LPAR2 is a class-A seven-transmembrane receptor for extracellular lysophosphatidic acid. At the plasma membrane it activates heterotrimeric G-protein signaling, including phospholipase-C-dependent calcium mobilization, contextual Gi-mediated inhibition of adenylyl cyclase, and Rho signaling. Recombinant human EDG4 also potentiates forskolin-stimulated cAMP accumulation in an insect-cell assay, indicating that the direction of cyclic-nucleotide responses depends on the signaling environment. Its C-terminal PDZ-binding motif recruits NHERF2 and MAGI3, while TRIP6 binds through LIM domains. These partners connect the receptor to spatially organized calcium, ion-transport, adhesion and migration responses. LPAR2 undergoes phosphorylation, desensitization and endocytic trafficking. RalA associates with LPAR2, although the demonstrated agonist-driven RalA activation in the original comparative study was LPA1-specific. Proteomic studies also detect associations with LGALS3 and RAMP proteins whose effects on receptor signaling remain incompletely characterized.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: The broad GPCR activity is valid but should be represented by the established ligand-specific receptor activity. Reason: LPAR2 is a seven-transmembrane receptor activated by lysophosphatidic acid. Direct human ligand-response studies support the more informative lysophosphatidic acid receptor activity term. 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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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. The broad GPCR activity is valid but should be represented by the established ligand-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 receptor–arrestin 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. The target is legitimate descendant experimental grounding for the IBD, not circular support. 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 LPAR2 receptor activity. Reason: LPAR2 is an integral seven-transmembrane receptor that recognizes extracellular lysophosphatidic acid 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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 LPAR2 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: The broad GPCR activity is valid but should be represented by the established ligand-specific receptor activity. Reason: LPAR2 is directly characterized as a lysophosphatidic acid receptor, making the ligand-specific molecular-function term more informative than generic GPCR 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 broad transferred concept, while human LPAR2 evidence supports the stated scoping decision. Proposed replacements: lysophosphatidic acid receptor activity |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as the core membrane location of LPAR2 receptor activity. Reason: The UniProt subcellular-location mapping agrees with direct cell-surface localization and the topology of an integral seven-transmembrane receptor. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER The UniProt subcellular-location mapping agrees with direct cell-surface localization and the topology of an integral seven-transmembrane receptor. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: Accepted as the core signaling process initiated by LPA-bound LPAR2. Reason: Direct recombinant-receptor experiments show that human LPAR2 transduces LPA signals through heterotrimeric G proteins, including Gi and Gq (PMID:9804623). Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00029021 SUPPORTS TRANSFER Direct recombinant-receptor experiments show that human LPAR2 transduces LPA signals through heterotrimeric G proteins, including Gi and Gq (PMID:9804623). InterPro:IPR000276 SUPPORTS TRANSFER Direct recombinant-receptor experiments show that human LPAR2 transduces LPA signals through heterotrimeric G proteins, including Gi and Gq (PMID:9804623). InterPro:IPR004065 SUPPORTS TRANSFER Direct recombinant-receptor experiments show that human LPAR2 transduces LPA signals through heterotrimeric G proteins, including Gi and Gq (PMID:9804623). InterPro:IPR004066 SUPPORTS TRANSFER Direct recombinant-receptor experiments show that human LPAR2 transduces LPA signals through heterotrimeric G proteins, including Gi and Gq (PMID:9804623). |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000117 | ACCEPT | Summary: Accepted as a direct second-messenger output of LPAR2 signaling. Reason: Human Edg4/LPAR2 expression confers LPA-induced intracellular calcium mobilization through PLC and both Gi- and Gq-dependent components (PMID:9804623). Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028136 SUPPORTS TRANSFER Human Edg4/LPAR2 expression confers LPA-induced intracellular calcium mobilization through PLC and both Gi- and Gq-dependent components (PMID:9804623). |
