{"gene":"LPAR2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2002,"finding":"LPA2 (EDG4) knockout mice show loss of LPA-induced signaling responses (PLC activation, Ca2+ mobilization, adenylyl cyclase activation, proliferation, JNK activation, Akt activation, stress fiber formation) in embryonic fibroblasts, acting redundantly with LPA1; double knockout of lpa1/lpa2 nearly abolishes all these LPA-mediated responses in fibroblasts.","method":"Genetic knockout (lpa2-/- and lpa1-/-/lpa2-/- mice), embryonic fibroblast signaling assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple orthogonal signaling readouts, replicated across single and double knockout genotypes in one rigorous study","pmids":["12215548"],"is_preprint":false},{"year":2000,"finding":"LPA2 (EDG4/LP(A2)) couples to multiple G proteins and mediates LPA-dependent inositol phosphate production, MAPK activation, arachidonic acid release, inhibition of cAMP accumulation, and cell rounding in neuronal cell lines; distinct from LPA3 which causes neurite elongation.","method":"Retrovirus expression system in B103 neuroblastoma cells (lacking endogenous LPA receptors), comparative signaling assays","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in receptor-null cells with multiple orthogonal functional readouts, single lab but multiple assay types","pmids":["11040035"],"is_preprint":false},{"year":2009,"finding":"LPA induces alphavbeta6 integrin-mediated TGF-beta activation in human epithelial cells via LPA2 receptor signaling through Galpha(q), RhoA, and Rho kinase.","method":"Pharmacological inhibition (Galpha(q) inhibitor, RhoA/Rho kinase inhibitors), siRNA knockdown of LPA2, TGF-beta activation assays in epithelial cells","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal perturbations (siRNA, pharmacological), defined signaling pathway with functional readout in one study","pmids":["19147812"],"is_preprint":false},{"year":2004,"finding":"LPA2, but not other LPA receptor isoforms, specifically interacts with NHERF2 via the C-terminal PDZ domain-binding motif of LPA2 and the second PDZ domain of NHERF2; this interaction forms a ternary complex (LPA2/NHERF2/PLC-beta3) that potentiates LPA-induced PLC-beta activation, ERK activation, and COX-2 induction.","method":"Co-immunoprecipitation, PDZ domain-binding motif mutation, NHERF2 gene silencing (siRNA), stable expression, inositol phosphate and ERK assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal co-IP, domain mutagenesis, RNAi knockdown, multiple signaling readouts; single lab but multiple orthogonal approaches","pmids":["15143197"],"is_preprint":false},{"year":2005,"finding":"LPA2 activates Akt (via Gi/pertussis-toxin-sensitive pathway) and Erk1/2 (via PLCbeta/U-73122-sensitive pathway) in human colon cancer cells, and mediates LPA-induced IL-8 synthesis; LPA2 physically interacts with NHERF2 and this interaction is required for efficient Akt and Erk1/2 activation.","method":"Pertussis toxin inhibition, PLC inhibitor (U-73122), NHERF2 siRNA knockdown, co-immunoprecipitation in colon cancer cells","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological perturbations plus RNAi with defined signaling readouts and Co-IP, single lab","pmids":["15728708"],"is_preprint":false},{"year":2000,"finding":"LPA-induced Ca2+ mobilization in SH-SY5Y neuroblastoma cells (which endogenously express EDG-4/LPA2) does not involve IP3 or ryanodine receptor pathways, but requires intracellular sphingosine 1-phosphate production via sphingosine kinase; LPA stimulates sphingosine 1-phosphate production and this lipid second messenger mobilizes intracellular Ca2+.","method":"45Ca2+ release assays in permeabilized cells, sphingosine kinase inhibitor (dimethylsphingosine), confocal Ca2+ imaging, IP3 receptor down-regulation, [3H]sphingosine 1-phosphate measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological and biochemical assays in cells with endogenous EDG-4/LPA2, single lab","pmids":["10954727"],"is_preprint":false},{"year":2009,"finding":"LPA2 receptor is coupled to the G12/13 protein/Rho-signaling pathway in pancreatic cancer cells, leading to RhoA activation and inhibition of EGF-induced cell migration and invasion; this is distinct from LPA1 which promotes migration.","method":"LPA2-specific siRNA knockdown, C3 toxin (RhoA inhibitor), LP-105 LPA2-selective agonist, pertussis toxin treatment, Transwell migration and Matrigel invasion assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific siRNA, selective agonist, and Rho inhibitor; multiple cell lines tested, single lab","pmids":["19129242"],"is_preprint":false},{"year":2010,"finding":"MAGI-3 competes with NHERF-2 for binding to LPA2 and to PLC-beta3; MAGI-3 increases LPA2 interaction with Galpha12 while NHERF-2 preferentially promotes interaction with Galphaq, thereby oppositely regulating LPA2-induced PLC activity, NF-kappaB activation, JNK activation, and cell migration/invasion.","method":"Co-immunoprecipitation, MAGI-3 overexpression and knockdown, NF-kappaB reporter assay, migration and invasion assays in colon cancer cells","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, gain- and loss-of-function, multiple signaling and functional readouts, single lab","pmids":["21134377"],"is_preprint":false},{"year":2012,"finding":"LPA2 receptor signals through Galphaqi to activate Rho/Rho-kinase and alphavbeta6 integrin-dependent TGF-beta1 transactivation in proximal tubule cells, leading to production and secretion of profibrotic cytokines PDGF-B and CTGF.","method":"LPA2 receptor assays in proximal tubule cells, pharmacological inhibitors (Rho kinase, alphavbeta6 integrin blocking antibody), TGF-beta activation assays, rat ischemia-reperfusion injury model","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent replication of LPA2/Gq/alphavbeta6/TGF-beta axis by same lab with in vivo validation (see also PMID:19147812), multiple orthogonal methods","pmids":["22885106"],"is_preprint":false},{"year":2014,"finding":"LPA2 mediates N-cadherin internalization in neural crest cells downstream of LPA, reducing cell-cell adhesion and triggering a partial mesenchymal phenotype that increases tissue fluidity and enables collective cell migration under physical constraints.","method":"Live imaging in Xenopus neural crest, LPA2 loss-of-function (morpholino), N-cadherin internalization assays, tissue rheology measurements","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct live imaging linked to functional consequence, loss-of-function with defined molecular mechanism (N-cadherin internalization), multiple orthogonal methods in vivo","pmids":["25002680"],"is_preprint":false},{"year":2012,"finding":"LPA2-specific nonlipid agonist GRI977143 promotes assembly of a macromolecular signaling complex consisting of LPA2, NHERF2, and TRIP6 (thyroid receptor interacting protein 6), which mediates antiapoptotic ERK1/2 activation and reduces caspase activation, DNA fragmentation, and Bax translocation.","method":"Co-immunoprecipitation, LPA2-reconstituted MEF cells (LPA1&2 double-KO background), caspase assays, PARP cleavage, DNA fragmentation, ERK1/2 phosphorylation assays","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with reconstituted receptor system (receptor-null MEFs), multiple signaling readouts, single lab","pmids":["22968304"],"is_preprint":false},{"year":2016,"finding":"TRIP6 (an LPA2-interacting adaptor) recruits TRAF6 to the LPA2 receptor upon LPA stimulation and promotes LPA-induced JNK and NF-kappaB activation in a TRAF6-dependent manner; TRIP6 antagonizes binding of deubiquitinases A20 and CYLD to TRAF6, sustaining TRAF6 E3 ligase activity and augmenting NF-kappaB