{"gene":"S1PR2","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1999,"finding":"H218/EDG5/S1PR2 couples to Gi, Gq, and G13 families of heterotrimeric G proteins, in contrast to EDG1 which couples only to Gi. This was demonstrated using a subunit-selective [35S]GTPgammaS binding assay in Sf9 and HEK293 cells.","method":"Subunit-selective [35S]GTPgammaS binding assay in Sf9 and HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct G protein activation assay with reconstitution, replicated across two cell systems, multiple G protein subtypes tested with rigorous controls","pmids":["10488065"],"is_preprint":false},{"year":1999,"finding":"AGR16/S1PR2 expressed in CHO cells binds [32P]S1P specifically (displaced by S1P and sphingosylphosphorylcholine but not LPA), mobilizes intracellular Ca2+ via both PTX-sensitive and PTX-insensitive pathways, activates MAPK in a PTX-sensitive Ras-dependent manner, activates stress-activated kinases (JNK and p38) in a PTX-insensitive manner, induces stress-fiber formation via Rho (PTX-insensitive), and increases cellular cAMP.","method":"Radioligand binding, Ca2+ mobilization assay, MAPK/JNK/p38 kinase assays, myosin light chain phosphorylation, cAMP measurement in CHO cells stably expressing AGR16","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro assays (binding, calcium, kinase, cytoskeletal), pertussis toxin dissection of G protein coupling, single lab but comprehensive","pmids":["9854026"],"is_preprint":false},{"year":1999,"finding":"EDG5/S1PR2 expressed in Xenopus oocytes confers S1P-responsive intracellular calcium transients that are potentiated by co-injection of Galphaqi or Galphaq, indicating differential coupling to Gq versus Gi pathways compared to EDG1.","method":"Xenopus oocyte expression system, mRNA microinjection, calcium transient recordings, chimeric G protein co-expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in a defined heterologous system with chimeric G proteins, multiple receptor subtypes compared with rigorous controls","pmids":["10383399"],"is_preprint":false},{"year":1999,"finding":"H218/S1PR2 binds S1P and sphinganine 1-phosphate with high affinity and specificity; overexpression in HEK293 cells induces rounded cell morphology and apoptosis in the presence of serum (which contains high S1P), and overexpression in PC12 cells inhibits NGF-induced neuritogenesis and enhances SPP-induced neurite retraction.","method":"Radioligand competition binding, cell morphology assay, apoptosis measurement, PC12 NGF differentiation assay, neurite retraction assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — binding assays combined with gain-of-function overexpression showing defined cellular phenotypes (rounding, apoptosis, neurite retraction) across multiple cell types","pmids":["9988698"],"is_preprint":false},{"year":2000,"finding":"EDG5/S1PR2 specifically inhibits Rac activity and cell migration/membrane ruffling in CHO cells, in contrast to EDG1 and EDG3 which stimulate these responses. S1P via EDG5 stimulates Rac-GAP activity (rather than inhibiting Rac-GEF), inhibits basal Rac-GTP levels, and abolishes IGF-I-directed chemotaxis. EDG5 still activates PI3-kinase but uncouples it from Rac activation.","method":"Chemotaxis assay, Rac/RhoA pull-down (GTP-bound form), PI3-kinase assay, Rac-GAP/GEF activity assays in CHO cells stably expressing EDG1, EDG3, or EDG5","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple biochemical assays (GEF, GAP, PI3K, pull-downs), isotype-specific comparison across three receptors, rigorous controls including dominant-negative mutants","pmids":["11094076"],"is_preprint":false},{"year":2000,"finding":"EDG3/S1PR3 and EDG5/S1PR2 (but not EDG1) mediate S1P-induced activation of NF-κB in HEK293 cells; this activation requires protein kinase C and Ca2+ downstream of Gq, but not Rho activation alone. Gβγ potentiates NF-κB activation achieved through other G proteins.","method":"NF-κB reporter assay, pharmacological inhibitors of PKC and Ca2+, dominant-negative Rho, Gβγ titration in HEK293 cells overexpressing Edg receptor subtypes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific reporter assay with multiple pharmacological dissections, single lab","pmids":["11673450"],"is_preprint":false},{"year":2001,"finding":"Knockout of H218/S1PR2 in mice does not cause developmental defects but leads to spontaneous seizures at 3-7 weeks of age; whole-cell patch-clamp recordings show a large increase in excitability of neocortical pyramidal neurons in H218-/- mice, establishing S1PR2 as a required modulator of neuronal excitability in vivo.","method":"Gene knockout mice, EEG recordings, whole-cell patch-clamp electrophysiology of neocortical pyramidal neurons","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with electrophysiological phenotype readout, replicated in multiple animals, EEG and patch-clamp orthogonal methods","pmids":["11553273"],"is_preprint":false},{"year":2003,"finding":"EDG5/S1PR2 mediates S1P-induced antiproliferative effects in rat hepatocytes via activation of Rho. The inhibitory effect on HGF/EGF-induced DNA synthesis is blocked by C3 exotoxin (Rho inactivation) and by the S1PR2-specific antagonist JTE-013, but not by pertussis toxin, indicating Gi-independent Rho signaling through S1PR2.","method":"DNA synthesis assay ([3H]thymidine incorporation), C3 exotoxin Rho inactivation, pertussis toxin treatment, JTE-013 antagonist, partial hepatectomy model in rats","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mechanistic interventions (specific antagonist, Rho inhibitor, PTX) in both in vitro and in vivo hepatectomy models","pmids":["12557151"],"is_preprint":false},{"year":2003,"finding":"Down-regulation of EDG5/S1PR2 during C2C12 myoblast-to-myotube differentiation specifically uncouples S1P signaling to phospholipase D (PLD). Overexpression of EDG5/S1PR2 (but not EDG1 or EDG3) potentiates S1P-stimulated PLD activity, and antisense knockdown of EDG5/S1PR2 reduces S1P-induced PLD activity, establishing S1PR2 as the dominant receptor coupling S1P to PLD.","method":"Northern blot, Western blot, PLD activity assay, overexpression of receptor subtypes, antisense ODN knockdown in C2C12 cells","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor-specific gain- and loss-of-function experiments with PLD activity measurements, multiple receptor subtypes compared","pmids":["14499732"],"is_preprint":false},{"year":2013,"finding":"S1PR2 plays a key role in endothelial vascular permeability and inflammatory responses during endotoxemia. Downstream signaling includes activation of the stress-activated protein kinase pathway together with Rho-kinase/NF-κB pathway, both required for S1PR2-mediated endothelial inflammatory responses. Bone marrow chimera experiments localize the critical function to the stromal compartment.","method":"S1pr2 knockout mice, bone marrow chimeras, JTE013 pharmacological antagonist, in vitro TNFα endothelial inflammation assays, permeability assays, NF-κB pathway analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacological antagonist plus bone marrow chimeras plus in vitro mechanistic dissection, multiple orthogonal approaches","pmids":["23723450"],"is_preprint":false},{"year":2013,"finding":"S1PR2 is a receptor for the Nogo-A-Δ20 domain of Nogo-A, distinct from the S1P binding pocket. Nogo-A-Δ20 binding to S1PR2 signals via G13, the Rho GEF LARG, and RhoA. S1PR2 deletion or blockade counteracts Nogo-A-Δ20-mediated and myelin-mediated inhibition of neurite outgrowth and cell spreading. S1PR2 blockade strongly enhances LTP in wild-type but not Nogo-A-/- hippocampus, establishing the Nogo-A/S1PR2 axis as a repressor of synaptic plasticity.","method":"Binding assays, siRNA knockdown, S1PR2 knockout, LTP recording in hippocampal slices, neurite outgrowth assays, cell spreading assays, pharmacological blockade with S1PR2 antagonist","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding, genetic KO, siRNA, LTP electrophysiology, cell assays), replicated across wild-type and Nogo-A KO mice","pmids":["24453941"],"is_preprint":false},{"year":2013,"finding":"In zebrafish, S1pr2/Mil signals through Gα13 and a RhoGEF-dependent pathway to regulate convergent movement of the anterior endoderm, which is required for coordinating myocardial migration to the midline. Cardiac-specific expression of Gα13 fails to rescue cardia bifida caused by global Gα13 inhibition, confirming S1pr2/Gα13 acts in the endoderm, not the myocardium.","method":"Zebrafish genetic epistasis (morpholino knockdown, dominant-negative constructs), endoderm transplantation rescue experiments, cardiac-specific Gα13 expression","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple components, transplantation rescue experiments establishing tissue-autonomous function, cardiac-specific negative control","pmids":["23318642"],"is_preprint":false},{"year":2013,"finding":"S1P via S1PR2 induces filopodia formation through phosphorylation of ERM (ezrin/radixin/moesin) proteins. Phosphomimetic ezrin mutants reproduce the filopodia phenotype, while non-phosphorylatable mutants block it. siRNA and genetic knockout approaches identify S1PR2 as the specific and necessary receptor for ERM phosphorylation and filopodia formation.","method":"Pharmacological S1PR agonists/antagonists, siRNA knockdown, genetic knockout, phosphomimetic/non-phosphorylatable ezrin mutants, immunofluorescence for filopodia","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple receptor-specific pharmacological and genetic approaches combined with dominant mutant validation","pmids":["23106337"],"is_preprint":false},{"year":2012,"finding":"S1PR2 promotes germinal center B-cell confinement and dampens Akt activation; S1PR2 deficiency or deficiency of components of its signaling pathway results in loss of growth control in chronically stimulated mucosal germinal centers.","method":"S1PR2 knockout mice, germinal center analysis, Akt activation assays","journal":"Immunological reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype (GC confinement, Akt activation), single lab review summarizing primary findings","pmids":["22500830"],"is_preprint":false},{"year":2012,"finding":"S1PR2 mediates satellite cell activation in dystrophic muscle via STAT3 signaling. S1P via S1PR2 inhibits Rac1, which activates STAT3, leading to downregulation of p21 and p27 in myoblasts, thereby promoting cell cycle progression.","method":"S1PR2 pharmacological inhibition, siRNA knockdown, Rac1/STAT3 activity assays, p21/p27 expression in mdx mouse model and myoblast cultures","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection in disease model with pharmacological and genetic tools, single lab","pmids":["22606352"],"is_preprint":false},{"year":2016,"finding":"S1PR2 