{"gene":"S1PR1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1998,"finding":"Sphingosine-1-phosphate (S1P/SPP) was identified as a high-affinity ligand for the orphan GPCR EDG-1 (S1PR1), binding with Kd ~8.1 nM; receptor overexpression induced cell-cell aggregation, cadherin upregulation, and adherens junction formation in an S1P- and Rho-dependent manner.","method":"Radioligand binding assay, receptor overexpression in HEK293 cells, morphological and biochemical assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay with Kd determination, functional validation, foundational ligand identification replicated in subsequent studies","pmids":["9488656"],"is_preprint":false},{"year":1998,"finding":"EDG-1 (S1PR1) couples exclusively to the Gi pathway: binding of S1P to EDG-1 inhibits forskolin-stimulated cAMP accumulation in a pertussis toxin-sensitive manner; S1P-induced mitogenesis and anti-apoptosis were independent of EDG-1 and correlated with intracellular S1P uptake.","method":"cAMP assay with pertussis toxin inhibition, intracellular microinjection of S1P, antisense and receptor expression studies","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods, pertussis toxin dissection of pathway, replicated in other papers","pmids":["9660876"],"is_preprint":false},{"year":1996,"finding":"The third cytosolic loop (i3) of EDG-1 (S1PR1) physically associates with Giα and Goα polypeptides in a GTPγS-sensitive manner; immunoprecipitation of EDG-1 co-precipitates Giα1 and Giα3; EDG-1 overexpression leads to sustained, pertussis toxin-sensitive MAP kinase activation.","method":"Co-immunoprecipitation, GTPγS competition assay, MAP kinase activity assay with pertussis toxin","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP with GTPγS competition, functional pertussis toxin studies, replicated across multiple labs","pmids":["8626678"],"is_preprint":false},{"year":1999,"finding":"EDG-1 (S1PR1) activates only Gi family members (not Gs, Gq, G12, or G13), as established by subunit-selective [35S]GTPγS binding in Sf9 and HEK293 cells; in contrast, EDG-3 and H218/EDG-5 additionally couple to Gq and G13.","method":"Subunit-selective [35S]GTPγS 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, two cell systems, clearly distinguished receptor coupling profiles","pmids":["10488065"],"is_preprint":false},{"year":1999,"finding":"S1P ligand binding specifically induces reversible trafficking of EDG-1 (S1PR1) from the plasma membrane to perinuclear endosomal/lysosomal vesicles (t1/2 ~15 min internalization, t1/2 ~30 min recycling); truncation of the C-terminus completely blocks internalization; C-terminal domain is essential for ligand-induced trafficking.","method":"EDG-1-GFP chimera live-cell imaging, subcellular colocalization with endocytic/lysosomal markers, C-terminal truncation mutant analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — GFP-chimera live imaging, organelle colocalization, domain deletion mutant, multiple methods in one study","pmids":["10198065"],"is_preprint":false},{"year":2000,"finding":"Genetic deletion of Edg-1 (S1PR1) in mice caused embryonic hemorrhage and death at E12.5–E14.5 due to deficient vascular smooth muscle cell/pericyte coverage; EDG-1-null cells failed to activate the small GTPase Rac in response to S1P, which is required for migration.","method":"Gene knockout in mice (Edg1−/− embryos), histology, Rac activation assay in mutant cells","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined vascular phenotype, biochemical Rac assay, replicated/cited widely","pmids":["11032855"],"is_preprint":false},{"year":2001,"finding":"S1P-induced endothelial cell migration requires Akt-mediated phosphorylation of EDG-1 (S1PR1) at the T236 residue in the third intracellular loop; activated Akt binds to EDG-1, and T236A mutant EDG-1 acts as a dominant-negative that sequesters Akt and blocks Rac activation, cortical actin assembly, and chemotaxis without affecting Gi-dependent signaling.","method":"Akt-EDG-1 binding assay, site-directed mutagenesis (T236A), in vitro migration/chemotaxis assay, Rac activation assay, dominant-negative analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis of specific phosphorylation site, in vitro kinase assay, dominant-negative approach, multiple orthogonal readouts","pmids":["11583630"],"is_preprint":false},{"year":2001,"finding":"PDGF-induced cell motility depends on EDG-1 (S1PR1): PDGF activates sphingosine kinase, raising intracellular S1P levels, which transactivates EDG-1 as demonstrated by β-arrestin translocation and EDG-1 phosphorylation; EDG-1-null