nonstabilized LPL and relative resistance of GPIHBP1-stabilized LPL. Retain lipase inhibitor activity with this assay-context dependence; differing potency under stabilizing conditions does not negate inhibition. Supporting Evidence: PMID:19542565 ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. |
| GO:0070328 triglyceride homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: ANGPTL3-dependent LPL inhibition and mouse ANGPTL3/8 cooperation support triglyceride homeostasis. Reason: ANGPTL3-dependent LPL inhibition and mouse ANGPTL3/8 cooperation support triglyceride homeostasis. Human ANGPTL3 in WITH/FROM is valid descendant evidence for the PAINT assertion. No donor-count or self-circularity objection is warranted. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1353627 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. PANTHER:PTN002709730 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9Y5C1 SUPPORTS TRANSFER Human ANGPTL3 is the target and an experimentally grounded descendant source. Target self-inclusion is appropriate PAINT provenance, not circularity; any term-scope refinement is discussed separately. |
| GO:0070328 triglyceride homeostasis | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic assertion is independently corroborated by target lipase inhibition and ANGPTL3/8-dependent triglyceride regulation. Reason: The combined electronic assertion is independently corroborated by target lipase inhibition and ANGPTL3/8-dependent triglyceride regulation. The exact historical ARBA rule and donor Ensembl version were not separately reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00092108 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. |
| GO:0070328 triglyceride homeostasis | IGI PMID:23150577 Atypical angiopoietin-like protein that regulates ANGPTL3. | ACCEPT | Summary: The source expresses human ANGPTL3 and ANGPTL8 in mouse liver, observes hypertriglyceridemia with coexpression, and finds that ANGPTL8 fails to raise triglycerides in Angptl3-null mice. Reason: The source expresses human ANGPTL3 and ANGPTL8 in mouse liver, observes hypertriglyceridemia with coexpression, and finds that ANGPTL8 fails to raise triglycerides in Angptl3-null mice. Plasma co-immunoprecipitation supports cooperation. Preserve the genetic interaction without treating the authors' cleavage-activation model as the only possible mechanism. Supporting Evidence: PMID:23150577 coexpression with ANGPTL8 resulted in hypertriglyceridemia |
| GO:0070328 triglyceride homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: The manually curated mouse ortholog transfer agrees with direct ANGPTL3 inhibition of LPL and the ANGPTL3-dependent plasma triglyceride phenotype. Reason: The manually curated mouse ortholog transfer agrees with direct ANGPTL3 inhibition of LPL and the ANGPTL3-dependent plasma triglyceride phenotype. The conserved homeostatic role is retained; this does not claim every mouse tissue-distribution detail was independently shown in humans. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. |
| GO:0090318 regulation of chylomicron remodeling | IDA PMID:19542565 GPIHBP1 stabilizes lipoprotein lipase and prevents its inhib... | ACCEPT | Summary: Inhibition of LPL provides a direct regulatory mechanism for chylomicron lipolytic remodeling. Reason: Inhibition of LPL provides a regulatory mechanism for chylomicron lipolytic remodeling. The original abstract reports enzyme inhibition and mouse lipid responses; the later human kinetic study independently examines chylomicron clearance. The physiological interpretation is retained without treating the original enzyme-activity experiment as a direct human chylomicron-particle assay. Supporting Evidence: PMID:19542565 ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. |
| GO:0090318 regulation of chylomicron remodeling | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic chylomicron-remodeling regulation assertion agrees with the extracellular LPL-inhibitory mechanism. Reason: The electronic chylomicron-remodeling regulation assertion agrees with the extracellular LPL-inhibitory mechanism. No direct lipid hydrolysis or physical transport activity is attributed to ANGPTL3; the historical rule/source execution was not independently reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00093707 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: |
| GO:1905883 regulation of triglyceride transport | IDA PMID:19542565 GPIHBP1 stabilizes lipoprotein lipase and prevents its inhib... | ACCEPT | Summary: ANGPTL3 regulates triglyceride flux by modulating LPL-dependent lipoprotein processing. Reason: ANGPTL3 regulates triglyceride flux by modulating LPL-dependent lipoprotein processing. The original abstract reports enzyme inhibition and mouse serum-triglyceride responses, while the later human tracer study independently addresses lipoprotein kinetics. ANGPTL3 regulates lipid delivery through inhibition; it is not a triglyceride transporter. Supporting Evidence: PMID:19542565 ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. |
| GO:1905883 regulation of triglyceride transport | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic assertion is consistent with regulation of triglyceride handling by LPL inhibition. Reason: The electronic assertion is consistent with regulation of triglyceride handling by LPL inhibition. Retain it as regulatory core biology, without implying that ANGPTL3 physically carries triglyceride across a membrane or that every source-rule step was independently recovered. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00098328 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. UniProtKB:Q9R182 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. ensembl:ENSMUSP00000030280 UNRESOLVED The original source identifier is preserved. Its exact historical annotation/rule or ancestral node was not independently reconstructed; target biological evidence is assessed separately in the row reason. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which original mouse or rat experiments support the early-endosome, Golgi, artery-morphogenesis, lamellipodium and hormone-response transfers, and what cellular contexts justify their application to human ANGPTL3?
Q: What native matrix-associated ANGPTL3 pool underlies the PAINT extracellular-matrix assertion, and which ancestral node and descendant experiments support it?
Q: How do circulating ANGPTL3 monomers, homotrimers and ANGPTL3/8 complexes divide endothelial-lipase and lipoprotein-lipase regulation under physiological conditions?
Q: Does the full PMID:12565906 storage experiment establish an ANGPTL3 role beyond the adipocyte lipid mobilization described in the abstract?
Q: How should ATP-independent unfolding of the LPL catalytic domain by ANGPTL3/8 be represented in GO without implying ATPase activity or assuming dissociation of a protein-containing complex?
Q: Should the directly demonstrated inhibitory step also carry GO:0060192 negative regulation of lipase activity or its LPL-specific child GO:0051005, given the existing inhibitor molecular-function annotation and the current activity-regulation term maintenance policy?
Experiment: Compare matched full-length human ANGPTL3, cleavage-resistant variants and defined ANGPTL3/8 complexes at physiological concentrations against human LPL and endothelial lipase, including native lipoprotein substrates and endothelial GPIHBP1.
Experiment: Use endogenous human ANGPTL3 labeling with secretion and expression controls to distinguish transient secretory traffic from functional Golgi/endosomal or podocyte-surface pools.
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