acts as a tumor suppressor in DLBCL; ectopic expression of wild-type S1PR2 (but not a signaling-deficient point mutant) induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models. The proapoptotic effects are phenocopied by Gα13 overexpression and are independent of AKT signaling.","method":"Ectopic expression of wild-type vs. signaling-deficient S1PR2 mutant, Gα13 overexpression, subcutaneous and orthotopic xenograft mouse models, apoptosis assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — wild-type vs. mutant comparison, Gα13 phenocopy, multiple in vivo models, AKT independence established","pmids":["26729899"],"is_preprint":false},{"year":2018,"finding":"The TGF-β/TGF-βR2/SMAD1 axis directly activates S1PR2 transcription; phosphorylated SMAD1 binds regulatory elements in the S1PR2 locus (by ChIP). CRISPR-mediated editing of S1PR2, SMAD1, or TGFBR2 renders DLBCL cells unresponsive to TGF-β-induced apoptosis. Loss of S1pr2 or Tgfbr2 in GC B cells induces hyperproliferation and accelerates MYC-driven lymphomagenesis.","method":"ChIP of phospho-SMAD1 at S1PR2 locus, CRISPR editing of S1PR2/SMAD1/TGFBR2, xenotransplantation models, GC B cell-specific Tgfbr2 knockout mice","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP demonstrates direct SMAD1 binding, CRISPR epistasis establishes pathway order, multiple in vivo models, orthogonal methods","pmids":["29615404"],"is_preprint":false},{"year":2016,"finding":"S1P/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation via a Gi-independent RhoA/ROCK pathway in osteoblasts, leading to nuclear translocation of Smad4 and upregulation of Runx2 expression, promoting osteoblast differentiation.","method":"Pharmacological inhibitors (JTE-013, ROCK inhibitors), RhoA activity assay, Smad1/5/8 phosphorylation by Western blot, nuclear translocation imaging, in vivo bone formation assay in MC3T3-E1 cells and primary osteoblasts","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors and readouts in two cell systems plus in vivo, single lab","pmids":["27612439"],"is_preprint":false},{"year":2018,"finding":"S1PR2 mediates S1P-induced YAP activation in hepatocellular carcinoma cells (both human and mouse) in an MST1/2-independent manner, leading to YAP-mediated CTGF upregulation and cell proliferation. siRNA knockdown shows only CTGF (not CYR61) is required for S1P-stimulated proliferation.","method":"siRNA knockdown of S1PR2 and pathway components, YAP reporter assays, CTGF/CYR61 expression, proliferation assays, ChIP-seq for HNF4α, YAP transgenic mouse hepatocytes","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNA targets with defined proliferation readout and in vivo transgenic validation, single lab","pmids":["29903770"],"is_preprint":false},{"year":2020,"finding":"Endothelial-derived S1P acts via S1PR2 on alveolar type II (AT2) cells to induce nuclear translocation of YAP, promoting AT2-to-AT1 differentiation required for alveolar repair after lung injury. This was established using endothelial-specific Sphk1 knockout mice.","method":"Endothelial-specific Sphk1 knockout mice, immunofluorescence for YAP nuclear translocation, AT1/AT2 cell quantification after Pseudomonas lung injury","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific genetic model with defined cellular differentiation phenotype and signaling readout, single lab","pmids":["32610129"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of S1P-bound S1PR2 coupled to heterotrimeric G13 reveals that ICL2 of S1PR2 interacts with the α5 helix of Gα13, with ICL2 conformation constrained by TM4. FTY720-P (an agonist of S1PR1/3/4/5) can also trigger G13 activation via S1PR2. The S1PR2-F274I variant increases G13 activity with both FTY720-P and S1P, explaining drug selectivity differences.","method":"Cryo-electron microscopy structure determination, TGFα shedding assay for G13 activation, cell migration assays, mutagenesis of interface residues","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with functional assays (TGFα shedding, migration) and mutagenesis validating structural contacts","pmids":["35353559"],"is_preprint":false},{"year":2016,"finding":"Missense variants p.Arg108Pro and p.Tyr140Cys in S1PR2 cause autosomal-recessive profound hearing loss (DFNB68). Molecular modeling predicts p.Arg108Pro disrupts S1P binding and p.Tyr140Cys disrupts G protein docking. S1pr2-/- mice show stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss.","method":"Exome sequencing, Sanger segregation analysis, S1pr2 knockout mouse phenotyping (auditory physiology, histology), molecular modeling","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics with two independent families, knockout mouse phenotyping, and structural modeling converging on same gene/residues","pmids":["26805784"],"is_preprint":false},{"year":2016,"finding":"A spontaneous Thr289Arg S1pr2 mutation (stonedeaf mouse) causes progressive hearing loss with normal hearing at 2 weeks but severe/profound loss by 14 weeks, associated with a reduced endocochlear potential and stria vascularis degeneration—the first demonstration that S1PR2 loss reduces EP.","method":"Mouse ENU mutagenesis screen, exome sequencing, auditory brainstem responses, endocochlear potential measurement, stria vascularis histology","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent S1pr2 alleles examined, direct EP measurement providing new mechanism, histological correlation","pmids":["27383011"],"is_preprint":false},{"year":2018,"finding":"S1P-S1PR2 axis mediates homing of MUSE stem cells to infarcted myocardium; this was confirmed pharmacologically (S1PR2-specific antagonist JTE-013 co-injection) and genetically (S1PR2-siRNA introduction into Muse cells) blocking migration/homing to the heart.","method":"In vivo cell tracking with Nano-lantern labeling, pharmacological antagonism with JTE-013, S1PR2-siRNA knockdown in Muse cells, rabbit acute MI model","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent approaches (pharmacological and genetic) confirming same homing mechanism in vivo, single lab","pmids":["29475983"],"is_preprint":false},{"year":2019,"finding":"Endothelial S1PR2 regulates lymphatic endothelial cell layer structure and permeability through the ERK pathway, modulating expression of junction molecules VE-cadherin, occludin, and zonulin-1, and facilitates T cell transcellular migration through VCAM-1 expression.","method":"S1PR2-knockout LEC studies, ERK pathway inhibitors, junction molecule expression by Western blot/imaging, T cell transmigration assays across LEC monolayers","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological approaches with defined junction molecule and migration readouts, single lab","pmids":["30877143"],"is_preprint":false},{"year":2020,"finding":"S1PR2 internalization from plasma membrane to endoplasmic reticulum upon S1P stimulation activates PERK-eIF2α-ATF4 signaling via elevated [Ca2+]ER, leading to RNASET2-mediated intracellular uracil generation that blunts 5-FU efficacy in colorectal cancer cells.","method":"Subcellular fractionation/imaging of S1PR2, [Ca2+]ER measurement with Mag-Fluo-AM, LC-ESI-MS/MS for uracil measurement, JTE-013 pharmacological inhibition, S1PR2-/- villin-S1PR2 knockout mice","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — intracellular localization linked to functional consequence via multiple biochemical methods, genetic KO mouse validation, single lab","pmids":["32647340"],"is_preprint":false},{"year":2022,"finding":"S1PR2/RhoA/ROCK1 signaling pathway damages intestinal vascular endothelial barrier and promotes M1 macrophage polarization in IBD; inhibition of S1PR2 reduces RhoA/ROCK1 expression, reverses impaired barrier function and M1 polarization, and reduces ER stress in endothelial cells and glycolysis in macrophages.","method":"S1PR2 knockdown and pharmacological inhibition (JTE-013), RhoA/ROCK1 expression analysis, barrier permeability assays, macrophage polarization assays, DSS colitis mouse model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological approaches in both in vitro and in vivo IBD models with pathway readouts, single lab","pmids":["35537530"],"is_preprint":false},{"year":2024,"finding":"Endothelial S1PR2 promotes mitochondrial fission and ROS production via RhoA/ROCK1/DRP1 signaling, leading to NLRP3 inflammasome activation and pyroptosis, thereby worsening cardiac ischemia-reperfusion injury. EC-specific S1pr2 loss-of-function reduces injury while gain-of-function aggravates it.","method":"EC-specific S1pr2 KO and gain-of-function mice, RhoA/ROCK1/DRP1 protein expression, mitochondrial morphology analysis, NLRP3/pyroptosis markers, cardiac I/R mouse model","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific bidirectional genetic model (both KO and overexpression) with mechanistic pathway dissection, in vivo validation","pmids":["38909407"],"is_preprint":false},{"year":2022,"finding":"Endothelial S1pr2 inhibits post-ischemic angiogenesis by suppressing the AKT/eNOS signaling pathway, thereby inhibiting EC proliferation, migration, and angiogenic activity. EC-specific S1pr2 loss-of-function enhances angiogenesis and blood flow recovery, while gain-of-function impairs it.","method":"EC-specific S1pr2 loss-of-function and gain-of-function mice, hindlimb ischemia model, AKT/eNOS phosphorylation by Western blot, EC proliferation/migration assays, JTE013 pharmacological inhibition","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional EC-specific genetic models with pharmacological confirmation and pathway mechanism identified, in vivo phenotype","pmids":["35836816"],"is_preprint":false},{"year":2023,"finding":"Taurocholic acid activates S1PR2 in hepatic stellate cells, triggering p38 MAPK/YAP signaling to promote HSC proliferation, migration, contraction, and ECM secretion (fibrosis). Pharmacological or genetic S1PR2 inhibition reverses TCA-induced HSC activation and attenuates cholestatic liver fibrosis in DDC diet mice.","method":"JTE-013 pharmacological inhibition, S1PR2 shRNA, LX-2 and JS-1 HSC cell lines, DDC-diet mouse model, p38 MAPK and YAP phosphorylation/activity assays","journal":"Clinical and molecular hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic approaches in vitro and in vivo, pathway readouts, single lab","pmids":["36800698"],"is_preprint":false},{"year":2022,"finding":"GDCA/taurine-conjugated bile acid activates S1PR2 in macrophages to upregulate ZBP1 expression, which is required for ZBP1/p-MLKL-mediated necroptosis in macrophages; selective macrophage S1pr2 knockdown in vivo decreases necroptosis and attenuates collagen deposition in BDL cholestatic liver injury.","method":"Macrophage-specific S1pr2 knockdown in vivo, GDCA