| GO:0008289 lipid binding | IEA GO_REF:0000117 | MODIFY | Summary: Generic lipid binding should be replaced by the demonstrated LPAR2 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 broad transferred concept, while human LPAR2 evidence supports the stated scoping decision. Proposed replacements: lysophosphatidic acid binding |
| GO:0009986 cell surface | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as a valid surface localization of the plasma-membrane receptor. Reason: Cell-surface localization is consistent with direct human localization and with LPAR2 binding an extracellular lipid ligand. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0310 SUPPORTS TRANSFER Cell-surface localization is consistent with direct human localization and with LPAR2 binding an extracellular lipid ligand. |
| 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:IPR004066 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:0070915 lysophosphatidic acid receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Accepted as the ligand-specific core molecular function of LPAR2. Reason: The LPAR2 subfamily signatures agree with direct human studies identifying Edg4/LPAR2 as a receptor for lysophosphatidic acid. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR004065 SUPPORTS TRANSFER The LPAR2 subfamily signatures agree with direct human studies identifying Edg4/LPAR2 as a receptor for lysophosphatidic acid. InterPro:IPR004066 SUPPORTS TRANSFER The LPAR2 subfamily signatures agree with direct human studies identifying Edg4/LPAR2 as a receptor for lysophosphatidic acid. |
| GO:0005515 protein binding | IPI PMID:16203867 Lysophosphatidic acid inhibits cholera toxin-induced secreto... | MODIFY | Summary: The direct NHERF2 interaction is mechanistically informative as PDZ-domain binding rather than generic protein binding. Reason: LPAR2 directly binds the PDZ scaffold NHERF2 through its C-terminal PDZ motif (PMID:16203867). GO:0030165 captures that direct receptor-scaffold interaction without incorrectly extending it to CFTR. Proposed replacements: PDZ domain binding |
| GO:0005515 protein binding | IPI PMID:16203867 Lysophosphatidic acid inhibits cholera toxin-induced secreto... | REMOVE | Summary: Marked as over-annotated because CFTR is linked to LPAR2 through NHERF2 rather than binding the receptor directly. Reason: PMID:16203867 reports NHERF2-mediated association of LPAR2 and CFTR rather than direct receptor-CFTR binding. Remove the generic protein-binding annotation as uninformative while preserving this experimentally supported complex association; do not infer a direct binding activity or an unsupported replacement function. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Retain the curated interaction as contextual evidence. 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:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Retain the curated interaction as contextual evidence. 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:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Retain reproducible LPAR2–RAMP association without assigning an untested signaling function. 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. Supporting Evidence: PMID:39083597 Nine GPCRs showed evidence for complex formation with all three RAMPs across all capture-detection methods: GABBR1, GPR143, GPR21, GPR61, HTR4, LPAR2, MTNR1A, OXER1, and P2RY11 |
| GO:0030165 PDZ domain binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retained as an LPAR2-specific regulatory scaffold interaction rather than the receptor core activity. Reason: The C-terminal PDZ motif of LPAR2 binds PDZ-domain scaffolds such as NHERF2 and organizes spatially restricted signaling. This is a meaningful LPAR2 regulatory feature but is secondary to LPA recognition and G-protein activation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9JL06 SUPPORTS TRANSFER The C-terminal PDZ motif of LPAR2 binds PDZ-domain scaffolds such as NHERF2 and organizes spatially restricted signaling. This is a meaningful LPAR2 regulatory feature but is secondary to LPA recognition and G-protein activation. ensembl:ENSMUSP00000034325 SUPPORTS TRANSFER The C-terminal PDZ motif of LPAR2 binds PDZ-domain scaffolds such as NHERF2 and organizes spatially restricted signaling. This is a meaningful LPAR2 regulatory feature but is secondary to LPA recognition and G-protein activation. |
