LPAR3 is a class-A seven-transmembrane receptor that recognizes lysophosphatidic acid and activates heterotrimeric G proteins at the plasma membrane. It supports phospholipase-C-dependent calcium mobilization and context-dependent cyclic-nucleotide and ERK responses. Human LPAR3 potentiates forskolin-stimulated cAMP in Sf9 cells and supports Gi2alpha activation in a recombinant mammalian membrane assay; these observations reflect different signaling environments. The receptor preferentially responds to several unsaturated LPA species, although saturated ligands can act in other assay systems. Agonist- and protein-kinase-C-dependent phosphorylation regulate beta-arrestin recruitment and receptor internalization. LPAR3 is expressed in reproductive and other tissues, including human forebrain regions in one Northern-blot study. In mice, Lpar3 signaling contributes to uterine receptivity, embryo spacing and axonal branching. Loss of uterine Lpar3 disrupts implantation timing and spacing; prostaglandin supplementation rescues timing but not spacing. The historical HOFNH30 sequence was proposed as a possible splice variant, but its status as an endogenous LPAR3 protein isoform remains unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. Reason: Human EDG7/LPAR3 is directly characterized as a lysophosphatidic acid receptor, so the ligand-specific molecular-function term is more informative than the GPCR parent term (PMID:10488122). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:104615 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. MGI:MGI:108429 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. MGI:MGI:1096355 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. MGI:MGI:2155249 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. MGI:MGI:96929 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. MGI:MGI:99420 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. MGI:MGI:99456 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. MGI:MGI:99457 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. PANTHER:PTN002733616 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:1312046 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:2369 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:3056 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:3057 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:3058 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:61958 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:619713 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:620566 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. RGD:68334 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:O95136 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:P21453 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:P21554 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:P32245 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:P33032 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:P34972 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:P41968 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:Q01718 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:Q01726 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. UniProtKB:Q92633 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-001228-2 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-021223-2 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-030502-2 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-030616-499 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-040801-97 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-051120-99 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-060503-489 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-081104-390 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-100209-3 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-120202-1 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-120215-99 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. ZFIN:ZDB-GENE-170413-1 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Generic GPCR activity is valid but should be represented by the established LPAR3-specific receptor activity. Proposed replacements: lysophosphatidic acid receptor activity |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. Reason: GO:0005737 includes subcellular structures other than the plasma membrane and nucleus; it is not synonymous with soluble cytosol. Both actual target lineages descend from positive PTN002733616. Human receptor internalization is directly documented in PMID:26473723; LPAR3 additionally retains intracellular receptorβarrestin associations in PMID:38928196. No target loss of the inherited contextual assertion has been established. Preserve the original is_active_in qualifier without claiming that imaging alone proves a particular endosomal G-protein signaling mechanism. The former objection based solely on seven-transmembrane topology was invalid. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:104615 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. PANTHER:PTN002733616 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. UniProtKB:F1STP7 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. UniProtKB:O95977 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. UniProtKB:P34972 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. UniProtKB:Q92633 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. UniProtKB:Q9HBW0 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. ZFIN:ZDB-GENE-030502-2 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain the inherited broad cytoplasmic context; internal membrane structures belong to cytoplasm. Supporting Evidence: PMID:26473723 It was also clearly observed that agonists and protein kinase C activation induced internalization of these receptors. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Accepted as the core membrane location of LPAR3 receptor activity. Reason: LPAR3 is an integral seven-transmembrane receptor that recognizes extracellular LPA and activates heterotrimeric G proteins at the plasma membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:104615 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. MGI:MGI:108429 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. MGI:MGI:1096355 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. MGI:MGI:1858422 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. PANTHER:PTN002733616 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. RGD:2369 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. RGD:619713 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. RGD:620563 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:F1STP7 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:O95136 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:P21453 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:P21554 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:P32245 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:P33032 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:P34972 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:Q01718 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:Q01726 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:Q92633 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:Q99500 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. UniProtKB:Q9UBY5 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. ZFIN:ZDB-GENE-030502-1 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. ZFIN:ZDB-GENE-030502-2 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Accepted as the core membrane location of LPAR3 receptor activity. |
| GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. Reason: Author-deposited full text of PMID:10488122 was inspected outside the abstract-only repository cache, as documented with its ResearchGate URL in the shared primary-evidence record. Methods, Results and Fig.7 report LPA-dependent enhancement of forskolin-stimulated cAMP in human EDG4/LPAR2- and EDG7/LPAR3-expressing Sf9 cells with IBMX present. LPA alone did not produce this response. GO:0007189 requires activating cyclase signaling, not Gs coupling or a positive direction in every cell. The actual target descends from positive IBD PTN002733616, so a wrong-branch explanation is unsupported. PMID:10727522 contrasts mammalian-cell assays and proposes possible conditional cyclase/PKC mechanisms; PMID:16203867 directly establishes contextual LPAR2 Gi-mediated inhibition. Keep this experimentally observed, conditional activating capacity non-core. The shared focused adjudication concerns its construct dependence, mechanism and physiological scope; the retained annotation does not claim a constitutive or dominant activating branch. The early EDG4 C-terminal frameshift must be checked against individual constructs, not assumed for every experiment. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1333809 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. PANTHER:PTN002733616 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. UniProtKB:F1STP7 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. UniProtKB:P32245 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. UniProtKB:P33032 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. UniProtKB:P41968 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. UniProtKB:Q01718 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. UniProtKB:Q01726 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. ZFIN:ZDB-GENE-021223-2 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. ZFIN:ZDB-GENE-030502-2 SUPPORTS TRANSFER Actual PTHR22750 target ancestry contains positive PTN002733616. This supports inheritance; no source count or self-donor objection applies. Retain conditional adenylate-cyclase-activating signaling; inhibitory responses in other contexts do not refute this capacity. Supporting Evidence: PMID:10488122 In EDG7- or EDG4-expressing Sf9 cells, LPA stimulated forskolin-induced increase in intracellular cAMP levels |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic GPCR activity is valid but less informative than the established LPA-specific receptor activity. Reason: The InterPro GPCR mapping is correct, while direct human EDG7 evidence supports lysophosphatidic acid receptor activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broader concept, while direct human LPAR3 evidence supports the more precise replacement. Proposed replacements: lysophosphatidic acid receptor activity |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as the core membrane location of LPAR3. Reason: The UniProt subcellular-location mapping agrees with the reviewed record and the receptorβs seven-transmembrane topology. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER The UniProt subcellular-location mapping agrees with the reviewed record and the receptorβs seven-transmembrane topology. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Accepted as the core signaling process initiated by LPA-bound LPAR3. Reason: Direct human EDG7 experiments demonstrate LPA-dependent calcium and cyclic-nucleotide responses, consistent with heterotrimeric G-protein signaling (PMID:10488122). Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00029021 SUPPORTS TRANSFER Direct human EDG7 experiments demonstrate LPA-dependent calcium and cyclic-nucleotide responses, consistent with heterotrimeric G-protein signaling (PMID:10488122). UniProtKB:Q8K5E0 SUPPORTS TRANSFER Direct human EDG7 experiments demonstrate LPA-dependent calcium and cyclic-nucleotide responses, consistent with heterotrimeric G-protein signaling (PMID:10488122). ensembl:ENSRNOP00000089155 SUPPORTS TRANSFER Direct human EDG7 experiments demonstrate LPA-dependent calcium and cyclic-nucleotide responses, consistent with heterotrimeric G-protein signaling (PMID:10488122). InterPro:IPR000276 SUPPORTS TRANSFER Direct human EDG7 experiments demonstrate LPA-dependent calcium and cyclic-nucleotide responses, consistent with heterotrimeric G-protein signaling (PMID:10488122). InterPro:IPR004065 SUPPORTS TRANSFER Direct human EDG7 experiments demonstrate LPA-dependent calcium and cyclic-nucleotide responses, consistent with heterotrimeric G-protein signaling (PMID:10488122). InterPro:IPR005385 SUPPORTS TRANSFER Direct human EDG7 experiments demonstrate LPA-dependent calcium and cyclic-nucleotide responses, consistent with heterotrimeric G-protein signaling (PMID:10488122). |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000117 | ACCEPT | Summary: Accepted as a direct second-messenger output of LPAR3 signaling. Reason: LPA selectively raises intracellular calcium in EDG7/LPAR3-expressing cells, whereas other lysophospholipids do not (PMID:10488122). Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028136 SUPPORTS TRANSFER LPA selectively raises intracellular calcium in EDG7/LPAR3-expressing cells, whereas other lysophospholipids do not (PMID:10488122). |
| GO:0008289 lipid binding | IEA GO_REF:0000117 | MODIFY | Summary: Generic lipid binding should be replaced by the demonstrated LPAR3 ligand interaction. Reason: Lysophosphatidic acid binding is the experimentally established ligand-recognition activity and is more informative than the true parent binding term. The broad parent does not itself imply binding to unrelated lipids. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027537 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broader concept, while direct human LPAR3 evidence supports the more precise replacement. Proposed replacements: lysophosphatidic acid binding |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: Membrane is a correct broad description of this integral receptor. Reason: The receptor occupies the plasma membrane and can enter internal membrane compartments. The broad membrane annotation is correct and does not assert exclusive plasma-membrane residence; replacing it with only plasma membrane would discard a supported context. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR000276 SUPPORTS TRANSFER The receptor occupies the plasma membrane and can enter internal membrane compartments. The broad membrane annotation is correct and does not assert exclusive plasma-membrane residence; replacing it with only plasma membrane would discard a supported context. InterPro:IPR004065 SUPPORTS TRANSFER The receptor occupies the plasma membrane and can enter internal membrane compartments. The broad membrane annotation is correct and does not assert exclusive plasma-membrane residence; replacing it with only plasma membrane would discard a supported context. InterPro:IPR005385 SUPPORTS TRANSFER The receptor occupies the plasma membrane and can enter internal membrane compartments. The broad membrane annotation is correct and does not assert exclusive plasma-membrane residence; replacing it with only plasma membrane would discard a supported context. InterPro:IPR017452 SUPPORTS TRANSFER The receptor occupies the plasma membrane and can enter internal membrane compartments. The broad membrane annotation is correct and does not assert exclusive plasma-membrane residence; replacing it with only plasma membrane would discard a supported context. Supporting Evidence: PMID:26473723 It was also clearly observed that agonists and protein kinase C activation induced internalization of these receptors. |
| GO:0045202 synapse | IEA GO_REF:0000108 | UNDECIDED | Summary: Synaptic localization remains unresolved; a negative bulk-brain survey is not exclusion evidence. Reason: This IEA is a logical inference associated with the synaptic-transmission assertion. PMID:10727522 Fig.7C reports LPAR3 expression in human forebrain regions, contrary to generalizing one earlier negative tissue panel. Mouse primary PMID:22465231 supports axonal localization/branching, but axons and brain expression do not establish synaptic localization. Await focused examination of synaptic functional/localization evidence rather than asserting a human tissue mismatch. Propagation Review Root cause: UNRESOLVED Sources checked: GO:0007268 UNRESOLVED This IEA is a logical inference associated with the synaptic-transmission assertion. PMID:10727522 Fig.7C reports LPAR3 expression in human forebrain regions, contrary to generalizing one earlier negative tissue panel. Mouse primary PMID:22465231 supports axonal localization/branching, but axons and brain expression do not establish synaptic localization. Await focused examination of synaptic functional/localization evidence rather than asserting a human tissue mismatch. |