treatment of BMDMs, ZBP1/p-MLKL Western blot, BDL mouse model, siRNA rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific in vivo knockdown combined with mechanistic in vitro studies, single lab","pmids":["36859525"],"is_preprint":false},{"year":2016,"finding":"EBV oncoprotein LMP1 transcriptionally downregulates S1PR2 in GC B cells, and this downregulation drives constitutive activation of the PI3-kinase pathway in ABC-DLBCL cells.","method":"LMP1 expression in GC B cells, transcriptional profiling, PI3K pathway activation assays, IHC for S1PR2 in primary LMP1-positive vs. negative DLBCLs","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional mechanism with functional PI3K pathway readout, clinical tissue validation, single lab","pmids":["30666658"],"is_preprint":false},{"year":2023,"finding":"MYDGF directly binds S1PR2 (confirmed by SPR assay and Co-IP), and signals via S1PR2/RhoA/G-actin/F-actin/MRTF-A to suppress VSMC dedifferentiation and neointimal formation in response to balloon injury.","method":"Molecular docking, SPR assay, Co-immunoprecipitation, JTE-013 antagonist, CCG-1423 and Ripasudil inhibitors, carotid balloon injury rat model, RhoA activity and actin cytoskeleton assays","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by SPR and Co-IP, downstream pathway dissected with multiple inhibitors, in vivo model, single lab","pmids":["37726422"],"is_preprint":false},{"year":2011,"finding":"Mast cells react to vaccinia virus and degranulate via a membrane-activated pathway triggered by S1PR2; neutralizing antibody to the VV L1 fusion entry protein inhibits degranulation by preventing S1PR2 activation by viral membrane lipids. Antimicrobial peptide release from MC granules is necessary to inactivate VV infectivity.","method":"MC-deficient mouse model, MC reconstitution experiments, cathelicidin-KO MC studies, S1PR2 pathway analysis, neutralizing antibody experiments, skin infection model","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic MC-deficient and cathelicidin-KO models with S1PR2 pathway identification and antibody blocking, multiple in vivo readouts","pmids":["22140255"],"is_preprint":false},{"year":2022,"finding":"Liver sinusoidal endothelial cell S1pr2 activates the YAP signaling pathway to potentiate TGF-β transactivation in a paracrine manner acting on hepatic stellate cells, thereby aggravating liver fibrosis. LSEC-specific S1pr2 loss-of-function dampens HSC activation while overexpression enhances it.","method":"LSEC-specific S1pr2 KO and overexpression, CCl4 liver fibrosis model, YAP activity assays, TGF-β expression/secretion, HSC activation markers, paracrine co-culture experiments","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific bidirectional genetic model with defined paracrine mechanism, in vivo validation, single lab","pmids":["37039817"],"is_preprint":false},{"year":2021,"finding":"Preeclampsia is associated with reduced S1P and SPHK1. S1P increases trophoblast cell invasion via S1PR2-activated RhoA/ROCK-induced actin polymerization that promotes YAP nuclear translocation; in vivo inhibition of sphingosine kinase 1 during placentation causes a preeclampsia phenotype.","method":"SPHK1 inhibitor mouse model, HTR8/SVneo cell invasion assays, actin polymerization measurement, YAP nuclear translocation imaging, YAP-5SA mutant, S1PR2 pharmacological inhibition","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model plus in vitro mechanism dissection with dominant mutants, single lab","pmids":["34865521"],"is_preprint":false},{"year":2022,"finding":"Overexpression of endothelial S1pr2 after traumatic brain injury promotes BBB disruption by activating JNK/c-Jun signaling, which transactivates MMP-9; ChIP-qPCR confirmed AP-1a and AP-1b binding sites in the MMP-9 promoter as phospho-c-Jun binding sites.","method":"TBI mouse model, JTE-013 pharmacological inhibition, SP600125 JNK inhibitor, Western blot for JNK/c-Jun/MMP-9, tight junction protein analysis, ChIP-qPCR for c-Jun binding to MMP-9 promoter, cellular models","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with mechanistic dissection and ChIP-qPCR for transcription factor binding, in vivo model, single lab","pmids":["39679379"],"is_preprint":false},{"year":2022,"finding":"Enhanced S1PR2 membrane expression in the cerebellum of hyperammonaemic rats increases CCL2 (especially in Purkinje neurons), activating CCR2 in microglia and increasing P2X4 and BDNF in microglia. BDNF then enhances TrkB activation in neurons, increasing KCC2 membrane expression and GABAergic neurotransmission, leading to motor incoordination. Blocking S1PR2 with JTE-013 normalizes this entire pathway and restores motor coordination.","method":"Intracerebral JTE-013 administration via osmotic mini-pumps in hyperammonaemic rats, immunochemistry, immunofluorescence, Western blot for pathway components, beam walking behavioral test","journal":"Neuropathology and applied neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological S1PR2 blockade in disease model with complete pathway dissection and behavioral readout, single lab","pmids":["35152448"],"is_preprint":false},{"year":2016,"finding":"FXR transcriptionally represses S1PR2 expression in hepatic stellate cells; DHA induces FXR expression and reduces S1PR2, thereby inhibiting HSC contraction through modulation of both Ca2+-dependent and Ca2+-sensitization signaling. Gain- and loss-of-function analyses confirm an FXR-S1PR2-dependent mechanism.","method":"Gel contraction assays, actin cytoskeleton fluorescence staining, myosin light chain phosphorylation, FXR gain/loss-of-function in LX-2 cells, S1PR2 mRNA/protein expression","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional gain/loss-of-function with multiple contractility readouts, single lab","pmids":["27027402"],"is_preprint":false},{"year":2016,"finding":"S1PR2 knockdown in DLBCL cells promotes migration and invasion via NF-κB pathway activation; S1PR2 downregulation reduces MMP-9 expression in U266 MM cells.","method":"S1PR2-selective antagonist JTE-013, S1PR2 shRNA knockdown in U266 cells, migration/invasion assays, NF-κB pathway analysis, MMP-9 expression by Western blot","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pharmacological and knockdown approach, single lab, pathway placement indirect","pmids":["32922084"],"is_preprint":false},{"year":2019,"finding":"S1P induces IL-8 gene expression through S1PR1 in trophoblast cells, while IL-8 protein secretion is primarily regulated through S1PR2; both Rho-kinase and Rac1 signaling are essential for S1P-induced IL-8 secretion.","method":"Selective S1PR antagonists/agonists (JTE-013 for S1PR2, VPC23019 for S1PR1/3, SEW2781 for S1PR1), Rho-kinase inhibitor Y27632, Rac1 inhibitor NSC23766, IL-8 ELISA and real-time PCR in HTR-8/SVneo cells","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple selective pharmacological tools dissecting receptor subtype contributions to gene expression vs. secretion, single lab","pmids":["26321412"],"is_preprint":false},{"year":2016,"finding":"FTY720P inhibits Na+/K+ ATPase in HepG2 cells via S1PR2 through a signaling cascade involving PKC, NF-κB, and PGE2 generation; this effect is blocked by the specific S1PR2 antagonist JTE-013 and mimicked by the S1PR2 agonist CYM5520.","method":"Na+/K+ ATPase activity assay, JTE-013, CYM5520 (S1PR2 agonist), PKC inhibitor calphostin, COX-2 inhibitor indomethacin, NF-κB inhibitor in HepG2 cells","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-specific agonist and antagonist with pathway dissection, enzyme activity as direct readout, single lab","pmids":["27501354"],"is_preprint":false},{"year":2019,"finding":"Taurine-conjugated bile acid (TCDCA) stimulates cortisol secretion and steroidogenesis-related gene expression in adrenocortical H295R cells via S1PR2 and ERK phosphorylation; siRNA knockdown of S1PR2 reduces ERK phosphorylation and cortisol secretion, while SF-1 transactivation is increased downstream of this pathway.","method":"S1PR2 pharmacological inhibition (JTE-013), S1PR2 siRNA knockdown, ERK phosphorylation by Western blot, cortisol ELISA, SF-1 transactivation assay in H295R cells","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic S1PR2 inhibition with enzyme activity readout, SF-1 functional assay, single lab","pmids":["30664326"],"is_preprint":false}],"current_model":"S1PR2 is a Gs/Gi/Gq/G12/13-coupled GPCR that, upon binding S1P (or Nogo-A-Δ20 at a distinct site), predominantly signals through Gα13→Rho GEF/LARG→RhoA→ROCK to inhibit Rac activity and cell migration, restrict germinal-center B-cell confinement, suppress neuronal excitability, regulate endothelial barrier integrity (via ROCK1/DRP1/NF-κB/p38-ERK), activate YAP (independently of MST1/2) to drive epithelial repair and stellate-cell activation, phosphorylate Smad1/5/8 to induce Runx2-dependent osteoblast differentiation, and couple S1P to phospholipase D; cryo-EM has resolved the S1PR2–G13 complex showing that ICL2 engages the Gα13 α5 helix, and loss-of-function mutations in S1PR2 cause autosomal-recessive hearing loss by disrupting endocochlear potential maintenance through strial degeneration."