signaling.","method":"Co-immunoprecipitation, TRIP6 shRNA/Cas9 knockdown/knockout, TRAF6 binding assays with A20/CYLD, NF-kappaB and JNK reporter assays in ovarian cancer cells","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IPs, CRISPR/shRNA loss-of-function, mechanistic dissection of TRAF6 ubiquitination regulation, single lab with multiple orthogonal methods","pmids":["27134758"],"is_preprint":false},{"year":2014,"finding":"A LPA gradient induces spatiotemporally restricted decrease in LPA2 mobility on fibroblasts, correlating with PDZ motif-mediated macromolecular complex assembly anchored to the cytoskeleton; this asymmetric complex generates a Ca2+ puff gradient that governs gradient sensing and directional migration. Disrupting the PDZ motif abolishes this gradient sensing.","method":"Single-particle tracking, PDZ motif mutagenesis, Ca2+ imaging, directional migration (chemotaxis) assays in fibroblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — single-particle tracking combined with domain mutagenesis and functional Ca2+ imaging and migration readouts, single lab","pmids":["25542932"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the NHERF2 PDZ1 domain in complex with the C-terminal LPA2 peptide sequence reveals that binding specificity is achieved through hydrogen bonds and hydrophobic contacts with the last four LPA2 residues; conformational flexibility in the ligand-binding pocket contributes to substrate recognition.","method":"X-ray crystallography of PDZ1–LPA2 C-terminal peptide complex","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with atomic-level resolution of the PDZ-LPA2 interaction, single lab","pmids":["24613836"],"is_preprint":false},{"year":2015,"finding":"Gamma-irradiation upregulates lpa2 expression in intestinal crypt cells via ATM kinase and NF-kappaB (mutation of NF-kappaB site in lpa2 promoter abolishes upregulation); LPA2 promotes DNA repair resolution (accelerated gamma-H2AX disappearance) via ERK1/2 and PI3K/AKT signaling; a C311A/C314A/L351A mutation in the LPA2 C-terminus abrogates this DNA repair function.","method":"Quantitative RT-PCR, promoter mutation analysis, gamma-H2AX immunofluorescence, pharmacological inhibition (CGK-733 ATM/ATR inhibitor, pertussis toxin), LPA2-reconstituted MEF cells, LPA2-KO mice, C-terminus mutagenesis","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — promoter mutagenesis, domain mutagenesis, in vivo KO validation, multiple orthogonal pharmacological and genetic approaches, single lab","pmids":["26027517"],"is_preprint":false},{"year":2011,"finding":"LPA stimulates DRA (SLC26A3) gene transcription via the LPA2 receptor and PI3K/AKT pathway; LPA induces DRA promoter activity in a c-Fos-dependent manner, and overexpression of c-Fos (but not c-Jun) enhances DRA promoter activity.","method":"Receptor-specific pharmacology, PI3K/AKT inhibitors, DRA promoter-reporter assays, EMSA, mutational analysis of promoter, siRNA in Caco-2 cells","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific pharmacology combined with promoter deletion, EMSA, and mutational analysis, single lab","pmids":["22159277"],"is_preprint":false},{"year":2007,"finding":"LPA2 mediates LPA-stimulated RhoA activation and cell migration in breast cancer cells (BT-20) with lower potency/efficacy than LPA1; LPA1 and LPA2 cooperate to promote LPA-stimulated chemotaxis, allowing response to a wider range of LPA concentrations.","method":"LPA2-specific siRNA knockdown, C3 exotransferase (RhoA inhibitor), LPA1 receptor overexpression, Ki16425 antagonist, Transwell chemotaxis assay","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific siRNA combined with pharmacological antagonism and gain-of-function, single lab","pmids":["17496233"],"is_preprint":false},{"year":2015,"finding":"Phosphorylation of LPA2 requires higher agonist and PKC activator concentrations compared to LPA1 and LPA3; LPA2 internalization upon agonist or PKC stimulation is less intense than other subtypes; homologous desensitization of LPA2 is not affected by PKC inhibition or down-regulation, unlike LPA1/LPA3.","method":"Receptor phosphorylation assays, internalization assays, PKC inhibition/down-regulation, agonist desensitization in C9 cells expressing individual LPA receptors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation assays and internalization measurements comparing LPA1/2/3, single lab","pmids":["26473723"],"is_preprint":false},{"year":2018,"finding":"LPA-induced migration of ovarian cancer cells (OVCAR-3) via LPA1 and LPA2 (but not LPA3) requires phosphorylation of ERM proteins (ezrin/radixin/moesin) at their C-termini through the Galpha12/13/RhoA pathway; dominant-negative ezrin (T567A) blocks LPA-induced migration.","method":"LPA1/LPA2 siRNA knockdown, Galpha12/13/RhoA pathway pharmacology, dominant-negative ezrin mutant overexpression, ERM phosphorylation assays, migration assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific siRNA combined with pathway inhibitors and dominant-negative mutant, single lab","pmids":["29329782"],"is_preprint":false},{"year":2022,"finding":"Endothelial LPA2 promotes angiogenesis and vascular homeostasis after myocardial infarction via PI3K-Akt/PLC-Raf1-Erk pathway (endothelial cell proliferation) and PKD1-CD36 signaling (tube formation); endothelial-specific Lpar2 KO phenocopies global KO with increased vascular leak, larger scar, and reduced vascular density.","method":"Global and endothelial-specific Lpar2 knockout mice, adenovirus-Lpar2 rescue, pharmacological LPA2 activation (DBIBB), MI and femoral artery ligation models, mechanistic pathway inhibitors","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO phenocopies global KO, adenoviral rescue, pharmacological activation, multiple signaling pathway inhibitors, in vivo and in vitro validation","pmids":["35920162"],"is_preprint":false},{"year":2017,"finding":"LPA upregulates MMP-9 expression in macrophages through LPA2-dependent NF-kappaB p65 activation; knockdown of LPA2 attenuates LPA-induced MMP-9 expression and nuclear p65 translocation. AP-1 and PPARgamma inhibitors do not affect this pathway.","method":"LPA2 siRNA knockdown, NF-kappaB inhibitor (PDTC), NF-κB p65 siRNA, MMP-9 expression/activity assays, THP-1-derived macrophages and primary human macrophages","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific siRNA with pathway-specific inhibitors and transcription factor knockdown, single lab","pmids":["28496416"],"is_preprint":false},{"year":2025,"finding":"LPA2 interacts with Wnt effectors Dvl2 and Dvl3 in colon cancer cells via the PDZ-interacting motif in the LPA2 C-terminus; the LPA2-PDZminus mutant (lacking PDZ interaction) inhibits cell migration but increases proliferation and impairs LPA2-mediated canonical Wnt signaling as well as Wnt-3a-induced beta-catenin signaling.","method":"Co-immunoprecipitation of LPA2 with Dvl2/Dvl3, LPA2-PDZminus mutant expression, beta-catenin reporter assay, ERK phosphorylation, migration and proliferation assays in colon cancer cells","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and domain mutagenesis with functional readouts, single lab","pmids":["41418976"],"is_preprint":false},{"year":2019,"finding":"LPA2 mediates LPA-induced migration, invasion, EMT, and cytoskeletal remodeling of SGC-7901 gastric cancer cells; LPA2 physically interacts with Notch1 (shown by co-immunoprecipitation), and LPA stimulates Notch1/Hes1 expression and Akt phosphorylation.","method":"Co-immunoprecipitation (LPA2/Notch1), LPA2 and Notch1 siRNA knockdown, Transwell migration and invasion assays, EMT marker expression, immunofluorescent staining","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with partial