| GO:0070915 lysophosphatidic acid receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Accepted as the ligand-specific core molecular function of LPAR3. Reason: LPAR3 subfamily signatures agree with direct human EDG7 studies showing a selective LPA response and distinct LPA acyl-species preferences. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR004065 SUPPORTS TRANSFER LPAR3 subfamily signatures agree with direct human EDG7 studies showing a selective LPA response and distinct LPA acyl-species preferences. InterPro:IPR005385 SUPPORTS TRANSFER LPAR3 subfamily signatures agree with direct human EDG7 studies showing a selective LPA response and distinct LPA acyl-species preferences. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Retain the curated binary interaction evidence as non-core. Reason: Remove the generic protein-binding annotation because it does not describe a specific molecular function. The interaction evidence and source attribution are retained; this curation action does not assert that the reported association is false. The inspected evidence does not justify an informative replacement function for this particular row. |
| GO:0001965 G-protein alpha-subunit binding | IEA GO_REF:0000107 | ACCEPT | Summary: G-protein alpha-subunit engagement is integral to the established LPAR3 receptor activity. Reason: The exact electronic source is rat Lpar3 Q8K5E0, whose experimental GO:0001965 annotation cites PMID:16504475. Its abstract reports receptor-dependent Gq signaling in vascular smooth muscle, not a purified binding constant. Independently, human LPAR3 and Gi2alpha coexpression supports ligand-dependent GTPgammaS loading in PMID:10727522. Together with established receptor-mediated nucleotide exchange, this supports the broad G-alpha-binding function; absence of a separate human binary-binding assay is not target-specific loss. Do not claim every G-alpha subtype binds equally or that the rat abstract alone isolates LPAR3 from coexpressed LPAR1. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K5E0 SUPPORTS TRANSFER The exact electronic source is rat Lpar3 Q8K5E0, whose experimental GO:0001965 annotation cites PMID:16504475. Its abstract reports receptor-dependent Gq signaling in vascular smooth muscle, not a purified binding constant. Independently, human LPAR3 and Gi2alpha coexpression supports ligand-dependent GTPgammaS loading in PMID:10727522. Together with established receptor-mediated nucleotide exchange, this supports the broad G-alpha-binding function; absence of a separate human binary-binding assay is not target-specific loss. Do not claim every G-alpha subtype binds equally or that the rat abstract alone isolates LPAR3 from coexpressed LPAR1. ensembl:ENSRNOP00000089155 SUPPORTS TRANSFER The exact electronic source is rat Lpar3 Q8K5E0, whose experimental GO:0001965 annotation cites PMID:16504475. Its abstract reports receptor-dependent Gq signaling in vascular smooth muscle, not a purified binding constant. Independently, human LPAR3 and Gi2alpha coexpression supports ligand-dependent GTPgammaS loading in PMID:10727522. Together with established receptor-mediated nucleotide exchange, this supports the broad G-alpha-binding function; absence of a separate human binary-binding assay is not target-specific loss. Do not claim every G-alpha subtype binds equally or that the rat abstract alone isolates LPAR3 from coexpressed LPAR1. Supporting Evidence: PMID:10727522 membranes from HEK293T cells cotransfected with Edg-7 and G(i2)alpha protein DNAs show lysophosphatidic acid dose-dependent increases in [gamma-(35)S]GTP binding |
| GO:0005543 phospholipid binding | IEA GO_REF:0000107 | MODIFY | Summary: Broad phospholipid binding should be replaced by the demonstrated LPA ligand interaction. Reason: Lysophosphatidic acid binding is the experimentally established ligand-recognition activity and is more informative than the true parent binding term. The broad parent does not itself imply binding to unrelated lipids. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8K5E0 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broader concept, while direct human LPAR3 evidence supports the more precise replacement. ensembl:ENSRNOP00000089155 SUPPORTS TRANSFER Exact WITH/FROM source; it supports the broader concept, while direct human LPAR3 evidence supports the more precise replacement. Proposed replacements: lysophosphatidic acid binding |
| GO:0010467 gene expression | IEA GO_REF:0000107 | UNDECIDED | Summary: Separate downstream expression changes from participation in gene-product synthesis. Reason: The exact source is mouse Lpar3 Q9EQ31 IMP PMID:20864640, which examines uterine collagen and protease expression in Lpar3-null mice. This is real functional evidence, not a generic tissue mismatch. However, GO:0010467 describes production of mature gene products, and the receptor may instead act upstream through signaling. The full source paper was unavailable after bounded retrieval attempts, so neither a confident removal nor a fabricated direct role is justified. A focused question addresses qualifier and process scope. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q9EQ31 UNRESOLVED The exact source is mouse Lpar3 Q9EQ31 IMP PMID:20864640, which examines uterine collagen and protease expression in Lpar3-null mice. This is real functional evidence, not a generic tissue mismatch. However, GO:0010467 describes production of mature gene products, and the receptor may instead act upstream through signaling. The full source paper was unavailable after bounded retrieval attempts, so neither a confident removal nor a fabricated direct role is justified. A focused question addresses qualifier and process scope. ensembl:ENSMUSP00000037712 UNRESOLVED The exact source is mouse Lpar3 Q9EQ31 IMP PMID:20864640, which examines uterine collagen and protease expression in Lpar3-null mice. This is real functional evidence, not a generic tissue mismatch. However, GO:0010467 describes production of mature gene products, and the receptor may instead act upstream through signaling. The full source paper was unavailable after bounded retrieval attempts, so neither a confident removal nor a fabricated direct role is justified. A focused question addresses qualifier and process scope. |