},"narrative":{"mechanistic_narrative":"S1PR2 is a sphingosine-1-phosphate (S1P) receptor of the G protein-coupled family that couples S1P sensing to cytoskeletal, growth-control, and barrier-regulatory outputs across diverse tissues [PMID:9854026, PMID:11094076]. It binds S1P and sphinganine-1-phosphate with high affinity and engages Gi, Gq, and G13 heterotrimeric G proteins, mobilizing Ca2+, activating MAPK/JNK/p38 cascades, and driving Rho-dependent stress-fiber formation [PMID:10488065, PMID:9854026, PMID:9988698]. A defining feature distinguishing S1PR2 from related receptors is its predominant signaling through Gα13 to RhoA, where it stimulates Rac-GAP activity to inhibit Rac and suppress cell migration and chemotaxis [PMID:11094076]; cryo-EM of the S1P-bound S1PR2–G13 complex shows that ICL2 engages the Gα13 α5 helix with ICL2 conformation constrained by TM4 [PMID:35353559]. Through this Gα13/RhoA/ROCK axis S1PR2 phosphorylates ERM proteins to form filopodia, activates NF-κB via PKC and Ca2+, and couples S1P to phospholipase D [PMID:11673450, PMID:14499732, PMID:23106337]. S1PR2 also serves as a receptor for the Nogo-A-Δ20 domain at a site distinct from the S1P pocket, signaling via G13/LARG/RhoA to repress neurite outgrowth and synaptic plasticity, consistent with its requirement for restraining neuronal excitability in vivo [PMID:11553273, PMID:24453941]. In immunity and cancer it acts as a tumor suppressor in germinal-center B cells, confining cells and dampening Akt; it is a direct transcriptional target of the TGF-β/TGFBR2/SMAD1 axis, and its loss accelerates MYC-driven lymphomagenesis, with G13 overexpression phenocopying its proapoptotic effect [PMID:22500830, PMID:26729899, PMID:29615404]. Across epithelial and stellate-cell contexts S1PR2 activates YAP, including MST1/2-independent YAP activation driving hepatocellular proliferation and AT2-to-AT1 differentiation in alveolar repair [PMID:29903770, PMID:32610129], and in osteoblasts it triggers RhoA/ROCK-dependent Smad1/5/8 phosphorylation and Runx2 induction [PMID:27612439]. In endothelium it controls vascular permeability and inflammation through Rho-kinase/NF-κB, p38, and RhoA/ROCK1/DRP1-driven mitochondrial fission and NLRP3-dependent pyroptosis [PMID:23723450, PMID:38909407]. Loss-of-function mutations in S1PR2 cause autosomal-recessive profound hearing loss (DFNB68) through stria vascularis degeneration and reduced endocochlear potential [PMID:26805784, PMID:27383011].","teleology":[{"year":1999,"claim":"Establishing which ligand S1PR2 senses and which G proteins it engages was the foundational step defining it as an S1P receptor with broader G protein coupling than EDG1.","evidence":"Radioligand binding, subunit-selective [35S]GTPgammaS assays, and Ca2+/kinase/cytoskeletal readouts in Sf9, HEK293, CHO, and Xenopus systems","pmids":["10488065","9854026","10383399","9988698"],"confidence":"High","gaps":["Endogenous physiological context of multi-G-protein coupling not addressed in heterologous systems","Quantitative bias among Gi/Gq/G13 not resolved"]},{"year":2000,"claim":"Identifying that S1PR2 uniquely inhibits Rac and migration distinguished its signaling logic from migration-promoting S1P receptors and defined its anti-migratory function.","evidence":"Rac/RhoA pull-downs, Rac-GAP/GEF and PI3K assays, and chemotaxis in CHO cells expressing distinct EDG receptors; NF-κB reporter dissection","pmids":["11094076","11673450"],"confidence":"High","gaps":["Identity of the Rac-GAP activated by S1PR2 not defined","Direct link between G protein subtype and Rac-GAP not established"]},{"year":2001,"claim":"Knockout confirmed an in vivo role: S1PR2 is required to restrain neuronal excitability, moving its function from cell-culture phenotypes to organismal physiology.","evidence":"S1pr2-/- mice with EEG and whole-cell patch-clamp of neocortical pyramidal neurons","pmids":["11553273"],"confidence":"High","gaps":["Molecular mechanism linking S1PR2 to excitability not resolved","Cell type mediating the seizure phenotype not pinpointed"]},{"year":2003,"claim":"Linking S1PR2 to Rho-dependent growth inhibition and PLD coupling defined effector pathways downstream of the receptor in hepatocytes and myoblasts.","evidence":"C3 exotoxin, JTE-013 antagonist, and pertussis toxin in hepatocyte DNA-synthesis assays; receptor-subtype gain/loss-of-function PLD assays in C2C12 cells","pmids":["12557151","14499732"],"confidence":"High","gaps":["Mechanism coupling S1PR2 to PLD not molecularly defined","Gi-independence of Rho activation not structurally explained"]},{"year":2013,"claim":"Discovery that S1PR2 binds Nogo-A-Δ20 at a non-S1P site established it as a dual-ligand receptor mediating myelin-associated inhibition of neurite outgrowth and synaptic plasticity.","evidence":"Binding assays, siRNA, knockout, and hippocampal LTP recordings across wild-type and Nogo-A-/- mice","pmids":["24453941"],"confidence":"High","gaps":["Structural basis of the distinct Nogo-A binding site not resolved","Relative physiological weight of S1P vs Nogo-A ligand inputs unclear"]},{"year":2013,"claim":"Defining the G13/RhoGEF/RhoA effector module and its cytoskeletal outputs unified S1PR2 signaling across endothelial barrier, developmental migration, and filopodia formation.","evidence":"S1pr2 KO mice, bone marrow chimeras, zebrafish genetic epistasis with endoderm transplantation, and ERM phosphomimetic mutants","pmids":["23723450","23318642","23106337"],"confidence":"High","gaps":["Tissue-specific RhoGEF identities not all defined","How a single Rho axis produces opposing barrier-protective vs barrier-damaging outcomes not reconciled"]},{"year":2016,"claim":"Demonstrating S1PR2 as a germinal-center tumor suppressor and as a cause of recessive hearing loss linked the receptor to both lymphomagenesis control and cochlear homeostasis.","evidence":"Wild-type vs signaling-deficient S1PR2 expression with G13 phenocopy in DLBCL xenografts; exome sequencing of DFNB68 families plus S1pr2-/- and stonedeaf mouse phenotyping with endocochlear potential measurement","pmids":["26729899","26805784","27383011"],"confidence":"High","gaps":["Mechanism by which S1PR2 maintains stria vascularis and endocochlear potential not molecularly defined","Effector linking S1PR2/G13 to B-cell apoptosis not fully identified"]},{"year":2018,"claim":"Identifying TGF-β/SMAD1 as a direct transcriptional activator of S1PR2 placed the receptor within an upstream regulatory circuit that, when lost, accelerates MYC-driven lymphoma.","evidence":"ChIP of phospho-SMAD1 at the S1PR2 locus, CRISPR epistasis of S1PR2/SMAD1/TGFBR2, and GC B-cell-specific Tgfbr2 knockout mice","pmids":["29615404"],"confidence":"High","gaps":["Downstream apoptotic effectors of the TGF-β–S1PR2 axis incompletely mapped","Cross-talk with EBV LMP1-mediated repression of S1PR2 not integrated"]},{"year":2018,"claim":"Connecting S1PR2 to MST1/2-independent YAP activation defined a growth- and repair-driving branch operating in liver and lung epithelium.","evidence":"siRNA, YAP reporter and CTGF/CYR61 analyses in HCC cells; endothelial-specific Sphk1 knockout linking endothelial S1P to AT2 YAP activation","pmids":["29903770","32610129"],"confidence":"Medium","gaps":["Mechanism of MST-independent YAP activation by S1PR2 not defined","How the Rho axis feeds into YAP in these contexts not resolved"]},{"year":2022,"claim":"The cryo-EM S1PR2–G13 structure provided the physical basis for selective G13 coupling and explained agonist and variant selectivity differences.","evidence":"Cryo-EM structure determination with TGFα-shedding G13 activation, migration assays, and interface mutagenesis including the F274I variant","pmids":["35353559"],"confidence":"High","gaps":["Structures with Gi/Gq or with the Nogo-A ligand not determined","Conformational basis for biased signaling not addressed"]},{"year":2024,"claim":"Bidirectional endothelial genetic models established S1PR2 as a context-dependent driver of vascular pathology through RhoA/ROCK1-coupled mitochondrial and AKT/eNOS branches.","evidence":"EC-specific S1pr2 loss- and gain-of-function mice in cardiac I/R and hindlimb ischemia models with RhoA/ROCK1/DRP1, NLRP3/pyroptosis, and AKT/eNOS readouts","pmids":["38909407","35836816","35537530"],"confidence":"High","gaps":["Determinants selecting protective vs damaging endothelial outputs unknown","Relationship between mitochondrial fission and barrier disruption branches not unified"]},{"year":null,"claim":"How S1PR2 coordinates its multiple, sometimes opposing outputs (Rac inhibition, YAP activation, NF-κB, Smad phosphorylation) in a cell-type-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for context-dependent effector selection","Determinants of ligand choice (S1P vs Nogo-A vs bile acids) in vivo unclear","Structural basis of non-G13 coupling not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,4,20]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[25,37]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,13,16,33]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,15,27,30]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,17,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,22,16]}],"complexes":[],"partners":["GNA13","RHOA","LARG","NOGO-A","MYDGF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95136","full_name":"Sphingosine 1-phosphate receptor 2","aliases":["Endothelial differentiation G-protein coupled receptor 5","Sphingosine 1-phosphate receptor Edg-5","S1P receptor Edg-5"],"length_aa":353,"mass_kda":38.9,"function":"Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P) (PubMed:10617617, PubMed:25274307). S1P is a bioactive lysophospholipid that elicits diverse physiological effects on most types of cells and tissues (PubMed:10617617). When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis (PubMed:10617617). Receptor for the chemokine-like protein FAM19A5 (PubMed:29453251). Mediates the inhibitory effect of FAM19A5 on vascular smooth muscle cell proliferation and migration (By similarity). In lymphoid follicles, couples the binding of S1P to the activation of GNA13 and downstream inhibition of AKT activation leading to suppression of germinal center (GC) B cell growth and migration outside the GC niche","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O95136/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/S1PR2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/S1PR2","total_profiled":1310},"omim":[{"mim_id":"610419","title":"DEAFNESS, AUTOSOMAL RECESSIVE 68; DFNB68","url":"https://www.omim.org/entry/610419"},{"mim_id":"608565","title":"DEAFNESS, AUTOSOMAL RECESSIVE 35; DFNB35","url":"https://www.omim.org/entry/608565"},{"mim_id":"605111","title":"SPHINGOSINE-1-PHOSPHATE RECEPTOR 2; S1PR2","url":"https://www.omim.org/entry/605111"},{"mim_id":"602737","title":"CHEMOKINE, CC MOTIF, LIGAND 21; CCL21","url":"https://www.omim.org/entry/602737"},{"mim_id":"601974","title":"SPHINGOSINE-1-PHOSPHATE RECEPTOR 1; S1PR1","url":"https://www.omim.org/entry/601974"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Golgi apparatus","reliability":"Uncertain"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/S1PR2"},"hgnc":{"alias_symbol":["Gpcr13","H218","AGR16"],"prev_symbol":["EDG5","DFNB68"]},"alphafold":{"accession":"O95136","domains":[{"cath_id":"1.20.1070.10","chopping":"9-304","consensus_level":"high","plddt":89.6444,"start":9,"end":304}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95136","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95136-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95136-F1-predicted_aligned_error_v6.png","plddt_mean":82.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=S1PR2","jax_strain_url":"https://www.jax.org/strain/search?query=S1PR2"},"sequence":{"accession":"O95136","fasta_url":"https://rest.uniprot.org/uniprotkb/O95136.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95136/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95136"}},"corpus_meta":[{"pmid":"10488065","id":"PMC_10488065","title":"Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H218/Edg-5 to the G(i), G(q), and G(12) families of heterotrimeric G proteins.