or kinase-inhibited cells fail to activate Rac or migrate toward PDGF.","method":"EDG-1 knockout fibroblasts, β-arrestin translocation assay (GPCR transactivation), sphingosine kinase inhibition, chemotaxis assay, Rac activation","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, multiple functional assays, receptor transactivation measured directly","pmids":["11230698"],"is_preprint":false},{"year":2001,"finding":"SPP-induced HUVEC migration requires signaling via EDG-1 and EDG-3 receptors through Rho activation (blocked by C3 exotoxin), leading to Rho-dependent integrin clustering (αvβ3 and β1) into focal contacts; Rac activation was dispensable for adhesion but EDG-1 and EDG-3 were both required for Rho activation.","method":"Antisense oligonucleotide knockdown of EDG-1 and EDG-3, C3 exotoxin treatment, integrin blocking antibodies, Rho activation assay, cell adhesion/migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — antisense knockdown + toxin inhibition + integrin blockade, multiple orthogonal approaches","pmids":["11150298"],"is_preprint":false},{"year":2000,"finding":"EDG-1 (S1PR1) localizes to caveolin-1-enriched plasmalemmal caveolae (~55% of protein); co-immunoprecipitation shows direct EDG-1/caveolin-1 interaction; S1P treatment increases EDG-1 targeting to caveolae (~93%); caveolin-1 overexpression inhibits S1P-mediated eNOS activation and attenuates agonist-induced EDG-1 phosphorylation by >90%.","method":"Sucrose gradient ultracentrifugation fractionation, co-immunoprecipitation with anti-caveolin-1 antibody, eNOS activity assay, caveolin-1 overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, subcellular fractionation, functional eNOS assay, multiple methods","pmids":["10921915"],"is_preprint":false},{"year":2001,"finding":"EDG-1 (S1PR1) expression in vascular smooth muscle cells (VSMCs) enhances S1P-induced proliferation via Gi-dependent p70 S6 kinase activation and cyclin D1 expression (blocked by pertussis toxin and rapamycin), and enhances migration via Gi activation but independently of p70 S6 kinase.","method":"Stable transfection of EDG-1 into adult VSMCs, pertussis toxin treatment, rapamycin treatment, p70 S6 kinase assay, cyclin D1 western blot, migration assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor overexpression with pharmacological dissection, multiple downstream readouts in single study","pmids":["11557736"],"is_preprint":false},{"year":1999,"finding":"EDG-1 (S1PR1) couples to Gi but not Gq: EDG-1 mRNA expression in Xenopus oocytes did not confer S1P-responsive intracellular calcium transients unless co-expressed with the chimeric Gαqi protein; in contrast, EDG-3 and EDG-5 alone conferred calcium responses to S1P, demonstrating differential Gq/Gi coupling among S1P receptors.","method":"Xenopus oocyte expression system, microinjection of receptor mRNA ± chimeric G-protein constructs, electrophysiological calcium transient recording","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in Xenopus oocytes, chimeric G-protein complementation, directly compared receptor subtypes","pmids":["10383399"],"is_preprint":false},{"year":2002,"finding":"EDG-1 (S1PR1) is N-glycosylated at asparagine-30 in its extracellular N-terminus; non-glycosylated mutant N30D-Edg-1 shows normal plasma membrane expression, ligand binding, and MAP kinase activation, but markedly reduced ligand-induced internalization and is not associated with caveolae membrane fractions.","method":"Site-directed mutagenesis (N30D), sucrose density gradient fractionation, radioligand binding assay, MAP kinase assay, internalization assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis + multiple functional and localization assays in same study","pmids":["12087059"],"is_preprint":false},{"year":2010,"finding":"STAT3 transcriptionally drives S1PR1 expression; reciprocally, S1PR1 activates STAT3 by upregulating JAK2 tyrosine kinase activity and IL-6 gene expression, forming a positive feedback loop that sustains persistent STAT3 activation in cancer cells; silencing S1PR1 inhibits STAT3 activity, tumor growth, and metastasis.","method":"S1PR1 siRNA knockdown in tumor/immune cells, STAT3 reporter assay, JAK2 kinase activity measurement, IL-6 ELISA, in vivo tumor models","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA in vitro and in vivo, kinase activity assay, cytokine measurement, multiple cell types and tumor models","pmids":["21102457"],"is_preprint":false},{"year":2012,"finding":"S1PR1 signaling restricts sprouting angiogenesis by inhibiting VEGF-A-induced signaling and stabilizing