| GO:0048787 presynaptic active zone membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retained as a neuron-specific localization inferred from mouse orthology. Reason: Presynaptic active-zone localization may define a specialized neuronal context, but the electronic transfer from mouse does not make it the general or core site of human LPAR2 action. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9JL06 SUPPORTS TRANSFER Presynaptic active-zone localization may define a specialized neuronal context, but the electronic transfer from mouse does not make it the general or core site of human LPAR2 action. ensembl:ENSMUSP00000034325 SUPPORTS TRANSFER Presynaptic active-zone localization may define a specialized neuronal context, but the electronic transfer from mouse does not make it the general or core site of human LPAR2 action. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retained as a neuron-specific localization inferred from mouse orthology. Reason: Glutamatergic-synapse localization is compatible with a specialized neuronal role, but it is contextual and is not required for the receptor’s general LPA-responsive GPCR function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9JL06 SUPPORTS TRANSFER Glutamatergic-synapse localization is compatible with a specialized neuronal role, but it is contextual and is not required for the receptor’s general LPA-responsive GPCR function. ensembl:ENSMUSP00000034325 SUPPORTS TRANSFER Glutamatergic-synapse localization is compatible with a specialized neuronal role, but it is contextual and is not required for the receptor’s general LPA-responsive GPCR function. |
| GO:0007186 G protein-coupled receptor signaling pathway | IDA PMID:9804623 Recombinant human G protein-coupled lysophosphatidic acid re... | ACCEPT | Summary: Accepted as direct evidence for LPAR2-mediated GPCR signaling. Reason: Recombinant human Edg4/LPAR2 confers LPA-responsive calcium mobilization through PLC, with both Gi- and Gq-dependent components (PMID:9804623). |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-379048 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR2 signaling. Reason: Reactome event R-HSA-379048 places LPAR2 in a ligand-binding or heterotrimeric G-protein activation step at the plasma membrane, consistent with direct receptor localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR2 signaling. Reason: Reactome event R-HSA-380073 places LPAR2 in a ligand-binding or heterotrimeric G-protein activation step at the plasma membrane, consistent with direct receptor localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-419389 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR2 signaling. Reason: Reactome event R-HSA-419389 places LPAR2 in a ligand-binding or heterotrimeric G-protein activation step at the plasma membrane, consistent with direct receptor localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749448 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR2 signaling. Reason: Reactome event R-HSA-749448 places LPAR2 in a ligand-binding or heterotrimeric G-protein activation step at the plasma membrane, consistent with direct receptor localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749452 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR2 signaling. Reason: Reactome event R-HSA-749452 places LPAR2 in a ligand-binding or heterotrimeric G-protein activation step at the plasma membrane, consistent with direct receptor localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR2 signaling. Reason: Reactome event R-HSA-749454 places LPAR2 in a ligand-binding or heterotrimeric G-protein activation step at the plasma membrane, consistent with direct receptor localization. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Accepted as the plasma-membrane location used in curated proximal LPAR2 signaling. Reason: Reactome event R-HSA-749456 places LPAR2 in a ligand-binding or heterotrimeric G-protein activation step at the plasma membrane, consistent with direct receptor localization. |
| GO:0005515 protein binding | IPI PMID:14688263 TRIP6 enhances lysophosphatidic acid-induced cell migration ... | MODIFY | Summary: Modified to capture the experimentally defined LIM-domain interaction with TRIP6. Reason: Activated LPAR2 directly binds the LIM domains of TRIP6 through its C-terminal tail and recruits this focal-adhesion scaffold (PMID:14688263). GO:0030274 records the informative partner domain, whereas generic protein binding obscures the demonstrated interaction class. The regulatory contact remains non-core. Proposed replacements: LIM domain binding |
| GO:0005515 protein binding | IPI PMID:19306925 Dual regulation of lysophosphatidic acid (LPA1) receptor sig... | REMOVE | Summary: Retain the curated regulatory interaction without inferring additional partner-specific activities. 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. Supporting Evidence: PMID:19306925 the small GTPase RalA associates with both LPA(1) and LPA(2) |
| GO:0009986 cell surface | IDA PMID:19306925 Dual regulation of lysophosphatidic acid (LPA1) receptor sig... | ACCEPT | Summary: Accepted as direct cell-surface localization of LPAR2. Reason: The study detects LPAR2 at the cell surface in the context of RalA/GRK2 regulation, consistent with its plasma-membrane receptor role (PMID:19306925). |