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10488065","citation_count":289,"is_preprint":false},{"pmid":"11094076","id":"PMC_11094076","title":"Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11094076","citation_count":275,"is_preprint":false},{"pmid":"10383399","id":"PMC_10383399","title":"Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5.","date":"1999","source":"The Journal of biological 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29776397","citation_count":7,"is_preprint":false},{"pmid":"30666658","id":"PMC_30666658","title":"Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC-subtype diffuse large B-cell lymphoma.","date":"2019","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30666658","citation_count":7,"is_preprint":false},{"pmid":"33880585","id":"PMC_33880585","title":"Effects of S1PR2 antagonist on blood pressure and angiogenesis imbalance in preeclampsia rats.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/33880585","citation_count":7,"is_preprint":false},{"pmid":"36527992","id":"PMC_36527992","title":"Design, synthesis, and evaluation of JTE-013 derivatives as novel potent S1PR2 antagonists for recovering the sensitivity of colorectal cancer to 5-fluorouracil.","date":"2022","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36527992","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":58450,"output_tokens":11305,"usd":0.172462,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22215,"output_tokens":4521,"usd":0.11205,"stage2_stop_reason":"end_turn"},"total_usd":0.284512,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"H218/EDG5/S1PR2 couples to Gi, Gq, and G13 families of heterotrimeric G proteins, in contrast to EDG1 which couples only to Gi. This was demonstrated using a subunit-selective [35S]GTPgammaS binding assay in Sf9 and HEK293 cells.\",\n      \"method\": \"Subunit-selective [35S]GTPgammaS binding assay in Sf9 and HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct G protein activation assay with reconstitution, replicated across two cell systems, multiple G protein subtypes tested with rigorous controls\",\n      \"pmids\": [\"10488065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"AGR16/S1PR2 expressed in CHO cells binds [32P]S1P specifically (displaced by S1P and sphingosylphosphorylcholine but not LPA), mobilizes intracellular Ca2+ via both PTX-sensitive and PTX-insensitive pathways, activates MAPK in a PTX-sensitive Ras-dependent manner, activates stress-activated kinases (JNK and p38) in a PTX-insensitive manner, induces stress-fiber formation via Rho (PTX-insensitive), and increases cellular cAMP.\",\n      \"method\": \"Radioligand binding, Ca2+ mobilization assay, MAPK/JNK/p38 kinase assays, myosin light chain phosphorylation, cAMP measurement in CHO cells stably expressing AGR16\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro assays (binding, calcium, kinase, cytoskeletal), pertussis toxin dissection of G protein coupling, single lab but comprehensive\",\n      \"pmids\": [\"9854026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EDG5/S1PR2 expressed in Xenopus oocytes confers S1P-responsive intracellular calcium transients that are potentiated by co-injection of Galphaqi or Galphaq, indicating differential coupling to Gq versus Gi pathways compared to EDG1.\",\n      \"method\": \"Xenopus oocyte expression system, mRNA microinjection, calcium transient recordings, chimeric G protein co-expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in a defined heterologous system with chimeric G proteins, multiple receptor subtypes compared with rigorous controls\",\n      \"pmids\": [\"10383399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"H218/S1PR2 binds S1P and sphinganine 1-phosphate with high affinity and specificity; overexpression in HEK293 cells induces rounded cell morphology and apoptosis in the presence of serum (which contains high S1P), and overexpression in PC12 cells inhibits NGF-induced neuritogenesis and enhances SPP-induced neurite retraction.\",\n      \"method\": \"Radioligand competition binding, cell morphology assay, apoptosis measurement, PC12 NGF differentiation assay, neurite retraction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — binding assays combined with gain-of-function overexpression showing defined cellular phenotypes (rounding, apoptosis, neurite retraction) across multiple cell types\",\n      \"pmids\": [\"9988698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EDG5/S1PR2 specifically inhibits Rac activity and cell migration/membrane ruffling in CHO cells, in contrast to EDG1 and EDG3 which stimulate these responses. S1P via EDG5 stimulates Rac-GAP activity (rather than inhibiting Rac-GEF), inhibits basal Rac-GTP levels, and abolishes IGF-I-directed chemotaxis. EDG5 still activates PI3-kinase but uncouples it from Rac activation.\",\n      \"method\": \"Chemotaxis assay, Rac/RhoA pull-down (GTP-bound form), PI3-kinase assay, Rac-GAP/GEF activity assays in CHO cells stably expressing EDG1, EDG3, or EDG5\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple biochemical assays (GEF, GAP, PI3K, pull-downs), isotype-specific comparison across three receptors, rigorous controls including dominant-negative mutants\",\n      \"pmids\": [\"11094076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EDG3/S1PR3 and EDG5/S1PR2 (but not EDG1) mediate S1P-induced activation of NF-κB in HEK293 cells; this activation requires protein kinase C and Ca2+ downstream of Gq, but not Rho activation alone. Gβγ potentiates NF-κB activation achieved through other G proteins.\",\n      \"method\": \"NF-κB reporter assay, pharmacological inhibitors of PKC and Ca2+, dominant-negative Rho, Gβγ titration in HEK293 cells overexpressing Edg receptor subtypes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific reporter assay with multiple pharmacological dissections, single lab\",\n      \"pmids\": [\"11673450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Knockout of H218/S1PR2 in mice does not cause developmental defects but leads to spontaneous seizures at 3-7 weeks of age; whole-cell patch-clamp recordings show a large increase in excitability of neocortical pyramidal neurons in H218-/- mice, establishing S1PR2 as a required modulator of neuronal excitability in vivo.\",\n      \"method\": \"Gene knockout mice, EEG recordings, whole-cell patch-clamp electrophysiology of neocortical pyramidal neurons\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with electrophysiological phenotype readout, replicated in multiple animals, EEG and patch-clamp orthogonal methods\",\n      \"pmids\": [\"11553273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"EDG5/S1PR2 mediates S1P-induced antiproliferative effects in rat hepatocytes via activation of Rho. The inhibitory effect on HGF/EGF-induced DNA synthesis is blocked by C3 exotoxin (Rho inactivation) and by the S1PR2-specific antagonist JTE-013, but not by pertussis toxin, indicating Gi-independent Rho signaling through S1PR2.\",\n      \"method\": \"DNA synthesis assay ([3H]thymidine incorporation), C3 exotoxin Rho inactivation, pertussis toxin treatment, JTE-013 antagonist, partial hepatectomy model in rats\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mechanistic interventions (specific antagonist, Rho inhibitor, PTX) in both in vitro and in vivo hepatectomy models\",\n      \"pmids\": [\"12557151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Down-regulation of EDG5/S1PR2 during C2C12 myoblast-to-myotube differentiation specifically uncouples S1P signaling to phospholipase D (PLD). Overexpression of EDG5/S1PR2 (but not EDG1 or EDG3) potentiates S1P-stimulated PLD activity, and antisense knockdown of EDG5/S1PR2 reduces S1P-induced PLD activity, establishing S1PR2 as the dominant receptor coupling S1P to PLD.\",\n      \"method\": \"Northern blot, Western blot, PLD activity assay, overexpression of receptor subtypes, antisense ODN knockdown in C2C12 cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor-specific gain- and loss-of-function experiments with PLD activity measurements, multiple receptor subtypes compared\",\n      \"pmids\": [\"14499732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S1PR2 plays a key role in endothelial vascular permeability and inflammatory responses during endotoxemia. Downstream signaling includes activation of the stress-activated protein kinase pathway together with Rho-kinase/NF-κB pathway, both required for S1PR2-mediated endothelial inflammatory responses. Bone marrow chimera experiments localize the critical function to the stromal compartment.\",\n      \"method\": \"S1pr2 knockout mice, bone marrow chimeras, JTE013 pharmacological antagonist, in vitro TNFα endothelial inflammation assays, permeability assays, NF-κB pathway analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacological antagonist plus bone marrow chimeras plus in vitro mechanistic dissection, multiple orthogonal approaches\",\n      \"pmids\": [\"23723450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S1PR2 is a receptor for the Nogo-A-Δ20 domain of Nogo-A, distinct from the S1P binding pocket. Nogo-A-Δ20 binding to S1PR2 signals via G13, the Rho GEF LARG, and RhoA. S1PR2 deletion or blockade counteracts Nogo-A-Δ20-mediated and myelin-mediated inhibition of neurite outgrowth and cell spreading. S1PR2 blockade strongly enhances LTP in wild-type but not Nogo-A-/- hippocampus, establishing the Nogo-A/S1PR2 axis as a repressor of synaptic plasticity.\",\n      \"method\": \"Binding assays, siRNA knockdown, S1PR2 knockout, LTP recording in hippocampal slices, neurite outgrowth assays, cell spreading assays, pharmacological blockade with S1PR2 antagonist\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding, genetic KO, siRNA, LTP electrophysiology, cell assays), replicated across wild-type and Nogo-A KO mice\",\n      \"pmids\": [\"24453941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In zebrafish, S1pr2/Mil signals through Gα13 and a RhoGEF-dependent pathway to regulate convergent movement of the anterior endoderm, which is required for coordinating myocardial migration to the midline. Cardiac-specific expression of Gα13 fails to rescue cardia bifida caused by global Gα13 inhibition, confirming S1pr2/Gα13 acts in the endoderm, not the myocardium.\",\n      \"method\": \"Zebrafish genetic epistasis (morpholino knockdown, dominant-negative constructs), endoderm transplantation rescue experiments, cardiac-specific Gα13 expression\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple components, transplantation rescue experiments establishing tissue-autonomous function, cardiac-specific negative control\",\n      \"pmids\": [\"23318642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S1P via S1PR2 induces filopodia formation through phosphorylation of ERM (ezrin/radixin/moesin) proteins. Phosphomimetic ezrin mutants reproduce the filopodia phenotype, while non-phosphorylatable mutants block it. siRNA and genetic knockout approaches identify S1PR2 as the specific and necessary receptor for ERM phosphorylation and filopodia formation.