mechanistic follow-up, single lab","pmids":["31115486"],"is_preprint":false},{"year":2021,"finding":"LPAR2 receptor activation protects colonic tight junctions from radiation injury via a Rho-kinase-dependent mechanism; Lpar2-/- mice show more severe TJ disruption after irradiation than wild-type; LPA2-specific agonist RP-1 alleviates radiation-induced barrier dysfunction and modulates cofilin activation and actin cytoskeleton remodeling.","method":"Lpar2-/- mice (total body irradiation), Caco-2/m-ICC12 cell monolayers, Rho-kinase inhibitor, barrier function (inulin permeability, TEER), TJ protein immunofluorescence, plasma LPS measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse combined with pharmacological agonist and inhibitor in vivo and in vitro, single lab","pmids":["32654268"],"is_preprint":false},{"year":2023,"finding":"LPA-LPA2 signaling protects vascular endothelial barrier in septic acute lung injury via the PLC-PKC-FAK pathway; Lpar2 deficiency increases vascular permeability and worsens lung injury, while pharmacological LPA2 activation (DBIBB) reduces inflammation and preserves tight junction proteins (ZO-1, claudin-5) and VE-cadherin.","method":"Lpar2-/- mice (LPS sepsis model), DBIBB pharmacological activation, Evans blue dye permeability assay, TEER in MLMECs, Western blot for PLC/PKC/FAK pathway activation, immunofluorescence for TJ proteins","journal":"Journal of inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype with pharmacological rescue and mechanistic pathway characterization, single lab","pmids":["38026263"],"is_preprint":false},{"year":2020,"finding":"LPA2 receptor mediates LPA-induced inhibition of neuronal network excitability in hippocampus; Lpar2-/- mice show decreased hippocampal network activity and increased LTP, with reduced transcription of neuronal activity markers (ARC, FOS, FOSB, NR4A2, NPAS4, EGR2) in dentate gyrus; pharmacological LPA2 blockade recapitulates this phenotype.","method":"Lpar2-/- mice, electrophysiology (LTP, network activity), RNAseq of dentate gyrus, pharmacological LPA2 antagonism, behavioral cognitive assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and pharmacological antagonism with electrophysiology and transcriptomics, single lab","pmids":["32468095"],"is_preprint":false},{"year":2020,"finding":"LPA2 in dendritic cells negatively regulates NF-kappaB-driven gene transcription; lpa2-/- dendritic cells are hyperactive and less susceptible to LPA-mediated inhibition; adoptive transfer of lpa2-/- DCs induces more lung inflammation than WT DCs.","method":"Lpa2-/- mice, DC adoptive transfer, NF-kappaB reporter (transient transfection), allergen challenge models (OVA and Schistosoma egg), BAL cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice combined with adoptive transfer and NF-kappaB reporter assay, single lab","pmids":["22427635"],"is_preprint":false},{"year":2022,"finding":"LPA2 promotes neuronal differentiation of neural stem/progenitor cells via ERK1/2 signaling, and promotes neurite elongation and branching; LPA2 activation with GRI977143 induces neuronal differentiation that is blocked by ERK1/2 inhibitor FR180204.","method":"LPA2-selective agonist (GRI977143), ERK1/2 inhibitor (FR180204), primary neural stem/progenitor cell culture, neuronal differentiation assays, neurite morphology analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific agonist with pathway inhibitor in primary cell culture, single lab","pmids":["35151977"],"is_preprint":false},{"year":2021,"finding":"LPA2 and GPR55 physically interact in live cells (BRET analysis); co-activation of both receptors synergistically reduces intracellular cAMP and promotes cell proliferation beyond either receptor alone; co-activation facilitates co-internalization of both receptors.","method":"Bioluminescence resonance energy transfer (BRET) in live cells, cAMP assay, proliferation assay, receptor co-internalization imaging","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BRET in live cells with functional cAMP and proliferation readouts, single lab","pmids":["33959968"],"is_preprint":false},{"year":2022,"finding":"LPA induces beta-catenin nuclear localization and transcriptional activity, GSK-3beta phosphorylation, Axin2 downregulation, and increased ATP production via both oxidative phosphorylation and glycolysis in gastric cancer cells, all through the LPAR2 receptor; LPAR2 antagonism or knockdown abrogates these effects.","method":"LPAR2 antagonist, LPAR2 siRNA knockdown, beta-catenin reporter and localization assays, Seahorse metabolic assay, Western blot for GSK-3beta/Axin2","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific antagonist and siRNA with multiple functional metabolic and signaling readouts, single lab","pmids":["36551233"],"is_preprint":false}],"current_model":"LPAR2 is a Gq/Gi/G12/13-coupled GPCR that mediates LPA signaling through a multi-scaffold complex at its PDZ-binding C-terminal tail: it directly binds NHERF2 (via the second PDZ domain) to form a ternary LPAR2/NHERF2/PLC-beta3 complex that drives PLC-beta activation, IP3/Ca2+ mobilization, ERK, and Akt signaling; MAGI-3 competes with NHERF2 and shifts coupling toward Galpha12-Rho; TRIP6 is recruited to the complex to activate TRAF6 and sustain NF-kappaB/JNK signaling; via Galpha12/13/RhoA, LPA2 phosphorylates ERM proteins and drives cell migration, while via Galphaq/Rho/Rho-kinase it transactivates alphavbeta6-integrin-dependent TGF-beta1 to promote fibrotic cytokine secretion; LPA2 also promotes DNA repair after irradiation through ERK1/2/PI3K-AKT signaling dependent on its C-terminal cysteines; in endothelial cells LPA2 maintains vascular barrier integrity via PLC-PKC-FAK; and in neural cells LPA2 drives neuronal differentiation through ERK1/2, while regulating hippocampal network excitability."},"narrative":{"mechanistic_narrative":"LPAR2 (LPA2/EDG4) is a lysophosphatidic acid-activated G protein-coupled receptor that transduces LPA signals through multiple heterotrimeric G proteins to control proliferation, survival, directional migration, barrier integrity, and tissue remodeling [PMID:12215548, PMID:11040035]. It couples to Gi (Akt activation), Gq/PLC-beta (IP3/Ca2+, ERK), and G12/13/RhoA, and these outputs are organized by its C-terminal PDZ-binding motif, which nucleates a cytoskeleton-anchored macromolecular signaling complex [PMID:15728708, PMID:25542932]. The receptor selectively binds the scaffold NHERF2 through the second PDZ domain to assemble a ternary LPA2/NHERF2/PLC-beta3 complex that potentiates PLC-beta, ERK, and Akt signaling and COX-2/IL-8 induction [PMID:15143197, PMID:15728708]; the structural basis of this interaction lies in hydrogen bonds and hydrophobic contacts to the terminal LPA2 residues within the NHERF2 PDZ1 pocket [PMID:24613836]. The competing scaffold MAGI-3 displaces NHERF2 and shifts coupling toward Galpha12, oppositely tuning PLC, NF-kappaB, JNK, and cell migration/invasion [PMID:21134377], while the adaptor TRIP6 recruits TRAF6 to sustain its E3 ligase activity by antagonizing A20/CYLD, thereby driving NF-kappaB and JNK signaling [PMID:27134758]. Through Galpha12/13/RhoA the receptor phosphorylates ERM proteins to enable migration [PMID:29329782], and through Galphaq/Rho/Rho-kinase it transactivates alphavbeta6-integrin-dependent TGF-beta1 to elicit profibrotic cytokine secretion in epithelial and renal tubule cells [PMID:19147812, PMID:22885106]. LPA2 also accelerates DNA repair after irradiation via ERK1/2 and PI3K/AKT in a manner dependent on its C-terminal cysteines [PMID:26027517], maintains endothelial and epithelial barrier integrity (PI3K-Akt/Erk and PLC-PKC-FAK pathways) [PMID:35920162, PMID:32654268, PMID:38026263], drives