| GO:0030139 endocytic vesicle | IDA PMID:19306925 Dual regulation of lysophosphatidic acid (LPA1) receptor sig... | KEEP AS NON CORE | Summary: Retained as ligand-regulated trafficking rather than a core receptor location. Reason: LPAR2 colocalization with an endocytic vesicle is consistent with receptor internalization and trafficking after signaling. This regulatory state is secondary to ligand recognition and G-protein activation at the cell surface. |
| GO:0004930 G protein-coupled receptor activity | TAS PMID:9525886 Characterization of a novel subtype of human G protein-coupl... | MODIFY | Summary: The established ligand-specific receptor activity is more informative than generic GPCR activity. Reason: The cited study molecularly identifies human Edg4/LPAR2 as a lysophosphatidic acid receptor and demonstrates LPA-dependent signaling (PMID:9525886). Proposed replacements: lysophosphatidic acid receptor activity |
| GO:0005886 plasma membrane | TAS PMID:9525886 Characterization of a novel subtype of human G protein-coupl... | ACCEPT | Summary: Accepted as the core membrane location of human LPAR2. Reason: The founding human receptor study characterizes LPAR2 as a membrane GPCR, consistent with subsequent direct cell-surface evidence (PMID:9525886). |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:9525886 Characterization of a novel subtype of human G protein-coupl... | ACCEPT | Summary: Accepted as the core signaling process mediated by LPA-bound LPAR2. Reason: Expression of human Edg4/LPAR2 produces LPA-responsive heterotrimeric G-protein signaling (PMID:9525886). |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | TAS PMID:9804623 Recombinant human G protein-coupled lysophosphatidic acid re... | ACCEPT | Summary: Accepted as a direct second-messenger response downstream of LPAR2. Reason: Recombinant human LPAR2 mediates LPA-induced intracellular calcium mobilization through PLC, with Gi and Gq contributions (PMID:9804623). |
| GO:0008289 lipid binding | TAS PMID:9525886 Characterization of a novel subtype of human G protein-coupl... | MODIFY | Summary: Generic lipid binding should be replaced by the demonstrated LPAR2 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:0035025 positive regulation of Rho protein signal transduction | IDA PMID:16904289 MAGI-3 regulates LPA-induced activation of Erk and RhoA. | NEW | Summary: Proposed as a new annotation for the experimentally supported LPAR2-to-RhoA signaling branch. Reason: LPAR2 is the ligand-activated signaling receptor upstream of the Rho exchange machinery, and PMID:16904289 links its MAGI3-dependent receptor complex to RhoA activation. This supports positive regulation, not intrinsic Rho GEF activity. A live same-role comparator check finds LPAR1 Q92633 carrying GO:0035025 by ortholog-supported evidence; ADRB2 and DRD2 do not carry the exact term. No local GO-CAM model for LPAR2 was indexed. Live is_a/part_of ancestors show no redundancy with the existing GPCR signaling or calcium terms. Retain this pre-existing NEW proposal conservatively; add no new annotation. Supporting Evidence: PMID:16904289 These results demonstrate that MAGI-3 interacts directly with LPA(2) and regulates the ability of LPA(2) to activate Erk and RhoA. PMID:9525886 This LPA-induced reporter gene activation could be partially inhibited by pretreatment with pertussis toxin or C3 exoenzyme, suggesting requirements for both a Gi protein and Rho GTPase. |
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Download this section (compressed HTML)Q: What are the relative Gi/Go, Gq, G12/13, and beta-arrestin coupling efficacies of endogenous human LPAR2 across tissues and LPA molecular species?
Q: Does the terminal DSTL motif mediate mutually exclusive or dynamic recruitment of NHERF2/PLCB3 and MAGI3, and how does scaffold choice alter proximal signaling?
Q: Which aspects of TRIP6 recruitment, RalA association, GRK2-dependent desensitization, and endocytic trafficking operate at endogenous LPAR2 levels?
Q: Do LGALS3 or RAMP1-3 alter LPAR2 pharmacology or trafficking in native human cells, or are the reported contacts limited to interaction-screen conditions?
Experiment: CRISPR-tag endogenous LPAR2 in epithelial and mesenchymal human models and use parallel conformational or BRET biosensors for Gi/o, Gq, G12/13, beta-arrestin, cAMP, IP3, calcium, and Rho. Resolve dose-response and time courses for defined LPA species with selective G-alpha knockout and rescue.
Hypothesis: Native LPAR2 coupling weights vary by cell type and LPA molecular species, with distinct Gi/Go, Gq, and G12/13 contributions to cAMP, calcium, and Rho outputs.
Type: endogenous multiplexed GPCR coupling analysis
Experiment: Compare endogenous proximity labeling and quantitative coimmunoprecipitation for wild-type LPAR2 and a precise DSTL-disrupting knock-in before and after LPA. Perturb NHERF2, PLCB3, and MAGI3 individually and measure coupling, local cAMP, PLC/calcium, ERK/Rho, internalization, and recycling.
Hypothesis: The terminal DSTL motif dynamically selects PDZ scaffolds that bias LPAR2 signaling and trafficking rather than forming one constitutive complex.