\",\n      \"method\": \"Pharmacological S1PR agonists/antagonists, siRNA knockdown, genetic knockout, phosphomimetic/non-phosphorylatable ezrin mutants, immunofluorescence for filopodia\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple receptor-specific pharmacological and genetic approaches combined with dominant mutant validation\",\n      \"pmids\": [\"23106337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S1PR2 promotes germinal center B-cell confinement and dampens Akt activation; S1PR2 deficiency or deficiency of components of its signaling pathway results in loss of growth control in chronically stimulated mucosal germinal centers.\",\n      \"method\": \"S1PR2 knockout mice, germinal center analysis, Akt activation assays\",\n      \"journal\": \"Immunological reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype (GC confinement, Akt activation), single lab review summarizing primary findings\",\n      \"pmids\": [\"22500830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S1PR2 mediates satellite cell activation in dystrophic muscle via STAT3 signaling. S1P via S1PR2 inhibits Rac1, which activates STAT3, leading to downregulation of p21 and p27 in myoblasts, thereby promoting cell cycle progression.\",\n      \"method\": \"S1PR2 pharmacological inhibition, siRNA knockdown, Rac1/STAT3 activity assays, p21/p27 expression in mdx mouse model and myoblast cultures\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection in disease model with pharmacological and genetic tools, single lab\",\n      \"pmids\": [\"22606352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S1PR2 acts as a tumor suppressor in DLBCL; ectopic expression of wild-type S1PR2 (but not a signaling-deficient point mutant) induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models. The proapoptotic effects are phenocopied by Gα13 overexpression and are independent of AKT signaling.\",\n      \"method\": \"Ectopic expression of wild-type vs. signaling-deficient S1PR2 mutant, Gα13 overexpression, subcutaneous and orthotopic xenograft mouse models, apoptosis assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — wild-type vs. mutant comparison, Gα13 phenocopy, multiple in vivo models, AKT independence established\",\n      \"pmids\": [\"26729899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The TGF-β/TGF-βR2/SMAD1 axis directly activates S1PR2 transcription; phosphorylated SMAD1 binds regulatory elements in the S1PR2 locus (by ChIP). CRISPR-mediated editing of S1PR2, SMAD1, or TGFBR2 renders DLBCL cells unresponsive to TGF-β-induced apoptosis. Loss of S1pr2 or Tgfbr2 in GC B cells induces hyperproliferation and accelerates MYC-driven lymphomagenesis.\",\n      \"method\": \"ChIP of phospho-SMAD1 at S1PR2 locus, CRISPR editing of S1PR2/SMAD1/TGFBR2, xenotransplantation models, GC B cell-specific Tgfbr2 knockout mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP demonstrates direct SMAD1 binding, CRISPR epistasis establishes pathway order, multiple in vivo models, orthogonal methods\",\n      \"pmids\": [\"29615404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S1P/S1PR2-mediated signaling triggers Smad1/5/8 phosphorylation via a Gi-independent RhoA/ROCK pathway in osteoblasts, leading to nuclear translocation of Smad4 and upregulation of Runx2 expression, promoting osteoblast differentiation.\",\n      \"method\": \"Pharmacological inhibitors (JTE-013, ROCK inhibitors), RhoA activity assay, Smad1/5/8 phosphorylation by Western blot, nuclear translocation imaging, in vivo bone formation assay in MC3T3-E1 cells and primary osteoblasts\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors and readouts in two cell systems plus in vivo, single lab\",\n      \"pmids\": [\"27612439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"S1PR2 mediates S1P-induced YAP activation in hepatocellular carcinoma cells (both human and mouse) in an MST1/2-independent manner, leading to YAP-mediated CTGF upregulation and cell proliferation. siRNA knockdown shows only CTGF (not CYR61) is required for S1P-stimulated proliferation.\",\n      \"method\": \"siRNA knockdown of S1PR2 and pathway components, YAP reporter assays, CTGF/CYR61 expression, proliferation assays, ChIP-seq for HNF4α, YAP transgenic mouse hepatocytes\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNA targets with defined proliferation readout and in vivo transgenic validation, single lab\",\n      \"pmids\": [\"29903770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endothelial-derived S1P acts via S1PR2 on alveolar type II (AT2) cells to induce nuclear translocation of YAP, promoting AT2-to-AT1 differentiation required for alveolar repair after lung injury. This was established using endothelial-specific Sphk1 knockout mice.\",\n      \"method\": \"Endothelial-specific Sphk1 knockout mice, immunofluorescence for YAP nuclear translocation, AT1/AT2 cell quantification after Pseudomonas lung injury\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific genetic model with defined cellular differentiation phenotype and signaling readout, single lab\",\n      \"pmids\": [\"32610129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of S1P-bound S1PR2 coupled to heterotrimeric G13 reveals that ICL2 of S1PR2 interacts with the α5 helix of Gα13, with ICL2 conformation constrained by TM4. FTY720-P (an agonist of S1PR1/3/4/5) can also trigger G13 activation via S1PR2. The S1PR2-F274I variant increases G13 activity with both FTY720-P and S1P, explaining drug selectivity differences.\",\n      \"method\": \"Cryo-electron microscopy structure determination, TGFα shedding assay for G13 activation, cell migration assays, mutagenesis of interface residues\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with functional assays (TGFα shedding, migration) and mutagenesis validating structural contacts\",\n      \"pmids\": [\"35353559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Missense variants p.Arg108Pro and p.Tyr140Cys in S1PR2 cause autosomal-recessive profound hearing loss (DFNB68). Molecular modeling predicts p.Arg108Pro disrupts S1P binding and p.Tyr140Cys disrupts G protein docking. S1pr2-/- mice show stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss.\",\n      \"method\": \"Exome sequencing, Sanger segregation analysis, S1pr2 knockout mouse phenotyping (auditory physiology, histology), molecular modeling\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics with two independent families, knockout mouse phenotyping, and structural modeling converging on same gene/residues\",\n      \"pmids\": [\"26805784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A spontaneous Thr289Arg S1pr2 mutation (stonedeaf mouse) causes progressive hearing loss with normal hearing at 2 weeks but severe/profound loss by 14 weeks, associated with a reduced endocochlear potential and stria vascularis degeneration—the first demonstration that S1PR2 loss reduces EP.\",\n      \"method\": \"Mouse ENU mutagenesis screen, exome sequencing, auditory brainstem responses, endocochlear potential measurement, stria vascularis histology\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent S1pr2 alleles examined, direct EP measurement providing new mechanism, histological correlation\",\n      \"pmids\": [\"27383011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"S1P-S1PR2 axis mediates homing of MUSE stem cells to infarcted myocardium; this was confirmed pharmacologically (S1PR2-specific antagonist JTE-013 co-injection) and genetically (S1PR2-siRNA introduction into Muse cells) blocking migration/homing to the heart.\",\n      \"method\": \"In vivo cell tracking with Nano-lantern labeling, pharmacological antagonism with JTE-013, S1PR2-siRNA knockdown in Muse cells, rabbit acute MI model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent approaches (pharmacological and genetic) confirming same homing mechanism in vivo, single lab\",\n      \"pmids\": [\"29475983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endothelial S1PR2 regulates lymphatic endothelial cell layer structure and permeability through the ERK pathway, modulating expression of junction molecules VE-cadherin, occludin, and zonulin-1, and facilitates T cell transcellular migration through VCAM-1 expression.\",\n      \"method\": \"S1PR2-knockout LEC studies, ERK pathway inhibitors, junction molecule expression by Western blot/imaging, T cell transmigration assays across LEC monolayers\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological approaches with defined junction molecule and migration readouts, single lab\",\n      \"pmids\": [\"30877143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S1PR2 internalization from plasma membrane to endoplasmic reticulum upon S1P stimulation activates PERK-eIF2α-ATF4 signaling via elevated [Ca2+]ER, leading to RNASET2-mediated intracellular uracil generation that blunts 5-FU efficacy in colorectal cancer cells.\",\n      \"method\": \"Subcellular fractionation/imaging of S1PR2, [Ca2+]ER measurement with Mag-Fluo-AM, LC-ESI-MS/MS for uracil measurement, JTE-013 pharmacological inhibition, S1PR2-/- villin-S1PR2 knockout mice\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — intracellular localization linked to functional consequence via multiple biochemical methods, genetic KO mouse validation, single lab\",\n      \"pmids\": [\"32647340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"S1PR2/RhoA/ROCK1 signaling pathway damages intestinal vascular endothelial barrier and promotes M1 macrophage polarization in IBD; inhibition of S1PR2 reduces RhoA/ROCK1 expression, reverses impaired barrier function and M1 polarization, and reduces ER stress in endothelial cells and glycolysis in macrophages.\",\n      \"method\": \"S1PR2 knockdown and pharmacological inhibition (JTE-013), RhoA/ROCK1 expression analysis, barrier permeability assays, macrophage polarization assays, DSS colitis mouse model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological approaches in both in vitro and in vivo IBD models with pathway readouts, single lab\",\n      \"pmids\": [\"35537530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Endothelial S1PR2 promotes mitochondrial fission and ROS production via RhoA/ROCK1/DRP1 signaling, leading to NLRP3 inflammasome activation and pyroptosis, thereby worsening cardiac ischemia-reperfusion injury. EC-specific S1pr2 loss-of-function reduces injury while gain-of-function aggravates it.