neuronal differentiation via ERK1/2 [PMID:35151977], and links LPA to canonical Wnt/beta-catenin signaling through PDZ-dependent interaction with Dishevelled [PMID:41418976].","teleology":[{"year":2000,"claim":"Established that LPA2 is a functional LPA receptor coupling to multiple G proteins, defining its core signaling repertoire before any scaffold or pathway context was known.","evidence":"Retroviral expression in receptor-null B103 neuroblastoma cells with comparative signaling assays","pmids":["11040035"],"confidence":"High","gaps":["Did not resolve which G protein drives which output","No scaffold or complex partners identified"]},{"year":2002,"claim":"Genetic knockout demonstrated that LPA2 contributes to LPA-induced PLC, Ca2+, adenylyl cyclase, proliferation, JNK, Akt, and stress fiber responses, acting redundantly with LPA1 in fibroblasts.","evidence":"lpa2-/- and lpa1-/-/lpa2-/- mice with embryonic fibroblast signaling assays","pmids":["12215548"],"confidence":"High","gaps":["Redundancy obscured LPA2-specific functions","No molecular mechanism for selectivity among outputs"]},{"year":2004,"claim":"Identified the receptor-specific scaffold mechanism: LPA2 alone binds NHERF2 via its C-terminal PDZ motif to form a ternary complex with PLC-beta3 that amplifies signaling.","evidence":"Reciprocal Co-IP, PDZ motif mutagenesis, NHERF2 siRNA, IP/ERK assays","pmids":["15143197"],"confidence":"High","gaps":["Atomic basis of binding specificity unresolved","Did not address competing scaffolds"]},{"year":2005,"claim":"Dissected the G protein origin of LPA2 outputs in cancer cells, showing Gi-dependent Akt and PLC-dependent ERK both require NHERF2 for full activation.","evidence":"Pertussis toxin, U-73122, NHERF2 siRNA, Co-IP in colon cancer cells","pmids":["15728708"],"confidence":"High","gaps":["Mechanism linking NHERF2 to Gi coupling not defined","Functional consequence beyond IL-8 limited"]},{"year":2009,"claim":"Defined a Galphaq/RhoA/Rho-kinase axis through which LPA2 transactivates alphavbeta6-integrin-dependent TGF-beta, connecting the receptor to fibrosis-relevant signaling.","evidence":"siRNA, Galphaq/Rho/Rho-kinase inhibitors, TGF-beta activation assays in epithelial cells; pancreatic cancer G12/13/Rho migration study","pmids":["19147812","19129242"],"confidence":"High","gaps":["Whether scaffold choice gates this axis not tested in this context","In vivo relevance not yet established at this stage"]},{"year":2010,"claim":"Revealed scaffold competition as a switch: MAGI-3 displaces NHERF2 to bias LPA2 toward Galpha12, oppositely regulating PLC, NF-kappaB, JNK, and invasion.","evidence":"Reciprocal Co-IP, MAGI-3 gain/loss-of-function, NF-kappaB reporter, migration/invasion assays in colon cancer","pmids":["21134377"],"confidence":"High","gaps":["Determinants controlling scaffold ratio in vivo unknown","Structural basis of competition not resolved"]},{"year":2012,"claim":"Extended the antiapoptotic and profibrotic roles of LPA2, identifying TRIP6 as a third complex member for survival ERK signaling and confirming the Gq/alphavbeta6/TGF-beta fibrotic axis in vivo.","evidence":"LPA2-selective agonist GRI977143, Co-IP in reconstituted MEFs, caspase/DNA-fragmentation assays; proximal tubule cells with rat ischemia-reperfusion model","pmids":["22968304","22885106"],"confidence":"Medium","gaps":["TRIP6 recruitment mechanism not yet defined","Causal contribution to organ fibrosis not isolated to LPA2"]},{"year":2014,"claim":"Provided structural and biophysical mechanism: a crystal structure of NHERF2 PDZ1 bound to the LPA2 C-terminus, plus single-particle tracking showing PDZ-anchored complex assembly creates a Ca2+ gradient for chemotactic sensing.","evidence":"X-ray crystallography of PDZ1-LPA2 peptide; single-particle tracking, PDZ mutagenesis, Ca2+ imaging, chemotaxis in fibroblasts; Xenopus neural crest N-cadherin internalization","pmids":["24613836","25542932","25002680"],"confidence":"High","gaps":["Full-length receptor-scaffold structure unavailable","Cytoskeletal anchor identity not defined"]},{"year":2015,"claim":"Established LPA2 as a radioprotective DNA-repair factor whose function depends on its C-terminal cysteines, and characterized its distinctive desensitization behavior.","evidence":"Promoter mutagenesis, gamma-H2AX imaging, C-terminus mutagenesis, LPA2-reconstituted MEFs and KO mice; phosphorylation/internalization assays in C9 cells","pmids":["26027517","26473723"],"confidence":"High","gaps":["Role of C-terminal cysteines mechanistically unexplained","Link between desensitization resistance and sustained signaling untested"]},{"year":2016,"claim":"Defined the molecular logic of LPA2-driven NF-kappaB/JNK signaling: TRIP6 recruits TRAF6 and protects its E3 ligase activity from deubiquitinases A20 and CYLD.","evidence":"Reciprocal Co-IP, TRIP6 shRNA/CRISPR, TRAF6-A20/CYLD binding assays, NF-kappaB/JNK reporters in ovarian cancer cells","pmids":["27134758"],"confidence":"High","gaps":["Ubiquitin chain types on TRAF6 not characterized","How LPA2 conformation triggers TRIP6 recruitment unknown"]},{"year":2020,"claim":"Expanded physiological roles to immune and neural systems: LPA2 negatively regulates NF-kappaB in dendritic cells and dampens hippocampal network excitability.","evidence":"lpa2-/- mice, DC adoptive transfer, NF-kappaB reporter; electrophysiology, dentate gyrus RNAseq, pharmacological antagonism","pmids":["22427635","32468095"],"confidence":"Medium","gaps":["Cell-autonomous neuronal mechanism not resolved","How the same receptor both activates and suppresses NF-kappaB in different cells unexplained"]},{"year":2022,"claim":"Demonstrated tissue-protective vascular and neurogenic functions through endothelial-specific genetics and pathway dissection.","evidence":"Endothelial-specific and global Lpar2 KO, adenoviral rescue, DBIBB activation, MI models; 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37758013","citation_count":3,"is_preprint":false},{"pmid":"35799024","id":"PMC_35799024","title":"Estrogen-increased SGK1 Promotes Endometrial Stromal Cell Invasion in Adenomyosis by Regulating with LPAR2.","date":"2022","source":"Reproductive sciences (Thousand Oaks, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/35799024","citation_count":2,"is_preprint":false},{"pmid":"39125747","id":"PMC_39125747","title":"Lysophosphatidic Acid Receptors LPAR5 and LPAR2 Inversely Control Hydroxychloroquine-Evoked Itch and Scratching in Mice.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39125747","citation_count":1,"is_preprint":false},{"pmid":"38986295","id":"PMC_38986295","title":"Circ_0007611 modulates the miR-34c-5p/LPAR2 cascade to suppress proliferation and enhance apoptosis of HTR-8/SVneo 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LPA-mediated responses in fibroblasts.\",\n      \"method\": \"Genetic knockout (lpa2-/- and lpa1-/-/lpa2-/- mice), embryonic fibroblast signaling assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple orthogonal signaling readouts, replicated across single and double knockout genotypes in one rigorous study\",\n      \"pmids\": [\"12215548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LPA2 (EDG4/LP(A2)) couples to multiple G proteins and mediates LPA-dependent inositol phosphate production, MAPK activation, arachidonic acid release, inhibition of cAMP accumulation, and cell rounding in neuronal cell lines; distinct from LPA3 which causes neurite elongation.