VE-cadherin localization at endothelial junctions; loss of S1PR1 in endothelial cells leads to increased sprouting and ectopic vessel branching.","method":"S1PR1 loss-of-function in endothelial cells (genetic deletion), VE-cadherin localization by immunofluorescence, VEGF-A signaling assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelial-specific genetic deletion with defined molecular phenotype, VE-cadherin localization and VEGF signaling as readouts","pmids":["22975327"],"is_preprint":false},{"year":2012,"finding":"S1PR1 (S1pr1) on megakaryocytes functions as a directional cue receptor for S1P gradients, guiding proplatelet extensions into bone marrow sinusoids; conditional S1pr1 deletion causes severe thrombocytopenia due to aberrant extravascular proplatelet formation and defective intravascular shedding.","method":"Conditional mouse mutants, intravital multiphoton microscopy of bone marrow, platelet counts","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with intravital imaging and defined platelet phenotype","pmids":["23148237"],"is_preprint":false},{"year":2001,"finding":"S1P activates NF-κB in a receptor-dependent fashion through EDG-3 and EDG-5 (which couple to Gi, Gq, and G13), but not through EDG-1 (S1PR1, which couples to Gi only); NF-κB activation requires protein kinase C and Ca2+ downstream of Gq; Rho activation alone by S1P was insufficient for NF-κB activation.","method":"HEK293 cells overexpressing individual Edg receptors, NF-κB reporter assay, PKC and Ca2+ inhibitor studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — receptor subtype comparison with specific pharmacological inhibitors, clear negative result for S1PR1","pmids":["11673450"],"is_preprint":false},{"year":2014,"finding":"Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling and T cell egress: in low S1P concentrations, dynamin 2 enables S1PR1 internalization/recycling which sustains signaling sufficient for egress; dynamin 2 deficiency limits T cells to a single pulse of S1PR1 signaling, insufficient for egress; transgenic S1PR1 overexpression rescues egress in dynamin 2 KO mice.","method":"T cell-specific dynamin 2 conditional KO mouse, S1PR1 transgenic rescue, T cell egress assay from thymus and lymph nodes","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with transgenic rescue, mechanistic epistasis established","pmids":["24638168"],"is_preprint":false},{"year":2016,"finding":"S1PR1 signaling suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells by accelerating IFNAR1 turnover/degradation and downregulating STAT1 phosphorylation; this suppression is pertussis toxin-resistant and requires S1PR1 internalization (blocked by a C-terminal Tat-peptide); endogenous S1P-S1PR1 signaling sets pDC sensitivity for IFN-α amplification.","method":"S1PR1 agonist treatment of pDCs, Tat-fusion receptor internalization blocking peptide, IFNAR1 turnover measurement, STAT1 phosphorylation assay, in vivo Ex26 antagonist, pertussis toxin studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple pharmacological and peptide tools, protein turnover assay, in vivo validation, multiple orthogonal methods","pmids":["26787880"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structures of S1PR1 and S1PR5 in complex with heterotrimeric Gi protein and diverse agonists (including drugs) were determined; structures reveal the binding modes of chemically distinct agonists, a mechanical switch activating the receptors, and the basis for ligand selectivity and G-protein coupling.","method":"Cryo-electron microscopy structure determination, functional assays for ligand activation and G-protein coupling","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM with functional validation, multiple structures and ligands","pmids":["34526663"],"is_preprint":false},{"year":2023,"finding":"CD69, a transmembrane protein expressed on activated lymphocytes, acts as a protein agonist of S1PR1 in cis: cryo-EM structure shows the transmembrane helix of one CD69 homodimer protomer contacts S1PR1-TM4, allosterically inducing movement of S1PR1-TMs 5-6 to activate receptor and engage heterotrimeric Gi; mutations at the CD69-S1PR1 interface reduce receptor internalization; CD69 promotes Gi-dependent S1PR1 internalization, loss of S1P gradient sensing, and inhibition of lymphocyte egress.","method":"Cryo-EM structure of CD69-S1PR1-Gi complex, mutagenesis of interface residues, receptor internalization assay, lymphocyte egress assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis and functional validation, novel mechanism