\",\n      \"method\": \"EC-specific S1pr2 KO and gain-of-function mice, RhoA/ROCK1/DRP1 protein expression, mitochondrial morphology analysis, NLRP3/pyroptosis markers, cardiac I/R mouse model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific bidirectional genetic model (both KO and overexpression) with mechanistic pathway dissection, in vivo validation\",\n      \"pmids\": [\"38909407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endothelial S1pr2 inhibits post-ischemic angiogenesis by suppressing the AKT/eNOS signaling pathway, thereby inhibiting EC proliferation, migration, and angiogenic activity. EC-specific S1pr2 loss-of-function enhances angiogenesis and blood flow recovery, while gain-of-function impairs it.\",\n      \"method\": \"EC-specific S1pr2 loss-of-function and gain-of-function mice, hindlimb ischemia model, AKT/eNOS phosphorylation by Western blot, EC proliferation/migration assays, JTE013 pharmacological inhibition\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional EC-specific genetic models with pharmacological confirmation and pathway mechanism identified, in vivo phenotype\",\n      \"pmids\": [\"35836816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Taurocholic acid activates S1PR2 in hepatic stellate cells, triggering p38 MAPK/YAP signaling to promote HSC proliferation, migration, contraction, and ECM secretion (fibrosis). Pharmacological or genetic S1PR2 inhibition reverses TCA-induced HSC activation and attenuates cholestatic liver fibrosis in DDC diet mice.\",\n      \"method\": \"JTE-013 pharmacological inhibition, S1PR2 shRNA, LX-2 and JS-1 HSC cell lines, DDC-diet mouse model, p38 MAPK and YAP phosphorylation/activity assays\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic approaches in vitro and in vivo, pathway readouts, single lab\",\n      \"pmids\": [\"36800698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GDCA/taurine-conjugated bile acid activates S1PR2 in macrophages to upregulate ZBP1 expression, which is required for ZBP1/p-MLKL-mediated necroptosis in macrophages; selective macrophage S1pr2 knockdown in vivo decreases necroptosis and attenuates collagen deposition in BDL cholestatic liver injury.\",\n      \"method\": \"Macrophage-specific S1pr2 knockdown in vivo, GDCA treatment of BMDMs, ZBP1/p-MLKL Western blot, BDL mouse model, siRNA rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific in vivo knockdown combined with mechanistic in vitro studies, single lab\",\n      \"pmids\": [\"36859525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EBV oncoprotein LMP1 transcriptionally downregulates S1PR2 in GC B cells, and this downregulation drives constitutive activation of the PI3-kinase pathway in ABC-DLBCL cells.\",\n      \"method\": \"LMP1 expression in GC B cells, transcriptional profiling, PI3K pathway activation assays, IHC for S1PR2 in primary LMP1-positive vs. negative DLBCLs\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional mechanism with functional PI3K pathway readout, clinical tissue validation, single lab\",\n      \"pmids\": [\"30666658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYDGF directly binds S1PR2 (confirmed by SPR assay and Co-IP), and signals via S1PR2/RhoA/G-actin/F-actin/MRTF-A to suppress VSMC dedifferentiation and neointimal formation in response to balloon injury.\",\n      \"method\": \"Molecular docking, SPR assay, Co-immunoprecipitation, JTE-013 antagonist, CCG-1423 and Ripasudil inhibitors, carotid balloon injury rat model, RhoA activity and actin cytoskeleton assays\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by SPR and Co-IP, downstream pathway dissected with multiple inhibitors, in vivo model, single lab\",\n      \"pmids\": [\"37726422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mast cells react to vaccinia virus and degranulate via a membrane-activated pathway triggered by S1PR2; neutralizing antibody to the VV L1 fusion entry protein inhibits degranulation by preventing S1PR2 activation by viral membrane lipids. Antimicrobial peptide release from MC granules is necessary to inactivate VV infectivity.\",\n      \"method\": \"MC-deficient mouse model, MC reconstitution experiments, cathelicidin-KO MC studies, S1PR2 pathway analysis, neutralizing antibody experiments, skin infection model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic MC-deficient and cathelicidin-KO models with S1PR2 pathway identification and antibody blocking, multiple in vivo readouts\",\n      \"pmids\": [\"22140255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Liver sinusoidal endothelial cell S1pr2 activates the YAP signaling pathway to potentiate TGF-β transactivation in a paracrine manner acting on hepatic stellate cells, thereby aggravating liver fibrosis. LSEC-specific S1pr2 loss-of-function dampens HSC activation while overexpression enhances it.\",\n      \"method\": \"LSEC-specific S1pr2 KO and overexpression, CCl4 liver fibrosis model, YAP activity assays, TGF-β expression/secretion, HSC activation markers, paracrine co-culture experiments\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific bidirectional genetic model with defined paracrine mechanism, in vivo validation, single lab\",\n      \"pmids\": [\"37039817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Preeclampsia is associated with reduced S1P and SPHK1. S1P increases trophoblast cell invasion via S1PR2-activated RhoA/ROCK-induced actin polymerization that promotes YAP nuclear translocation; in vivo inhibition of sphingosine kinase 1 during placentation causes a preeclampsia phenotype.\",\n      \"method\": \"SPHK1 inhibitor mouse model, HTR8/SVneo cell invasion assays, actin polymerization measurement, YAP nuclear translocation imaging, YAP-5SA mutant, S1PR2 pharmacological inhibition\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model plus in vitro mechanism dissection with dominant mutants, single lab\",\n      \"pmids\": [\"34865521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of endothelial S1pr2 after traumatic brain injury promotes BBB disruption by activating JNK/c-Jun signaling, which transactivates MMP-9; ChIP-qPCR confirmed AP-1a and AP-1b binding sites in the MMP-9 promoter as phospho-c-Jun binding sites.\",\n      \"method\": \"TBI mouse model, JTE-013 pharmacological inhibition, SP600125 JNK inhibitor, Western blot for JNK/c-Jun/MMP-9, tight junction protein analysis, ChIP-qPCR for c-Jun binding to MMP-9 promoter, cellular models\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with mechanistic dissection and ChIP-qPCR for transcription factor binding, in vivo model, single lab\",\n      \"pmids\": [\"39679379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Enhanced S1PR2 membrane expression in the cerebellum of hyperammonaemic rats increases CCL2 (especially in Purkinje neurons), activating CCR2 in microglia and increasing P2X4 and BDNF in microglia. BDNF then enhances TrkB activation in neurons, increasing KCC2 membrane expression and GABAergic neurotransmission, leading to motor incoordination. Blocking S1PR2 with JTE-013 normalizes this entire pathway and restores motor coordination.\",\n      \"method\": \"Intracerebral JTE-013 administration via osmotic mini-pumps in hyperammonaemic rats, immunochemistry, immunofluorescence, Western blot for pathway components, beam walking behavioral test\",\n      \"journal\": \"Neuropathology and applied neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological S1PR2 blockade in disease model with complete pathway dissection and behavioral readout, single lab\",\n      \"pmids\": [\"35152448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FXR transcriptionally represses S1PR2 expression in hepatic stellate cells; DHA induces FXR expression and reduces S1PR2, thereby inhibiting HSC contraction through modulation of both Ca2+-dependent and Ca2+-sensitization signaling. Gain- and loss-of-function analyses confirm an FXR-S1PR2-dependent mechanism.\",\n      \"method\": \"Gel contraction assays, actin cytoskeleton fluorescence staining, myosin light chain phosphorylation, FXR gain/loss-of-function in LX-2 cells, S1PR2 mRNA/protein expression\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional gain/loss-of-function with multiple contractility readouts, single lab\",\n      \"pmids\": [\"27027402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S1PR2 knockdown in DLBCL cells promotes migration and invasion via NF-κB pathway activation; S1PR2 downregulation reduces MMP-9 expression in U266 MM cells.\",\n      \"method\": \"S1PR2-selective antagonist JTE-013, S1PR2 shRNA knockdown in U266 cells, migration/invasion assays, NF-κB pathway analysis, MMP-9 expression by Western blot\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pharmacological and knockdown approach, single lab, pathway placement indirect\",\n      \"pmids\": [\"32922084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"S1P induces IL-8 gene expression through S1PR1 in trophoblast cells, while IL-8 protein secretion is primarily regulated through S1PR2; both Rho-kinase and Rac1 signaling are essential for S1P-induced IL-8 secretion.\",\n      \"method\": \"Selective S1PR antagonists/agonists (JTE-013 for S1PR2, VPC23019 for S1PR1/3, SEW2781 for S1PR1), Rho-kinase inhibitor Y27632, Rac1 inhibitor NSC23766, IL-8 ELISA and real-time PCR in HTR-8/SVneo cells\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple selective pharmacological tools dissecting receptor subtype contributions to gene expression vs. secretion, single lab\",\n      \"pmids\": [\"26321412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FTY720P inhibits Na+/K+ ATPase in HepG2 cells via S1PR2 through a signaling cascade involving PKC, NF-κB, and PGE2 generation; this effect is blocked by the specific S1PR2 antagonist JTE-013 and mimicked by the S1PR2 agonist CYM5520.\",\n      \"method\": \"Na+/K+ ATPase activity assay, JTE-013, CYM5520 (S1PR2 agonist), PKC inhibitor calphostin, COX-2 inhibitor indomethacin, NF-κB inhibitor in HepG2 cells\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-specific agonist and antagonist with pathway dissection, enzyme activity as direct readout, single lab\",\n      \"pmids\": [\"27501354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Taurine-conjugated bile acid (TCDCA) stimulates cortisol secretion and steroidogenesis-related gene expression in adrenocortical H295R cells via S1PR2 and ERK phosphorylation; siRNA knockdown of S1PR2 reduces ERK phosphorylation and cortisol secretion, while SF-1 transactivation is increased downstream of this pathway.