\",\n      \"method\": \"Retrovirus expression system in B103 neuroblastoma cells (lacking endogenous LPA receptors), comparative signaling assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in receptor-null cells with multiple orthogonal functional readouts, single lab but multiple assay types\",\n      \"pmids\": [\"11040035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LPA induces alphavbeta6 integrin-mediated TGF-beta activation in human epithelial cells via LPA2 receptor signaling through Galpha(q), RhoA, and Rho kinase.\",\n      \"method\": \"Pharmacological inhibition (Galpha(q) inhibitor, RhoA/Rho kinase inhibitors), siRNA knockdown of LPA2, TGF-beta activation assays in epithelial cells\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal perturbations (siRNA, pharmacological), defined signaling pathway with functional readout in one study\",\n      \"pmids\": [\"19147812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LPA2, but not other LPA receptor isoforms, specifically interacts with NHERF2 via the C-terminal PDZ domain-binding motif of LPA2 and the second PDZ domain of NHERF2; this interaction forms a ternary complex (LPA2/NHERF2/PLC-beta3) that potentiates LPA-induced PLC-beta activation, ERK activation, and COX-2 induction.\",\n      \"method\": \"Co-immunoprecipitation, PDZ domain-binding motif mutation, NHERF2 gene silencing (siRNA), stable expression, inositol phosphate and ERK assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal co-IP, domain mutagenesis, RNAi knockdown, multiple signaling readouts; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"15143197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LPA2 activates Akt (via Gi/pertussis-toxin-sensitive pathway) and Erk1/2 (via PLCbeta/U-73122-sensitive pathway) in human colon cancer cells, and mediates LPA-induced IL-8 synthesis; LPA2 physically interacts with NHERF2 and this interaction is required for efficient Akt and Erk1/2 activation.\",\n      \"method\": \"Pertussis toxin inhibition, PLC inhibitor (U-73122), NHERF2 siRNA knockdown, co-immunoprecipitation in colon cancer cells\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological perturbations plus RNAi with defined signaling readouts and Co-IP, single lab\",\n      \"pmids\": [\"15728708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LPA-induced Ca2+ mobilization in SH-SY5Y neuroblastoma cells (which endogenously express EDG-4/LPA2) does not involve IP3 or ryanodine receptor pathways, but requires intracellular sphingosine 1-phosphate production via sphingosine kinase; LPA stimulates sphingosine 1-phosphate production and this lipid second messenger mobilizes intracellular Ca2+.\",\n      \"method\": \"45Ca2+ release assays in permeabilized cells, sphingosine kinase inhibitor (dimethylsphingosine), confocal Ca2+ imaging, IP3 receptor down-regulation, [3H]sphingosine 1-phosphate measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological and biochemical assays in cells with endogenous EDG-4/LPA2, single lab\",\n      \"pmids\": [\"10954727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LPA2 receptor is coupled to the G12/13 protein/Rho-signaling pathway in pancreatic cancer cells, leading to RhoA activation and inhibition of EGF-induced cell migration and invasion; this is distinct from LPA1 which promotes migration.\",\n      \"method\": \"LPA2-specific siRNA knockdown, C3 toxin (RhoA inhibitor), LP-105 LPA2-selective agonist, pertussis toxin treatment, Transwell migration and Matrigel invasion assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific siRNA, selective agonist, and Rho inhibitor; multiple cell lines tested, single lab\",\n      \"pmids\": [\"19129242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAGI-3 competes with NHERF-2 for binding to LPA2 and to PLC-beta3; MAGI-3 increases LPA2 interaction with Galpha12 while NHERF-2 preferentially promotes interaction with Galphaq, thereby oppositely regulating LPA2-induced PLC activity, NF-kappaB activation, JNK activation, and cell migration/invasion.\",\n      \"method\": \"Co-immunoprecipitation, MAGI-3 overexpression and knockdown, NF-kappaB reporter assay, migration and invasion assays in colon cancer cells\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, gain- and loss-of-function, multiple signaling and functional readouts, single lab\",\n      \"pmids\": [\"21134377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LPA2 receptor signals through Galphaqi to activate Rho/Rho-kinase and alphavbeta6 integrin-dependent TGF-beta1 transactivation in proximal tubule cells, leading to production and secretion of profibrotic cytokines PDGF-B and CTGF.\",\n      \"method\": \"LPA2 receptor assays in proximal tubule cells, pharmacological inhibitors (Rho kinase, alphavbeta6 integrin blocking antibody), TGF-beta activation assays, rat ischemia-reperfusion injury model\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent replication of LPA2/Gq/alphavbeta6/TGF-beta axis by same lab with in vivo validation (see also PMID:19147812), multiple orthogonal methods\",\n      \"pmids\": [\"22885106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LPA2 mediates N-cadherin internalization in neural crest cells downstream of LPA, reducing cell-cell adhesion and triggering a partial mesenchymal phenotype that increases tissue fluidity and enables collective cell migration under physical constraints.\",\n      \"method\": \"Live imaging in Xenopus neural crest, LPA2 loss-of-function (morpholino), N-cadherin internalization assays, tissue rheology measurements\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging linked to functional consequence, loss-of-function with defined molecular mechanism (N-cadherin internalization), multiple orthogonal methods in vivo\",\n      \"pmids\": [\"25002680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LPA2-specific nonlipid agonist GRI977143 promotes assembly of a macromolecular signaling complex consisting of LPA2, NHERF2, and TRIP6 (thyroid receptor interacting protein 6), which mediates antiapoptotic ERK1/2 activation and reduces caspase activation, DNA fragmentation, and Bax translocation.\",\n      \"method\": \"Co-immunoprecipitation, LPA2-reconstituted MEF cells (LPA1&2 double-KO background), caspase assays, PARP cleavage, DNA fragmentation, ERK1/2 phosphorylation assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with reconstituted receptor system (receptor-null MEFs), multiple signaling readouts, single lab\",\n      \"pmids\": [\"22968304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIP6 (an LPA2-interacting adaptor) recruits TRAF6 to the LPA2 receptor upon LPA stimulation and promotes LPA-induced JNK and NF-kappaB activation in a TRAF6-dependent manner; TRIP6 antagonizes binding of deubiquitinases A20 and CYLD to TRAF6, sustaining TRAF6 E3 ligase activity and augmenting NF-kappaB signaling.\",\n      \"method\": \"Co-immunoprecipitation, TRIP6 shRNA/Cas9 knockdown/knockout, TRAF6 binding assays with A20/CYLD, NF-kappaB and JNK reporter assays in ovarian cancer cells\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IPs, CRISPR/shRNA loss-of-function, mechanistic dissection of TRAF6 ubiquitination regulation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27134758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A LPA gradient induces spatiotemporally restricted decrease in LPA2 mobility on fibroblasts, correlating with PDZ motif-mediated macromolecular complex assembly anchored to the cytoskeleton; this asymmetric complex generates a Ca2+ puff gradient that governs gradient sensing and directional migration. Disrupting the PDZ motif abolishes this gradient sensing.