established","pmids":["37039481"],"is_preprint":false},{"year":2015,"finding":"Phosphorylation of S1PR1 at tyrosine-143 (Y143) is required for S1P-induced receptor internalization in endothelial cells; Y143 phosphorylation correlates with maximal receptor internalization at 20 min and Y143 dephosphorylation accompanies receptor recycling to the cell surface at ~1 h; phospho-defective Y143F mutant fails to internalize while phospho-mimicking Y143D shows constitutive high internalization; C-terminal serine phosphorylation did not modulate Y143-dependent internalization.","method":"Site-directed mutagenesis (Y143F, Y143D), flow cytometry/immunofluorescence internalization assay, endothelial barrier resistance measurement","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific residue with multiple phosphorylation mutants, internalization and barrier function readouts","pmids":["25588843"],"is_preprint":false},{"year":1998,"finding":"Edg-1 (S1PR1) expression in Sf9 and COS-7 cells confers S1P-induced adenylate cyclase inhibition and MAP kinase activation (Gi-mediated), but not Ca2+ mobilization; LPA does not activate EDG-1 and Vzg-1/Edg-2 cannot substitute for Edg-1.","method":"Heterologous expression in Sf9 and COS-7 cells, adenylate cyclase assay, MAP kinase assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct heterologous expression with multiple signaling readouts, receptor specificity confirmed by negative controls","pmids":["9480864"],"is_preprint":false},{"year":2017,"finding":"S1PR1 signaling in endothelial cells activates the ERK/CSF1 pathway, enhancing CSF1 expression in a cell-contact-dependent manner, which promotes Ly6clow reparative macrophage proliferation after myocardial infarction; endothelial S1pr1-specific deletion reduces reparative macrophage accumulation and worsens cardiac remodeling; pharmacological S1pr1 activation ameliorates post-MI cardiac remodeling.","method":"Endothelial-specific S1pr1 KO mouse model, pharmacological S1pr1 activation, flow cytometry for macrophage subsets, CSF1 signaling blockade, ERK activation assay","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelial-specific KO + pharmacological rescue + CSF1 blockade epistasis, mechanistic pathway defined","pmids":["32091582"],"is_preprint":false},{"year":2016,"finding":"In T lymphocytes, CCR7/CCL19 signaling upregulates S1PR1 (EDG-1) expression via ERK5 activation and induction of the KLF2 transcription factor; CCR7/CCL19-stimulated T cells show increased S1PR1-ligand-directed migration at 48 h, which is abolished in ERK5-deficient T cells.","method":"ERK5 conditional KO mouse (ERK5flox/flox/Lck-Cre), primary murine T cell stimulation, migration assay to S1PR1 ligands, KLF2 and S1PR1 expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with functional migration readout, pathway placement established by epistasis, single lab","pmids":["22334704"],"is_preprint":false},{"year":2004,"finding":"S1P1 (S1PR1) signaling in the developing vasculature regulates limb development non-cell-autonomously: loss of S1P1 in endothelium causes HIF-1α and VEGF induction in limbs (but not in embryonic fibroblasts), leading to hyperplastic vasculature and defective digit/chondrocyte morphogenesis; endothelium-specific S1P1 null mice recapitulate limb defects.","method":"Whole-body and endothelium-specific S1p1 KO mice, HIF-1α/VEGF immunostaining, limb histology","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO, non-cell-autonomous mechanism demonstrated by comparison of whole-body vs. endothelial KO","pmids":["15063179"],"is_preprint":false},{"year":2016,"finding":"T cell-intrinsic S1PR1 is required for effector T cell entry into lymphatic sinuses and egress from draining lymph nodes during infection; using inducible T cell-specific S1PR1 KO, WT and S1PR1-deficient effector T cells both migrate to sinus-adjacent positions but only WT T cells enter sinuses, even when CCR7 retention signals are downregulated.","method":"Inducible T cell-specific S1PR1 gene deletion, intravital two-photon microscopy of lymph node, viral infection model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible conditional KO with direct intravital imaging, mechanistic epistasis with CCR7","pmids":["26862175"],"is_preprint":false},{"year":2019,"finding":"CD4 T cell S1PR1 and S1PR4, and endothelial cell S1PR2, are each required for T cell migration across lymphatic endothelial cells (LECs) and into afferent lymphatic vessels and draining lymph nodes; S1PR1 and S1PR4 differentially regulate T cell motility and VCAM-1 binding; S1PR2 in LECs regulates VE-cadherin, occludin, and zonulin-1 