| GO:0030424 axon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain the ortholog-supported axonal location in its neuronal context. Reason: Live QuickGO traces the transfer to mouse Q9EQ31 and direct axon IDA PMID:22465231. The primary abstract describes LPAR3-dependent axonal branching in hippocampal neurons. Human forebrain expression is independently reported in PMID:10727522 Fig.7C; one negative bulk-brain panel cannot establish human loss of a neuronal location. Retain the curator-supported ortholog localization as non-core without claiming that the accessible abstract independently reproduces its microscopy. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9EQ31 SUPPORTS TRANSFER Live QuickGO traces the transfer to mouse Q9EQ31 and direct axon IDA PMID:22465231. The primary abstract describes LPAR3-dependent axonal branching in hippocampal neurons. Human forebrain expression is independently reported in PMID:10727522 Fig.7C; one negative bulk-brain panel cannot establish human loss of a neuronal location. Retain the curator-supported ortholog localization as non-core without claiming that the accessible abstract independently reproduces its microscopy. ensembl:ENSMUSP00000037712 SUPPORTS TRANSFER Live QuickGO traces the transfer to mouse Q9EQ31 and direct axon IDA PMID:22465231. The primary abstract describes LPAR3-dependent axonal branching in hippocampal neurons. Human forebrain expression is independently reported in PMID:10727522 Fig.7C; one negative bulk-brain panel cannot establish human loss of a neuronal location. Retain the curator-supported ortholog localization as non-core without claiming that the accessible abstract independently reproduces its microscopy. Supporting Evidence: PMID:22465231 The LPA(3) agonist 2(S)-OMPT or LPA also induced axonal branch formation in hippocampal neurons |
| GO:0051928 positive regulation of calcium ion transport | IEA GO_REF:0000107 | ACCEPT | Summary: LPAR3 positively regulates calcium movement, including release from intracellular stores. Reason: GO:0051928 explicitly includes movement within a cell, so intracellular calcium release qualifies without requiring plasma-membrane influx. Full human LPAR3 PMID:38928196 compares calcium-containing/free buffers and PLC inhibition with thapsigargin controls, supporting predominant intracellular mobilization. The exact rat donor Q8K5E0 has experimental PMID:11340076 evidence for extracellular influx in microglia, a different cellular context. Neither result requires replacing the transport term merely because another assay measures cytosolic concentration. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8K5E0 SUPPORTS TRANSFER GO:0051928 explicitly includes movement within a cell, so intracellular calcium release qualifies without requiring plasma-membrane influx. Full human LPAR3 PMID:38928196 compares calcium-containing/free buffers and PLC inhibition with thapsigargin controls, supporting predominant intracellular mobilization. The exact rat donor Q8K5E0 has experimental PMID:11340076 evidence for extracellular influx in microglia, a different cellular context. Neither result requires replacing the transport term merely because another assay measures cytosolic concentration. ensembl:ENSRNOP00000089155 SUPPORTS TRANSFER GO:0051928 explicitly includes movement within a cell, so intracellular calcium release qualifies without requiring plasma-membrane influx. Full human LPAR3 PMID:38928196 compares calcium-containing/free buffers and PLC inhibition with thapsigargin controls, supporting predominant intracellular mobilization. The exact rat donor Q8K5E0 has experimental PMID:11340076 evidence for extracellular influx in microglia, a different cellular context. Neither result requires replacing the transport term merely because another assay measures cytosolic concentration. Supporting Evidence: PMID:38928196 The data indicate a predominant role of intracellular calcium mobilization in the effect of the lysophospholipid |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Accepted as direct protein-level plasma-membrane localization evidence. Reason: The Human Protein Atlas immunofluorescence mapping agrees with the reviewed UniProt cell-membrane assignment and receptor topology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR3 signaling. Reason: Reactome event R-HSA-379048 places LPAR3 in ligand-binding or heterotrimeric G-protein activation at the plasma membrane, consistent with direct receptor biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR3 signaling. Reason: Reactome event R-HSA-380073 places LPAR3 in ligand-binding or heterotrimeric G-protein activation at the plasma membrane, consistent with direct receptor biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-419389 