\",\n      \"method\": \"Single-particle tracking, PDZ motif mutagenesis, Ca2+ imaging, directional migration (chemotaxis) assays in fibroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — single-particle tracking combined with domain mutagenesis and functional Ca2+ imaging and migration readouts, single lab\",\n      \"pmids\": [\"25542932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the NHERF2 PDZ1 domain in complex with the C-terminal LPA2 peptide sequence reveals that binding specificity is achieved through hydrogen bonds and hydrophobic contacts with the last four LPA2 residues; conformational flexibility in the ligand-binding pocket contributes to substrate recognition.\",\n      \"method\": \"X-ray crystallography of PDZ1–LPA2 C-terminal peptide complex\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with atomic-level resolution of the PDZ-LPA2 interaction, single lab\",\n      \"pmids\": [\"24613836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Gamma-irradiation upregulates lpa2 expression in intestinal crypt cells via ATM kinase and NF-kappaB (mutation of NF-kappaB site in lpa2 promoter abolishes upregulation); LPA2 promotes DNA repair resolution (accelerated gamma-H2AX disappearance) via ERK1/2 and PI3K/AKT signaling; a C311A/C314A/L351A mutation in the LPA2 C-terminus abrogates this DNA repair function.\",\n      \"method\": \"Quantitative RT-PCR, promoter mutation analysis, gamma-H2AX immunofluorescence, pharmacological inhibition (CGK-733 ATM/ATR inhibitor, pertussis toxin), LPA2-reconstituted MEF cells, LPA2-KO mice, C-terminus mutagenesis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — promoter mutagenesis, domain mutagenesis, in vivo KO validation, multiple orthogonal pharmacological and genetic approaches, single lab\",\n      \"pmids\": [\"26027517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LPA stimulates DRA (SLC26A3) gene transcription via the LPA2 receptor and PI3K/AKT pathway; LPA induces DRA promoter activity in a c-Fos-dependent manner, and overexpression of c-Fos (but not c-Jun) enhances DRA promoter activity.\",\n      \"method\": \"Receptor-specific pharmacology, PI3K/AKT inhibitors, DRA promoter-reporter assays, EMSA, mutational analysis of promoter, siRNA in Caco-2 cells\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific pharmacology combined with promoter deletion, EMSA, and mutational analysis, single lab\",\n      \"pmids\": [\"22159277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LPA2 mediates LPA-stimulated RhoA activation and cell migration in breast cancer cells (BT-20) with lower potency/efficacy than LPA1; LPA1 and LPA2 cooperate to promote LPA-stimulated chemotaxis, allowing response to a wider range of LPA concentrations.\",\n      \"method\": \"LPA2-specific siRNA knockdown, C3 exotransferase (RhoA inhibitor), LPA1 receptor overexpression, Ki16425 antagonist, Transwell chemotaxis assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific siRNA combined with pharmacological antagonism and gain-of-function, single lab\",\n      \"pmids\": [\"17496233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Phosphorylation of LPA2 requires higher agonist and PKC activator concentrations compared to LPA1 and LPA3; LPA2 internalization upon agonist or PKC stimulation is less intense than other subtypes; homologous desensitization of LPA2 is not affected by PKC inhibition or down-regulation, unlike LPA1/LPA3.\",\n      \"method\": \"Receptor phosphorylation assays, internalization assays, PKC inhibition/down-regulation, agonist desensitization in C9 cells expressing individual LPA receptors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation assays and internalization measurements comparing LPA1/2/3, single lab\",\n      \"pmids\": [\"26473723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LPA-induced migration of ovarian cancer cells (OVCAR-3) via LPA1 and LPA2 (but not LPA3) requires phosphorylation of ERM proteins (ezrin/radixin/moesin) at their C-termini through the Galpha12/13/RhoA pathway; dominant-negative ezrin (T567A) blocks LPA-induced migration.\",\n      \"method\": \"LPA1/LPA2 siRNA knockdown, Galpha12/13/RhoA pathway pharmacology, dominant-negative ezrin mutant overexpression, ERM phosphorylation assays, migration assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific siRNA combined with pathway inhibitors and dominant-negative mutant, single lab\",\n      \"pmids\": [\"29329782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endothelial LPA2 promotes angiogenesis and vascular homeostasis after myocardial infarction via PI3K-Akt/PLC-Raf1-Erk pathway (endothelial cell proliferation) and PKD1-CD36 signaling (tube formation); endothelial-specific Lpar2 KO phenocopies global KO with increased vascular leak, larger scar, and reduced vascular density.\",\n      \"method\": \"Global and endothelial-specific Lpar2 knockout mice, adenovirus-Lpar2 rescue, pharmacological LPA2 activation (DBIBB), MI and femoral artery ligation models, mechanistic pathway inhibitors\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO phenocopies global KO, adenoviral rescue, pharmacological activation, multiple signaling pathway inhibitors, in vivo and in vitro validation\",\n      \"pmids\": [\"35920162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LPA upregulates MMP-9 expression in macrophages through LPA2-dependent NF-kappaB p65 activation; knockdown of LPA2 attenuates LPA-induced MMP-9 expression and nuclear p65 translocation. AP-1 and PPARgamma inhibitors do not affect this pathway.\",\n      \"method\": \"LPA2 siRNA knockdown, NF-kappaB inhibitor (PDTC), NF-κB p65 siRNA, MMP-9 expression/activity assays, THP-1-derived macrophages and primary human macrophages\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific siRNA with pathway-specific inhibitors and transcription factor knockdown, single lab\",\n      \"pmids\": [\"28496416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LPA2 interacts with Wnt effectors Dvl2 and Dvl3 in colon cancer cells via the PDZ-interacting motif in the LPA2 C-terminus; the LPA2-PDZminus mutant (lacking PDZ interaction) inhibits cell migration but increases proliferation and impairs LPA2-mediated canonical Wnt signaling as well as Wnt-3a-induced beta-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation of LPA2 with Dvl2/Dvl3, LPA2-PDZminus mutant expression, beta-catenin reporter assay, ERK phosphorylation, migration and proliferation assays in colon cancer cells\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and domain mutagenesis with functional readouts, single lab\",\n      \"pmids\": [\"41418976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LPA2 mediates LPA-induced migration, invasion, EMT, and cytoskeletal remodeling of SGC-7901 gastric cancer cells; LPA2 physically interacts with Notch1 (shown by co-immunoprecipitation), and LPA stimulates Notch1/Hes1 expression and Akt phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation (LPA2/Notch1), LPA2 and Notch1 siRNA knockdown, Transwell migration and invasion assays, EMT marker expression, immunofluorescent staining\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with partial mechanistic follow-up, single lab\",\n      \"pmids\": [\"31115486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LPAR2 receptor activation protects colonic tight junctions from radiation injury via a Rho-kinase-dependent mechanism; Lpar2-/- mice show more severe TJ disruption after irradiation than wild-type; LPA2-specific agonist RP-1 alleviates radiation-induced barrier dysfunction and modulates cofilin activation and actin cytoskeleton remodeling.