expression via ERK.","method":"Receptor-specific KO and blockade, transwell migration assay across LECs, intravital imaging, VCAM-1 binding assay, VE-cadherin/occludin/ZO-1 immunostaining","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple receptor-specific KO models, functional migration assay, junction molecule mechanistic readouts","pmids":["30877143"],"is_preprint":false},{"year":2012,"finding":"HGF activates S1PR1 transactivation via c-Met: c-Met, S1PR1, and integrin β4 (ITGB4) are recruited to caveolin-enriched lipid rafts upon HGF treatment; co-immunoprecipitation shows direct c-Met interaction with both S1PR1 and ITGB4; S1PR1 siRNA attenuates ITGB4 and Rac1 activation, c-Met/ITGB4 interaction, and transendothelial electrical resistance.","method":"Co-immunoprecipitation, lipid raft fractionation, siRNA knockdown of S1PR1 and ITGB4, Rac1 activation assay, transendothelial electrical resistance measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP demonstrating protein complex, siRNA knockdown with multiple functional readouts","pmids":["23212923"],"is_preprint":false},{"year":2016,"finding":"S1PR1 regulates lymphatic vascular quiescence by antagonizing laminar shear stress (LSS)-mediated VEGF-C/VEGFR3 signaling; S1PR1 inhibits RhoA activity to promote membrane localization of claudin-5 (tight junction molecule); S1pr1 loss in LECs induces hypersprouting rescued by reducing Vegfr3 gene dosage in vivo.","method":"LEC-specific S1pr1 KO, Vegfr3 heterozygous rescue genetics, in vitro LSS experiments, RhoA activation assay, claudin-5 membrane localization","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue epistasis in vivo, biochemical RhoA assay, junction protein localization","pmids":["32544090"],"is_preprint":false},{"year":2017,"finding":"S1PR1 signaling in tumor-associated macrophages (TAMs) promotes lymphangiogenesis and pulmonary metastasis via NLRP3 inflammasome activation and IL-1β production; macrophage-specific S1pr1 deletion reduces Nlrp3 expression in TAMs and prevents tumor lymphangiogenesis and metastasis; macrophage-dependent lymphangiogenesis in vitro requires both S1PR1 signaling and IL-1β production.","method":"CD11b+ macrophage-specific S1pr1 KO mouse, transcriptome analysis of isolated TAMs, in vitro lymphangiogenesis assay, inflammasome activation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO, transcriptomic + in vitro mechanistic validation, two tumor model systems","pmids":["28739604"],"is_preprint":false},{"year":2021,"finding":"S1PR1 limits apoptosis in T cells by maintaining BCL2 family member balance via restraint of JNK activity; the same intracellular residues enabling S1PR1 internalization are required to prevent the proapoptotic cascade; this is distinct from S1PR1's role in directing egress.","method":"Mouse genetic models (S1PR1 internalization-deficient mutants), JNK activity assay, BCL2 family member expression, T cell survival assay; findings confirmed in ozanimod-treated ulcerative colitis patients","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mutagenesis of receptor internalization residues, JNK pathway dissection, murine and human patient validation","pmids":["38194271"],"is_preprint":false},{"year":2013,"finding":"β1-adrenergic receptor (β1AR) and S1PR1 physically interact and show reciprocal cross-regulation: S1PR1 agonist (S1P) can induce β1AR downregulation, and β-AR agonist (isoproterenol) can induce S1PR1 downregulation; G-protein-coupled receptor kinase-2 (GRK2) is involved; this cross-talk is observed in mouse hearts under chronic β-AR stimulation and in a rat heart failure model.","method":"HEK293 cells overexpressing both receptors, receptor downregulation assays, co-immunoprecipitation, in vivo mouse cardiac model, rat heart failure model","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP + cross-stimulation experiments in vitro and in vivo, single lab","pmids":["23969695"],"is_preprint":false},{"year":1998,"finding":"Lysophosphatidic acid (LPA) is a low-affinity agonist for EDG-1 (S1PR1): LPA binds with Kd ~2.3 μM (vs ~8 nM for S1P), induces receptor phosphorylation, MAP kinase activation, and Rho-dependent morphogenesis.","method":"Radioligand binding assay, receptor phosphorylation assay, MAP kinase assay, morphological analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding with Kd measurement, functional signaling assays, single lab","pmids":["9705355"],"is_preprint":false},{"year":2001,"finding":"PDGF-induced focal adhesion formation and activation of FAK, Src, and p38 are dysregulated in EDG-1-null fibroblasts; PDGF-induced