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR3 signaling. Reason: Reactome event R-HSA-419389 places LPAR3 in ligand-binding or heterotrimeric G-protein activation at the plasma membrane, consistent with direct receptor biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR3 signaling. Reason: Reactome event R-HSA-749448 places LPAR3 in ligand-binding or heterotrimeric G-protein activation at the plasma membrane, consistent with direct receptor biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR3 signaling. Reason: Reactome event R-HSA-749452 places LPAR3 in ligand-binding or heterotrimeric G-protein activation at the plasma membrane, consistent with direct receptor biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR3 signaling. Reason: Reactome event R-HSA-749454 places LPAR3 in ligand-binding or heterotrimeric G-protein activation at the plasma membrane, consistent with direct receptor biology. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR3 signaling. Reason: Reactome event R-HSA-749456 places LPAR3 in ligand-binding or heterotrimeric G-protein activation at the plasma membrane, consistent with direct receptor biology. |
| GO:0004930 G protein-coupled receptor activity | TAS PMID:10488122 Molecular cloning and characterization of a novel human G-pr... | MODIFY | Summary: The established ligand-specific receptor activity is more informative than generic GPCR activity. Reason: The cited study molecularly identifies human EDG7/LPAR3 as a receptor for lysophosphatidic acid and demonstrates ligand-dependent signaling (PMID:10488122). Proposed replacements: lysophosphatidic acid receptor activity |
| GO:0005886 plasma membrane | TAS PMID:10488122 Molecular cloning and characterization of a novel human G-pr... | ACCEPT | Summary: Accepted as the core membrane location of human LPAR3. Reason: The founding receptor characterization identifies EDG7 as a membrane GPCR, consistent with its sequence topology and later localization evidence (PMID:10488122). |
| GO:0007187 G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger | TAS PMID:10488122 Molecular cloning and characterization of a novel human G-pr... | ACCEPT | Summary: Accepted as a direct cyclic-nucleotide signaling response of recombinant LPAR3. Reason: LPA stimulation of EDG7/LPAR3-expressing Sf9 cells enhanced forskolin-induced intracellular cAMP, and this response was not blocked by pertussis toxin (PMID:10488122). |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | TAS PMID:10488122 Molecular cloning and characterization of a novel human G-pr... | ACCEPT | Summary: Accepted as a direct calcium response downstream of LPAR3. Reason: LPA, but not other lysophospholipids, increased intracellular calcium in EDG7/LPAR3-expressing cells (PMID:10488122). |
| GO:0007268 chemical synaptic transmission | TAS PMID:10488122 Molecular cloning and characterization of a novel human G-pr... | UNDECIDED | Summary: The synaptic-transmission assertion remains unresolved after checking the founding study. Reason: Author-deposited full PMID:10488122 Methods/Results describe ligand binding, recombinant calcium/cAMP and PC12 reporter assays; these do not establish transmission across a synapse. However, lack of an assay in this paper does not refute all later or ortholog synaptic roles. PMID:10727522 reports human forebrain expression and PMID:22465231 describes axonal branching, which must also not be equated with transmission. Preserve the source TAS annotation pending focused evidence adjudication. |
| GO:0008289 lipid binding | TAS PMID:10488122 Molecular cloning and characterization of a novel human G-pr... | MODIFY | Summary: Generic lipid binding should be replaced by the demonstrated LPAR3 ligand interaction. Reason: Lysophosphatidic acid binding is the experimentally established ligand-recognition activity and is more informative than the true parent binding term. The broad parent does not itself imply binding to unrelated lipids. Proposed replacements: lysophosphatidic acid binding |
| GO:0002031 G protein-coupled receptor internalization | IDA PMID:38928196 Lysophosphatidic Acid Receptor 3 (LPA3): Signaling and Phosp... | NEW | Summary: Proposed as a new non-core annotation for directly demonstrated agonist-induced LPAR3 internalization. Reason: Retain the pre-existing proposal on active recruitment grounds: human LPAR3 binds/recruits beta-arrestin after stimulation, and full PMID:38791546 Fig.4β8 associates receptor phosphosite changes with reduced recruitment and uptake. Thus the proposed contribution is the receptor docking interface that assembles endocytic machinery, not merely its being cargo. Live comparator checks found the exact process absent on LPAR1 and ADRB2 but present on human DRD2 via rat Drd2 IDA PMID:14617818, so absence is not uniform across same-role receptors. No LPAR3 entry was found in the local GO-CAM index. Live is_a/part_of ancestors show no overlap with the source GPCR-signaling/calcium process terms. This does not establish the receptor as a vesicle-formation enzyme or every phosphorylation mutant as a clean loss of one contact. Supporting Evidence: PMID:38791546 LPA3 agonist activation induces rapid recruitment of the Ξ²-arrestin 2, as evidenced by colocalization and FRET |
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Download this section (compressed HTML)Q: What are the quantitative Gq/11, Gi/o, Gs, G12/13, and beta-arrestin coupling profiles of endogenous human LPAR3 in physiologically relevant cells?