\",\n      \"method\": \"Lpar2-/- mice (total body irradiation), Caco-2/m-ICC12 cell monolayers, Rho-kinase inhibitor, barrier function (inulin permeability, TEER), TJ protein immunofluorescence, plasma LPS measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse combined with pharmacological agonist and inhibitor in vivo and in vitro, single lab\",\n      \"pmids\": [\"32654268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LPA-LPA2 signaling protects vascular endothelial barrier in septic acute lung injury via the PLC-PKC-FAK pathway; Lpar2 deficiency increases vascular permeability and worsens lung injury, while pharmacological LPA2 activation (DBIBB) reduces inflammation and preserves tight junction proteins (ZO-1, claudin-5) and VE-cadherin.\",\n      \"method\": \"Lpar2-/- mice (LPS sepsis model), DBIBB pharmacological activation, Evans blue dye permeability assay, TEER in MLMECs, Western blot for PLC/PKC/FAK pathway activation, immunofluorescence for TJ proteins\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype with pharmacological rescue and mechanistic pathway characterization, single lab\",\n      \"pmids\": [\"38026263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LPA2 receptor mediates LPA-induced inhibition of neuronal network excitability in hippocampus; Lpar2-/- mice show decreased hippocampal network activity and increased LTP, with reduced transcription of neuronal activity markers (ARC, FOS, FOSB, NR4A2, NPAS4, EGR2) in dentate gyrus; pharmacological LPA2 blockade recapitulates this phenotype.\",\n      \"method\": \"Lpar2-/- mice, electrophysiology (LTP, network activity), RNAseq of dentate gyrus, pharmacological LPA2 antagonism, behavioral cognitive assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and pharmacological antagonism with electrophysiology and transcriptomics, single lab\",\n      \"pmids\": [\"32468095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LPA2 in dendritic cells negatively regulates NF-kappaB-driven gene transcription; lpa2-/- dendritic cells are hyperactive and less susceptible to LPA-mediated inhibition; adoptive transfer of lpa2-/- DCs induces more lung inflammation than WT DCs.\",\n      \"method\": \"Lpa2-/- mice, DC adoptive transfer, NF-kappaB reporter (transient transfection), allergen challenge models (OVA and Schistosoma egg), BAL cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice combined with adoptive transfer and NF-kappaB reporter assay, single lab\",\n      \"pmids\": [\"22427635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LPA2 promotes neuronal differentiation of neural stem/progenitor cells via ERK1/2 signaling, and promotes neurite elongation and branching; LPA2 activation with GRI977143 induces neuronal differentiation that is blocked by ERK1/2 inhibitor FR180204.\",\n      \"method\": \"LPA2-selective agonist (GRI977143), ERK1/2 inhibitor (FR180204), primary neural stem/progenitor cell culture, neuronal differentiation assays, neurite morphology analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific agonist with pathway inhibitor in primary cell culture, single lab\",\n      \"pmids\": [\"35151977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LPA2 and GPR55 physically interact in live cells (BRET analysis); co-activation of both receptors synergistically reduces intracellular cAMP and promotes cell proliferation beyond either receptor alone; co-activation facilitates co-internalization of both receptors.\",\n      \"method\": \"Bioluminescence resonance energy transfer (BRET) in live cells, cAMP assay, proliferation assay, receptor co-internalization imaging\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BRET in live cells with functional cAMP and proliferation readouts, single lab\",\n      \"pmids\": [\"33959968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LPA induces beta-catenin nuclear localization and transcriptional activity, GSK-3beta phosphorylation, Axin2 downregulation, and increased ATP production via both oxidative phosphorylation and glycolysis in gastric cancer cells, all through the LPAR2 receptor; LPAR2 antagonism or knockdown abrogates these effects.\",\n      \"method\": \"LPAR2 antagonist, LPAR2 siRNA knockdown, beta-catenin reporter and localization assays, Seahorse metabolic assay, Western blot for GSK-3beta/Axin2\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific antagonist and siRNA with multiple functional metabolic and signaling readouts, single lab\",\n      \"pmids\": [\"36551233\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LPAR2 is a Gq/Gi/G12/13-coupled GPCR that mediates LPA signaling through a multi-scaffold complex at its PDZ-binding C-terminal tail: it directly binds NHERF2 (via the second PDZ domain) to form a ternary LPAR2/NHERF2/PLC-beta3 complex that drives PLC-beta activation, IP3/Ca2+ mobilization, ERK, and Akt signaling; MAGI-3 competes with NHERF2 and shifts coupling toward Galpha12-Rho; TRIP6 is recruited to the complex to activate TRAF6 and sustain NF-kappaB/JNK signaling; via Galpha12/13/RhoA, LPA2 phosphorylates ERM proteins and drives cell migration, while via Galphaq/Rho/Rho-kinase it transactivates alphavbeta6-integrin-dependent TGF-beta1 to promote fibrotic cytokine secretion; LPA2 also promotes DNA repair after irradiation through ERK1/2/PI3K-AKT signaling dependent on its C-terminal cysteines; in endothelial cells LPA2 maintains vascular barrier integrity via PLC-PKC-FAK; and in neural cells LPA2 drives neuronal differentiation through ERK1/2, while regulating hippocampal network excitability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LPAR2 (LPA2/EDG4) is a lysophosphatidic acid-activated G protein-coupled receptor that transduces LPA signals through multiple heterotrimeric G proteins to control proliferation, survival, directional migration, barrier integrity, and tissue remodeling [#0, #1]. It couples to Gi (Akt activation), Gq/PLC-beta (IP3/Ca2+, ERK), and G12/13/RhoA, and these outputs are organized by its C-terminal PDZ-binding motif, which nucleates a cytoskeleton-anchored macromolecular signaling complex [#4, #12]. The receptor selectively binds the scaffold NHERF2 through the second PDZ domain to assemble a ternary LPA2/NHERF2/PLC-beta3 complex that potentiates PLC-beta, ERK, and Akt signaling and COX-2/IL-8 induction [#3, #4]; the structural basis of this interaction lies in hydrogen bonds and hydrophobic contacts to the terminal LPA2 residues within the NHERF2 PDZ1 pocket [#13]. The competing scaffold MAGI-3 displaces NHERF2 and shifts coupling toward Galpha12, oppositely tuning PLC, NF-kappaB, JNK, and cell migration/invasion [#7], while the adaptor TRIP6 recruits TRAF6 to sustain its E3 ligase activity by antagonizing A20/CYLD, thereby driving NF-kappaB and JNK signaling [#11]. Through Galpha12/13/RhoA the receptor phosphorylates ERM proteins to enable migration [#18], and through Galphaq/Rho/Rho-kinase it transactivates alphavbeta6-integrin-dependent TGF-beta1 to elicit profibrotic cytokine secretion in epithelial and renal tubule cells [#2, #8]. LPA2 also accelerates DNA repair after irradiation via ERK1/2 and PI3K/AKT in a manner dependent on its C-terminal cysteines [#14], maintains endothelial and epithelial barrier integrity (PI3K-Akt/Erk and PLC-PKC-FAK pathways) [#19, #23, #24], drives neuronal differentiation via ERK1/2 [#27], and links LPA to canonical Wnt/beta-catenin signaling through PDZ-dependent interaction with Dishevelled [#21].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that LPA2 is a functional LPA receptor coupling to multiple G proteins, defining its core signaling repertoire before any scaffold or pathway context was known.\",\n      \"evidence\": \"Retroviral expression in receptor-null B103 neuroblastoma cells with comparative signaling assays\",\n      \"pmids\": [\"11040035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which G protein drives which output\", \"No scaffold or complex partners identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic knockout demonstrated that LPA2 contributes to LPA-induced PLC, Ca2+, adenylyl cyclase, proliferation, JNK, Akt, and stress fiber responses, acting redundantly with LPA1 in fibroblasts.