lamellipodia extension and cell motility are abrogated in EDG-1-null cells; in contrast, mitogenesis, survival responses, and ERK1/2 activation by PDGF or S1P are unaffected by EDG-1 deletion, indicating EDG-1 is required for cytoskeletal integration but not growth signals.","method":"EDG-1-null fibroblasts, FAK/Src/p38 kinase activation assays, lamellipodia observation, cell motility assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with biochemical and morphological readouts, clear separation of cytoskeletal vs. growth signaling outputs","pmids":["11726541"],"is_preprint":false},{"year":2016,"finding":"miR302-367 elevation in endothelial cells promotes vascular stability and reduces sprouting angiogenesis via an Erk1/2-Klf2-S1pr1 pathway: downregulation of Erk1/2 increases Klf2, which induces S1pr1 and its target VE-cadherin; pharmacological blockade or genetic deletion of S1pr1 in ECs reverses the antiangiogenic effect of miR302-367.","method":"miRNA overexpression in ECs, retinal vascular assay, endothelial-specific S1pr1 deletion, ERK/KLF2/S1PR1/VE-cadherin expression and function assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis validated by genetic S1pr1 deletion rescue + pharmacological blockade, pathway defined by multiple manipulations","pmids":["27756792"],"is_preprint":false},{"year":2017,"finding":"S1PR1 signaling in endothelial cells controls blood pressure and flow-mediated mechanotransduction: endothelial-specific S1PR1 deletion decreases basal and stimulated eNOS-derived nitric oxide and elevates baseline blood pressure; FTY720 (functional S1PR1 antagonist) markedly decreases endothelial S1PR1, increases blood pressure in control mice, and exacerbates angiotensin II-induced hypertension.","method":"Endothelial-specific S1PR1 KO mice, eNOS activity assay, blood pressure measurement, FTY720 pharmacological treatment, angiotensin II hypertension model","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelial-specific KO + pharmacological validation in multiple models, mechanistic eNOS assay","pmids":["28607130"],"is_preprint":false},{"year":2016,"finding":"S1P in HDL promotes physical interaction between SR-BI and S1PR1 on the plasma membrane; HDL-derived S1P initiates S1PR1 internalization and intracellular calcium flux; HDL without supplemented S1P did not trigger these responses, establishing S1P as the active component mediating HDL-induced S1PR1 activation and SR-BI/S1PR1 interaction.","method":"Protein-fragment complementation assay (SR-BI/S1PR1 interaction), confocal microscopy, calcium flux assay, recombinant HDL particles ± S1P, primary vascular smooth muscle cells and HEK293 cells","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complementation assay + calcium flux + confocal colocalization, single lab","pmids":["27881715"],"is_preprint":false},{"year":2021,"finding":"aPC/PAR1 anti-apoptotic signaling is mediated by a discrete β-arrestin-2-SphK1-S1PR1-Akt axis in endothelial cells: aPC activates PAR1 to engage β-arr2, which activates SphK1 independent of Dvl2, leading to S1PR1 transactivation and Akt-dependent cell survival; endogenous PAR1 and S1PR1 co-reside in caveolin-1-rich microdomains, and Cav1 is required for this pathway.","method":"Endothelial cell siRNA knockdown of β-arr2, SphK1, S1PR1, Cav1; co-immunoprecipitation; Akt phosphorylation; cell apoptosis assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple siRNA knockdowns with functional apoptosis readout, co-IP, pathway epistasis established","pmids":["34873055"],"is_preprint":false},{"year":2014,"finding":"S1P/S1PR1 signaling in hypothalamic POMC neurons activates STAT3 and the melanocortin system to reduce food intake and increase energy expenditure; STAT3 controls S1PR1 expression in neurons via a positive feedback; selective disruption of hypothalamic S1PR1 increases food intake and reduces respiratory exchange ratio.","method":"Intracerebroventricular S1P injection, hypothalamic S1PR1-selective disruption in rodents, STAT3 activity assay, food intake and energy expenditure measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct CNS injection, regional gene disruption, STAT3 pathway validation, multiple physiological readouts","pmids":["25255053"],"is_preprint":false},{"year":2020,"finding":"STAT1 transcriptionally regulates S1PR1 expression by binding its promoter in the region -29 to -12 bp upstream of TSS; STAT1 knockdown reduces S1PR1 expression, STAT1 overexpression upregulates it, and IFN-γ activation of STAT1 increases S1PR1 mRNA and protein; confirmed by EMSA and ChIP assays.","method":"STAT1 