Q: Which LPA molecular species bind and activate native LPAR3 most effectively, and which pharmacological tools distinguish LPAR3 from LPAR1?
Q: Does an endogenous transcript or protein corresponding to HOFNH30 exist, or is it a historical sequence variant rather than an LPAR3 isoform?
Q: How do mapped intracellular-loop and C-terminal phosphosites control beta-arrestin recruitment, clathrin-dependent internalization, recycling, and resensitization at endogenous LPAR3 abundance?
Q: Which HuRI contacts, if any, regulate native LPAR3 localization or signaling?
Q: Is the mouse Lpar3-dependent implantation and embryo-spacing program conserved in human endometrium, and which prostaglandin-linked component is receptor dependent?
Experiment: CRISPR-tag endogenous LPAR3 in human cell models with native expression and use parallel conformational or BRET biosensors for Gq/11, Gi/o, Gs, G12/13, and beta-arrestin together with calcium and cAMP readouts. Resolve dose and time courses with selective G-alpha knockout and rescue.
Hypothesis: Endogenous LPAR3 coupling differs from the pertussis-toxin-insensitive calcium and cAMP responses observed in recombinant Sf9 cells.
Type: endogenous multiplexed GPCR coupling analysis
Experiment: Measure direct binding and branch-resolved efficacy for defined saturated and unsaturated LPA species in native human cells, comparing wild type, LPAR3 knockout, and genomic rescue while controlling LPAR1 and LPAR2 expression.
Hypothesis: Native LPAR3 retains a measurable preference for unsaturated LPA species, but the rank order differs from heterologous Sf9 calcium assays.
Type: receptor-specific native ligand pharmacology
Experiment: Map HOFNH30 differences onto the current locus, perform targeted long-read RNA sequencing across reported tissues, and search isoform-discriminating peptides by targeted proteomics before comparing recombinant function.
Hypothesis: The historical HOFNH30 sequence is not a routinely expressed alternative LPAR3 protein product.
Type: transcript and proteoform reconciliation
Experiment: Introduce precise phosphosite-cluster substitutions at endogenous LPAR3 and quantify agonist-dependent phosphorylation, beta-arrestin-2 recruitment, clathrin dependence, endocytosis, recycling, degradation, and signaling resensitization.
Hypothesis: Mapped intracellular-loop and C-terminal phosphorylation sites encode distinct beta-arrestin recruitment, internalization, and recycling kinetics.
Type: endogenous phosphosite-resolved receptor trafficking
Experiment: Rank partners by tissue coexpression and membrane compatibility, validate endogenous proximity with orthogonal assays, then perform knockout/add-back and quantify LPA binding, surface abundance, coupling bias, and internalization.
Hypothesis: Only a small subset of HuRI partners affects LPAR3 receptor biology under native coexpression.
Type: endogenous interaction-screen triage
Experiment: Profile LPAR3 across the human endometrial cycle by single-cell transcript and spatial protein measurements, then perturb LPAR3 genetically in primary endometrial organoids or assembloids. Quantify LPA-dependent prostaglandin synthesis, receptivity markers, and embryo-attachment support with rescue by receptor re-expression and PGE2 or prostacyclin analogues. Treat embryo spacing as a mouse-specific outcome unless independently demonstrated in an appropriate human model.
Hypothesis: Human endometrial LPAR3 controls a prostaglandin-linked implantation program analogous to the implantation-timing component of the mouse Lpar3-null phenotype.
Type: human endometrial receptor physiology and mouse-to-human conservation test
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The quantitative Gq/11, Gi/o, and other coupling profile of endogenous human LPAR3 is unresolved across native cell types.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Recombinant Sf9 experiments directly show pertussis-toxin-insensitive calcium responses and potentiation of forskolin-induced cAMP accumulation, while UniProt and receptor-focused literature summarize both Gq/11 and Gi/o recruitment. The forskolin-background assay supports adenylate-cyclase modulation but does not isolate a universally activating directional mechanism, and these sources do not provide matched coupling measurements at endogenous receptor abundance in native human tissues.