Type: endogenous receptor-scaffold dynamics and genetic epistasis
Experiment: Use endogenous knockouts and interaction-defective rescue alleles for TRIP6, GRK2, and RalA in matched human cells. Measure receptor-proximal G-protein activation, PLC output, desensitization, endocytosis, focal-adhesion recruitment, and migration without extrapolating an LPAR1 result to LPAR2.
Hypothesis: TRIP6 and GRK2 regulate separable LPAR2 states, whereas RalA association does not confer the LPAR1-specific Ral-dependent PLC mechanism on LPAR2.
Type: paralog-aware receptor-regulator dissection
Experiment: Select human cells with endogenous LPAR2 and candidate expression, verify membrane-proximal interactions by orthogonal assays, then perform knockout and add-back while measuring LPA binding, surface abundance, coupling bias, beta-arrestin recruitment, internalization, and desensitization.
Hypothesis: A subset of the LGALS3 and RAMP1-3 screen contacts modulates LPAR2 only in cells with native coexpression.
Type: endogenous interaction validation and receptor pharmacology
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The quantitative Gi/Go, Gq, and G12/13 coupling preferences of endogenous human LPAR2 remain unresolved across physiological cell types and LPA molecular species.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Recombinant human studies directly resolve mixed Gi/Gq input to PLC-dependent calcium signaling and a Gi-dependent cAMP-inhibitory response. G12/13 coupling is supported by the reviewed UniProt synthesis and is consistent with Rho-sensitive outputs, but the audited sources do not provide matched quantitative coupling measurements for all three branches in native human cells.
Significance: Coupling weights determine whether LPAR2 primarily changes cAMP, calcium, Rho signaling, or a combination in each physiological setting.
What would resolve it: Measure endogenous LPAR2 coupling with parallel Gi/o, Gq, G12/13, beta-arrestin, cAMP, IP3, calcium, and Rho biosensors across matched LPA dose, molecular-species, and time-course conditions.
Gap: How the terminal DSTL motif partitions LPAR2 among NHERF2/PLCB3, MAGI3, and other PDZ scaffolds in native human tissues is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Direct interaction and motif-mutagenesis studies establish NHERF2 and MAGI3 as LPAR2-selective partners, and NHERF2 can organize epithelial LPAR2-CFTR coupling. These experiments do not establish the occupancy, exchange kinetics, or universality of any one assembly at endogenous abundance.
Significance: Dynamic scaffold selection may explain cell-specific PLCB3 efficiency, compartmentalized cAMP regulation, ERK/Rho output, and receptor trafficking without requiring a constitutive stable complex.
What would resolve it: Quantify endogenous motif-dependent interactions before and after LPA exposure, then test how partner-specific perturbation changes branch-resolved signaling, desensitization, internalization, and recycling.
Provenance (the field's own admissions):
Gap: The endogenous regulatory roles of TRIP6, RalA, and GRK2 around LPAR2 are not fully separated from cell-model-specific signaling and trafficking effects.
OPEN BIOLOGY
What is known: TRIP6 directly binds the LPAR2 tail and regulates migration in SKOV3 cells, and GRK2 is required for LPAR2 desensitization. RalA associates with LPAR2, but the accessible evidence assigns agonist-triggered RalA activation and Ral-dependent PLC activity to LPAR1, not LPAR2.
Significance: Resolving these roles is necessary to distinguish direct LPAR2 regulatory mechanisms from paralog transfer and cancer-cell-specific downstream effects.
What would resolve it: Perturb TRIP6, RalA, and GRK2 individually at endogenous abundance in multiple human cell types while measuring LPAR2-proximal coupling, desensitization, internalization, recycling, focal-adhesion recruitment, and migration.
Gap: The physiological consequences of screen-detected LPAR2 interactions with LGALS3 and RAMP1-3 are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Proteome-scale AP-MS identifies LGALS3 and a systematic coexpression screen detects all three RAMPs, but the audited evidence does not establish native tissue interactions or LPAR2-specific changes in ligand affinity, surface delivery, coupling bias, or desensitization.
Significance: Functional validation could reveal context-specific receptor modulators while preventing screen-level contacts from being mistaken for core components.
What would resolve it: Validate endogenous proximity and genetic dependence in human cells that naturally coexpress each candidate, followed by receptor pharmacology, trafficking, and branch-specific signaling assays.
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