siRNA knockdown, STAT1 overexpression, EMSA, ChIP assay at S1PR1 promoter, luciferase reporter assay with truncated promoter fragments, IFN-γ stimulation","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — EMSA + ChIP + functional promoter reporter + gain- and loss-of-function in single study","pmids":["32006593"],"is_preprint":false},{"year":2021,"finding":"SMYD3 promotes S1PR1 expression in hepatocellular carcinoma by methylating histone H3 at lysine 4 (H3K4me3) at the S1PR1 promoter; SMYD3 expression is positively correlated with S1PR1 in HCC and promotes HCC cell growth and migration in a manner partially dependent on S1PR1 upregulation.","method":"Chromatin immunoprecipitation (H3K4me3 at S1PR1 promoter), SMYD3 overexpression/knockdown, S1PR1 promoter activity assay, in vitro and in vivo tumor growth assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with histone mark at S1PR1 promoter, gain/loss of function, single lab","pmids":["34301921"],"is_preprint":false},{"year":2023,"finding":"S1PR1 directly activates STAT3 in esophageal squamous cell carcinoma cells: co-immunoprecipitation demonstrates direct binding of S1PR1 and STAT3; S1PR1 silencing reduces STAT3 phosphorylation (p-STAT3), while S1PR1 overexpression increases p-STAT3 and promotes proliferation and suppresses apoptosis.","method":"Co-immunoprecipitation (S1PR1-STAT3 interaction), siRNA knockdown, S1PR1 overexpression, STAT3 phosphorylation western blot, in vitro and in vivo tumor assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single co-IP + functional KD/OE readouts, single lab","pmids":["31438989"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, loss of s1pr1 disrupts astrocyte process elaboration and extension/retraction dynamics; pharmacological modulation of S1pr1 balances astrocyte process growth; functional analog of Drosophila Tre1, with loss of either causing motor behavioral defects.","method":"s1pr1 loss-of-function in zebrafish, live imaging of astrocyte process dynamics, pharmacological S1PR1 modulation, behavioral assays","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in zebrafish with live imaging and pharmacology; ortholog evidence but not in mammalian cells","pmids":["38096817"],"is_preprint":false},{"year":2019,"finding":"Endothelial S1PR1 activates the AKT/eNOS signaling pathway, producing nitric oxide that inhibits cardiomyocyte hypertrophy and cardiac fibroblast transformation; endothelial-specific S1pr1 deletion aggravates pressure overload-induced cardiac hypertrophy and fibrosis; inhibition of AKT/eNOS reverses S1pr1-overexpression-mediated protection.","method":"Endothelial-specific S1pr1 KO (TAC model), S1pr1 overexpression, AKT/eNOS phosphorylation assay, NO production measurement, AKT inhibitor epistasis","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — endothelial KO + overexpression + pathway inhibitor epistasis, multiple cardiac phenotype readouts","pmids":["31854513"],"is_preprint":false}],"current_model":"S1PR1 (EDG-1) is a Gi-coupled GPCR that binds sphingosine-1-phosphate with high affinity (~8 nM Kd) and signals exclusively through Gi (not Gq, G12/13) to activate MAP kinase, inhibit cAMP, and promote Rac-dependent cytoskeletal rearrangements required for cell migration, vascular maturation, and lymphocyte egress; receptor activity is regulated by Akt-mediated phosphorylation at T236 (enabling Rac activation and chemotaxis), tyrosine-143 phosphorylation (controlling receptor internalization/recycling), N-glycosylation at Asn30 (required for internalization and caveolae association), and interaction with CD69 (a transmembrane protein agonist that activates S1PR1-Gi to drive internalization and block lymphocyte egress); the receptor forms a positive feedback loop with STAT3 (STAT3 drives S1PR1 transcription, S1PR1 sustains STAT3 via JAK2), localizes to caveolin-1-enriched caveolae where it is subject to caveolin-1 inhibitory interactions, and in endothelial cells activates eNOS via AKT to regulate vascular tone and blood pressure."