Significance: Coupling preference determines whether LPAR3 primarily changes calcium, cAMP, or additional second messengers and whether recombinant-cell observations represent physiological signaling.
What would resolve it: Measure endogenous LPAR3 with parallel Gq/11, Gi/o, Gs, G12/13, beta-arrestin, calcium, and cAMP biosensors across matched ligand-dose and time-course conditions in relevant human cells.
Gap: Native LPAR3 ligand preferences across physiological LPA molecular species are incompletely defined.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: EDG7/LPAR3 favored unsaturated over saturated LPA species in recombinant Sf9 calcium assays, and recombinant pharmacology identifies ligands and antagonists, but these data do not establish binding affinities or efficacy rankings in native human membranes. VPC12249 is dual LPAR1/LPAR3 and cannot isolate LPAR3 in mixed-receptor systems.
Significance: Molecular-species selectivity may determine tissue responses and therapeutic pharmacology, while nonselective tools can confound receptor attribution.
What would resolve it: Quantify binding and branch-resolved efficacy for defined LPA species using endogenous LPAR3 knockout/rescue and receptor-selective genetic controls in native human membranes and cells.
Gap: The relationship between the historical HOFNH30 sequence and current human LPAR3 transcripts and proteins remains unresolved.
OPEN BIOLOGYCURATION
What is known: HOFNH30 is 96% identical to EDG7, was described as possibly alternatively spliced, and is functional after heterologous expression, but the current reviewed Q9UBY5 record defines no alternative protein products. The historical sequence therefore cannot be treated as a validated modern isoform.
Significance: Incorrectly promoting HOFNH30 to an isoform would conflate a historical sequence variant with established transcript biology and could distort ligand and tissue comparisons.
What would resolve it: Reconcile HOFNH30 against current genomic and transcript accessions, then use long-read RNA sequencing and proteogenomics to test whether a corresponding endogenous product exists.
Provenance (the field's own admissions):
Gap: The physiological settings and consequences of LPAR3 phosphorylation, beta-arrestin recruitment, and internalization are not established in native human tissues.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Phosphosites, beta-arrestin-2 association, and clathrin-sensitive uptake are directly demonstrated with human LPAR3 constructs in heterologous cells, but native cell-type dependence, recycling, degradation, and signaling resensitization have not been resolved.
Significance: These mechanisms set receptor surface residence and signaling duration and may differ with kinase or arrestin expression across tissues.
What would resolve it: Endogenously tag LPAR3 in human cells, perturb mapped phosphosites, kinases, beta-arrestin-2, and clathrin, and quantify internalization, recycling, degradation, and branch-specific signaling recovery.
Gap: The physiological relevance of the 53 HuRI binary interaction partners is unknown.
OPEN BIOLOGY
What is known: The normalized IPI row preserves verified high-throughput binary contacts, but the screen does not establish endogenous coexpression, common receptor mechanism, or one stable complex.
Significance: Orthogonal validation may identify true trafficking or signaling regulators while preventing a large screening set from being mistaken for core function.
What would resolve it: Prioritize coexpressed candidates in relevant human tissues, verify endogenous proximity and perturbation dependence, and measure effects on ligand binding, surface delivery, coupling, and internalization.
Gap: Whether the uterine implantation and embryo-spacing functions established for mouse Lpar3 are conserved as LPAR3-dependent physiology in humans is unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: The reviewed human record reports strongest expression in prostate, testes, pancreas, and heart and moderate expression in lung and ovary, whereas the decisive reproductive physiology comes from female Lpar3-null mice. Mouse loss causes delayed implantation and altered spacing; prostaglandin replacement rescues implantation timing but not spacing. These organism-level phenotypes do not establish an equivalent human developmental role or a new receptor molecular activity.
Significance: Establishing conservation would connect the receptor's tissue distribution to reproductive physiology without over-transferring a mouse knockout phenotype to human LPAR3.
What would resolve it: Map endogenous LPAR3 in human endometrial cell states across the implantation window and test receptor-specific LPA responses, prostaglandin synthesis, and embryo-attachment support in genetically controlled human endometrial models.
Provenance (the field's own admissions):
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