\",\n      \"evidence\": \"lpa2-/- and lpa1-/-/lpa2-/- mice with embryonic fibroblast signaling assays\",\n      \"pmids\": [\"12215548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy obscured LPA2-specific functions\", \"No molecular mechanism for selectivity among outputs\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the receptor-specific scaffold mechanism: LPA2 alone binds NHERF2 via its C-terminal PDZ motif to form a ternary complex with PLC-beta3 that amplifies signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, PDZ motif mutagenesis, NHERF2 siRNA, IP/ERK assays\",\n      \"pmids\": [\"15143197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of binding specificity unresolved\", \"Did not address competing scaffolds\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Dissected the G protein origin of LPA2 outputs in cancer cells, showing Gi-dependent Akt and PLC-dependent ERK both require NHERF2 for full activation.\",\n      \"evidence\": \"Pertussis toxin, U-73122, NHERF2 siRNA, Co-IP in colon cancer cells\",\n      \"pmids\": [\"15728708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking NHERF2 to Gi coupling not defined\", \"Functional consequence beyond IL-8 limited\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined a Galphaq/RhoA/Rho-kinase axis through which LPA2 transactivates alphavbeta6-integrin-dependent TGF-beta, connecting the receptor to fibrosis-relevant signaling.\",\n      \"evidence\": \"siRNA, Galphaq/Rho/Rho-kinase inhibitors, TGF-beta activation assays in epithelial cells; pancreatic cancer G12/13/Rho migration study\",\n      \"pmids\": [\"19147812\", \"19129242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether scaffold choice gates this axis not tested in this context\", \"In vivo relevance not yet established at this stage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed scaffold competition as a switch: MAGI-3 displaces NHERF2 to bias LPA2 toward Galpha12, oppositely regulating PLC, NF-kappaB, JNK, and invasion.\",\n      \"evidence\": \"Reciprocal Co-IP, MAGI-3 gain/loss-of-function, NF-kappaB reporter, migration/invasion assays in colon cancer\",\n      \"pmids\": [\"21134377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants controlling scaffold ratio in vivo unknown\", \"Structural basis of competition not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the antiapoptotic and profibrotic roles of LPA2, identifying TRIP6 as a third complex member for survival ERK signaling and confirming the Gq/alphavbeta6/TGF-beta fibrotic axis in vivo.\",\n      \"evidence\": \"LPA2-selective agonist GRI977143, Co-IP in reconstituted MEFs, caspase/DNA-fragmentation assays; proximal tubule cells with rat ischemia-reperfusion model\",\n      \"pmids\": [\"22968304\", \"22885106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIP6 recruitment mechanism not yet defined\", \"Causal contribution to organ fibrosis not isolated to LPA2\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided structural and biophysical mechanism: a crystal structure of NHERF2 PDZ1 bound to the LPA2 C-terminus, plus single-particle tracking showing PDZ-anchored complex assembly creates a Ca2+ gradient for chemotactic sensing.\",\n      \"evidence\": \"X-ray crystallography of PDZ1-LPA2 peptide; single-particle tracking, PDZ mutagenesis, Ca2+ imaging, chemotaxis in fibroblasts; Xenopus neural crest N-cadherin internalization\",\n      \"pmids\": [\"24613836\", \"25542932\", \"25002680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor-scaffold structure unavailable\", \"Cytoskeletal anchor identity not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established LPA2 as a radioprotective DNA-repair factor whose function depends on its C-terminal cysteines, and characterized its distinctive desensitization behavior.\",\n      \"evidence\": \"Promoter mutagenesis, gamma-H2AX imaging, C-terminus mutagenesis, LPA2-reconstituted MEFs and KO mice; phosphorylation/internalization assays in C9 cells\",\n      \"pmids\": [\"26027517\", \"26473723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of C-terminal cysteines mechanistically unexplained\", \"Link between desensitization resistance and sustained signaling untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the molecular logic of LPA2-driven NF-kappaB/JNK signaling: TRIP6 recruits TRAF6 and protects its E3 ligase activity from deubiquitinases A20 and CYLD.\",\n      \"evidence\": \"Reciprocal Co-IP, TRIP6 shRNA/CRISPR, TRAF6-A20/CYLD binding assays, NF-kappaB/JNK reporters in ovarian cancer cells\",\n      \"pmids\": [\"27134758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin chain types on TRAF6 not characterized\", \"How LPA2 conformation triggers TRIP6 recruitment unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded physiological roles to immune and neural systems: LPA2 negatively regulates NF-kappaB in dendritic cells and dampens hippocampal network excitability.\",\n      \"evidence\": \"lpa2-/- mice, DC adoptive transfer, NF-kappaB reporter; electrophysiology, dentate gyrus RNAseq, pharmacological antagonism\",\n      \"pmids\": [\"22427635\", \"32468095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-autonomous neuronal mechanism not resolved\", \"How the same receptor both activates and suppresses NF-kappaB in different cells unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated tissue-protective vascular and neurogenic functions through endothelial-specific genetics and pathway dissection.\",\n      \"evidence\": \"Endothelial-specific and global Lpar2 KO, adenoviral rescue, DBIBB activation, MI models; neural stem/progenitor differentiation with GRI977143 and ERK inhibitor\",\n      \"pmids\": [\"35920162\", \"35151977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endothelial scaffold partners not identified\", \"Connection between barrier-protective and proliferative signaling branches unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked LPA2 to canonical Wnt signaling, showing PDZ-dependent interaction with Dishevelled 2/3 couples the receptor to beta-catenin signaling and migration.\",\n      \"evidence\": \"Co-IP of LPA2 with Dvl2/Dvl3, PDZminus mutant, beta-catenin reporter, migration/proliferation assays in colon cancer\",\n      \"pmids\": [\"41418976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without structural validation\", \"How Dvl recruitment competes with NHERF2/MAGI-3 at the same motif unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single C-terminal PDZ motif arbitrates among competing scaffolds (NHERF2, MAGI-3, TRIP6, Dishevelled) to select distinct G protein outputs and physiological outcomes in a cell-type-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative model of scaffold competition in vivo\", \"No full-length receptor-scaffold complex structure\", \"Cell-type determinants of scaffold availability uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 7, 11]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12, 17, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 20, 26]}\n    ],\n    \"complexes\": [\n      \"LPA2/NHERF2/PLC-beta3 ternary complex\",\n      \"LPA2/NHERF2/TRIP6 signaling complex\"\n    ],\n    \"partners\": [\n      \"NHERF2\",\n      \"PLCB3\",\n      \"MAGI3\",\n      \"TRIP6\",\n      \"TRAF6\",\n      \"DVL2\",\n      \"DVL3\",\n      \"GPR55\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}