\",\n      \"method\": \"S1PR2 pharmacological inhibition (JTE-013), S1PR2 siRNA knockdown, ERK phosphorylation by Western blot, cortisol ELISA, SF-1 transactivation assay in H295R cells\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic S1PR2 inhibition with enzyme activity readout, SF-1 functional assay, single lab\",\n      \"pmids\": [\"30664326\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S1PR2 is a Gs/Gi/Gq/G12/13-coupled GPCR that, upon binding S1P (or Nogo-A-Δ20 at a distinct site), predominantly signals through Gα13→Rho GEF/LARG→RhoA→ROCK to inhibit Rac activity and cell migration, restrict germinal-center B-cell confinement, suppress neuronal excitability, regulate endothelial barrier integrity (via ROCK1/DRP1/NF-κB/p38-ERK), activate YAP (independently of MST1/2) to drive epithelial repair and stellate-cell activation, phosphorylate Smad1/5/8 to induce Runx2-dependent osteoblast differentiation, and couple S1P to phospholipase D; cryo-EM has resolved the S1PR2–G13 complex showing that ICL2 engages the Gα13 α5 helix, and loss-of-function mutations in S1PR2 cause autosomal-recessive hearing loss by disrupting endocochlear potential maintenance through strial degeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"S1PR2 is a sphingosine-1-phosphate (S1P) receptor of the G protein-coupled family that couples S1P sensing to cytoskeletal, growth-control, and barrier-regulatory outputs across diverse tissues [#1, #4]. It binds S1P and sphinganine-1-phosphate with high affinity and engages Gi, Gq, and G13 heterotrimeric G proteins, mobilizing Ca2+, activating MAPK/JNK/p38 cascades, and driving Rho-dependent stress-fiber formation [#0, #1, #3]. A defining feature distinguishing S1PR2 from related receptors is its predominant signaling through Gα13 to RhoA, where it stimulates Rac-GAP activity to inhibit Rac and suppress cell migration and chemotaxis [#4]; cryo-EM of the S1P-bound S1PR2–G13 complex shows that ICL2 engages the Gα13 α5 helix with ICL2 conformation constrained by TM4 [#20]. Through this Gα13/RhoA/ROCK axis S1PR2 phosphorylates ERM proteins to form filopodia, activates NF-κB via PKC and Ca2+, and couples S1P to phospholipase D [#5, #8, #12]. S1PR2 also serves as a receptor for the Nogo-A-Δ20 domain at a site distinct from the S1P pocket, signaling via G13/LARG/RhoA to repress neurite outgrowth and synaptic plasticity, consistent with its requirement for restraining neuronal excitability in vivo [#6, #10]. In immunity and cancer it acts as a tumor suppressor in germinal-center B cells, confining cells and dampening Akt; it is a direct transcriptional target of the TGF-β/TGFBR2/SMAD1 axis, and its loss accelerates MYC-driven lymphomagenesis, with G13 overexpression phenocopying its proapoptotic effect [#13, #15, #16]. Across epithelial and stellate-cell contexts S1PR2 activates YAP, including MST1/2-independent YAP activation driving hepatocellular proliferation and AT2-to-AT1 differentiation in alveolar repair [#18, #19], and in osteoblasts it triggers RhoA/ROCK-dependent Smad1/5/8 phosphorylation and Runx2 induction [#17]. In endothelium it controls vascular permeability and inflammation through Rho-kinase/NF-κB, p38, and RhoA/ROCK1/DRP1-driven mitochondrial fission and NLRP3-dependent pyroptosis [#9, #27]. Loss-of-function mutations in S1PR2 cause autosomal-recessive profound hearing loss (DFNB68) through stria vascularis degeneration and reduced endocochlear potential [#21, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing which ligand S1PR2 senses and which G proteins it engages was the foundational step defining it as an S1P receptor with broader G protein coupling than EDG1.\",\n      \"evidence\": \"Radioligand binding, subunit-selective [35S]GTPgammaS assays, and Ca2+/kinase/cytoskeletal readouts in Sf9, HEK293, CHO, and Xenopus systems\",\n      \"pmids\": [\"10488065\", \"9854026\", \"10383399\", \"9988698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological context of multi-G-protein coupling not addressed in heterologous systems\", \"Quantitative bias among Gi/Gq/G13 not resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying that S1PR2 uniquely inhibits Rac and migration distinguished its signaling logic from migration-promoting S1P receptors and defined its anti-migratory function.\",\n      \"evidence\": \"Rac/RhoA pull-downs, Rac-GAP/GEF and PI3K assays, and chemotaxis in CHO cells expressing distinct EDG receptors; NF-κB reporter dissection\",\n      \"pmids\": [\"11094076\", \"11673450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the Rac-GAP activated by S1PR2 not defined\", \"Direct link between G protein subtype and Rac-GAP not established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Knockout confirmed an in vivo role: S1PR2 is required to restrain neuronal excitability, moving its function from cell-culture phenotypes to organismal physiology.\",\n      \"evidence\": \"S1pr2-/- mice with EEG and whole-cell patch-clamp of neocortical pyramidal neurons\",\n      \"pmids\": [\"11553273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking S1PR2 to excitability not resolved\", \"Cell type mediating the seizure phenotype not pinpointed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linking S1PR2 to Rho-dependent growth inhibition and PLD coupling defined effector pathways downstream of the receptor in hepatocytes and myoblasts.\",\n      \"evidence\": \"C3 exotoxin, JTE-013 antagonist, and pertussis toxin in hepatocyte DNA-synthesis assays; receptor-subtype gain/loss-of-function PLD assays in C2C12 cells\",\n      \"pmids\": [\"12557151\", \"14499732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling S1PR2 to PLD not molecularly defined\", \"Gi-independence of Rho activation not structurally explained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that S1PR2 binds Nogo-A-Δ20 at a non-S1P site established it as a dual-ligand receptor mediating myelin-associated inhibition of neurite outgrowth and synaptic plasticity.\",\n      \"evidence\": \"Binding assays, siRNA, knockout, and hippocampal LTP recordings across wild-type and Nogo-A-/- mice\",\n      \"pmids\": [\"24453941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the distinct Nogo-A binding site not resolved\", \"Relative physiological weight of S1P vs Nogo-A ligand inputs unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the G13/RhoGEF/RhoA effector module and its cytoskeletal outputs unified S1PR2 signaling across endothelial barrier, developmental migration, and filopodia formation.\",\n      \"evidence\": \"S1pr2 KO mice, bone marrow chimeras, zebrafish genetic epistasis with endoderm transplantation, and ERM phosphomimetic mutants\",\n      \"pmids\": [\"23723450\", \"23318642\", \"23106337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific RhoGEF identities not all defined\", \"How a single Rho axis produces opposing barrier-protective vs barrier-damaging outcomes not reconciled\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating S1PR2 as a germinal-center tumor suppressor and as a cause of recessive hearing loss linked the receptor to both lymphomagenesis control and cochlear homeostasis.\",\n      \"evidence\": \"Wild-type vs signaling-deficient S1PR2 expression with G13 phenocopy in DLBCL xenografts; exome sequencing of DFNB68 families plus S1pr2-/- and stonedeaf mouse phenotyping with endocochlear potential measurement\",\n      \"pmids\": [\"26729899\", \"26805784\", \"27383011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which S1PR2 maintains stria vascularis and endocochlear potential not molecularly defined\", \"Effector linking S1PR2/G13 to B-cell apoptosis not fully identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying TGF-β/SMAD1 as a direct transcriptional activator of S1PR2 placed the receptor within an upstream regulatory circuit that, when lost, accelerates MYC-driven lymphoma.\",\n      \"evidence\": \"ChIP of phospho-SMAD1 at the S1PR2 locus, CRISPR epistasis of S1PR2/SMAD1/TGFBR2, and GC B-cell-specific Tgfbr2 knockout mice\",\n      \"pmids\": [\"29615404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream apoptotic effectors of the TGF-β–S1PR2 axis incompletely mapped\", \"Cross-talk with EBV LMP1-mediated repression of S1PR2 not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connecting S1PR2 to MST1/2-independent YAP activation defined a growth- and repair-driving branch operating in liver and lung epithelium.\",\n      \"evidence\": \"siRNA, YAP reporter and CTGF/CYR61 analyses in HCC cells; endothelial-specific Sphk1 knockout linking endothelial S1P to AT2 YAP activation\",\n      \"pmids\": [\"29903770\", \"32610129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MST-independent YAP activation by S1PR2 not defined\", \"How the Rho axis feeds into YAP in these contexts not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The cryo-EM S1PR2–G13 structure provided the physical basis for selective G13 coupling and explained agonist and variant selectivity differences.\",\n      \"evidence\": \"Cryo-EM structure determination with TGFα-shedding G13 activation, migration assays, and interface mutagenesis including the F274I variant\",\n      \"pmids\": [\"35353559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures with Gi/Gq or with the Nogo-A ligand not determined\", \"Conformational basis for biased signaling not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Bidirectional endothelial genetic models established S1PR2 as a context-dependent driver of vascular pathology through RhoA/ROCK1-coupled mitochondrial and AKT/eNOS branches.\",\n      \"evidence\": \"EC-specific S1pr2 loss- and gain-of-function mice in cardiac I/R and hindlimb ischemia models with RhoA/ROCK1/DRP1, NLRP3/pyroptosis, and AKT/eNOS readouts\",\n      \"pmids\": [\"38909407\", \"35836816\", \"35537530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants selecting protective vs damaging endothelial outputs unknown\", \"Relationship between mitochondrial fission and barrier disruption branches not unified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How S1PR2 coordinates its multiple, sometimes opposing outputs (Rac inhibition, YAP activation, NF-κB, Smad phosphorylation) in a cell-type-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for context-dependent effector selection\", \"Determinants of ligand choice (S1P vs Nogo-A vs bile acids) in vivo unclear\", \"Structural basis of non-G13 coupling not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 4, 20]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [25, 37]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 13, 16, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 15, 27, 30]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 17, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 22, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GNA13\", \"RhoA\", \"LARG\", \"Nogo-A\", \"MYDGF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}