},"narrative":{"mechanistic_narrative":"S1PR1 (EDG-1) is a high-affinity (~8 nM Kd) G protein-coupled receptor for sphingosine-1-phosphate that signals exclusively through the Gi family to control cell migration, vascular integrity, and lymphocyte trafficking [PMID:9488656, PMID:10488065]. Its third intracellular loop binds Giα/Goα in a GTPγS-sensitive manner, and ligand engagement inhibits adenylate cyclase and drives sustained, pertussis toxin-sensitive MAP kinase activation without coupling to Gq, G12, or G13 [PMID:9660876, PMID:8626678, PMID:10383399]. A defining output is Gi-dependent activation of the small GTPase Rac, which is required for cortical actin assembly, lamellipodia formation, and chemotaxis; Rac activation additionally requires Akt-mediated phosphorylation of the receptor at T236, while cytoskeletal integration of growth factor cues (PDGF, HGF, aPC/PAR1) proceeds through S1PR1 transactivation downstream of sphingosine kinase and β-arrestin [PMID:11032855, PMID:11583630, PMID:11230698, PMID:23212923, PMID:34873055]. Genetic deletion is embryonic lethal from vascular hemorrhage due to defective mural-cell coverage, and in endothelium S1PR1 stabilizes VE-cadherin junctions, restrains VEGF/VEGFR3-driven sprouting via RhoA inhibition, and activates AKT/eNOS to set vascular tone and blood pressure [PMID:11032855, PMID:22975327, PMID:32544090, PMID:28607130, PMID:31854513]. In the immune system, S1PR1 senses S1P gradients to drive lymphocyte egress from thymus and lymph nodes, a function dependent on dynamin 2-mediated internalization/recycling that sustains signaling [PMID:24638168, PMID:26862175]. Receptor trafficking is governed by an essential C-terminal domain, N-glycosylation at Asn30 (required for internalization and caveolae targeting), and tyrosine-143 phosphorylation; CD69 acts as a cis transmembrane protein agonist contacting TM4 to allosterically activate the receptor and drive internalization that blocks egress [PMID:10198065, PMID:12087059, PMID:25588843, PMID:37039481]. S1PR1 resides in caveolin-1-enriched caveolae where caveolin-1 inhibits its signaling, and it forms a STAT3-driven positive feedback loop (via JAK2/IL-6) that sustains STAT3 activity in tumors and hypothalamic neurons [PMID:10921915, PMID:21102457, PMID:25255053]. Cryo-EM structures of S1PR1-Gi complexes define agonist binding modes and the activation switch [PMID:34526663].","teleology":[{"year":1996,"claim":"Established that the orphan receptor EDG-1 engages inhibitory G proteins through a defined cytosolic interface, providing the first mechanistic link to a signaling output.","evidence":"Co-IP and GTPγS competition mapping i3 loop association with Giα/Goα plus pertussis toxin-sensitive MAPK assays","pmids":["8626678"],"confidence":"High","gaps":["Endogenous ligand not yet known at this point","No structural detail of coupling"]},{"year":1998,"claim":"Identified S1P as the high-affinity physiological ligand and showed receptor engagement drives Gi-restricted cAMP inhibition and Rho-dependent morphogenesis, defining EDG-1 as the S1P receptor.","evidence":"Radioligand binding (Kd ~8 nM), heterologous expression with cAMP/MAPK assays, pertussis toxin dissection","pmids":["9488656","9660876","9480864","9705355"],"confidence":"High","gaps":["LPA acts only as a low-affinity agonist; physiological relevance unclear","Selectivity among Gi members not yet resolved"]},{"year":1999,"claim":"Resolved that S1PR1 couples exclusively to Gi (not Gq/G12/G13), distinguishing it from sibling S1P receptors and explaining its calcium-silent, migration-centric signaling.","evidence":"Subunit-selective [35S]GTPγS binding in Sf9/HEK293 and Xenopus oocyte chimeric Gαqi complementation","pmids":["10488065","10383399"],"confidence":"High","gaps":["Downstream effectors of Gi not fully enumerated","Does not address receptor trafficking"]},{"year":2000,"claim":"Demonstrated S1PR1 is essential for vascular maturation in vivo and links receptor activity to Rac-dependent migration, defining its developmental role.","evidence":"Edg1-/- mouse knockout with vascular histology and Rac activation assays; caveolae fractionation showing caveolin-1 interaction","pmids":["11032855","10921915"],"confidence":"High","gaps":["Cell-type-specific contributions not separated","How caveolin-1 inhibits signaling mechanistically unresolved"]},{"year":2001,"claim":"Defined Akt phosphorylation at T236 as a switch enabling Rac activation and chemotaxis, and established S1PR1 as the obligatory transactivation node for PDGF-driven cytoskeletal remodeling.","evidence":"Site-directed mutagenesis (T236A dominant-negative), Akt-receptor binding, β-arrestin translocation, EDG-1-null fibroblast chemotaxis and FAK/Src/p38 assays","pmids":["11583630","11230698","11726541","11150298","11557736"],"confidence":"High","gaps":["Whether T236 phosphorylation is direct in vivo across cell types","Integration of Rho vs Rac outputs context-dependent"]},{"year":2002,"claim":"Mapped receptor trafficking determinants — C-terminus and Asn30 N-glycosylation — required for ligand-induced internalization and caveolae targeting.","evidence":"GFP-chimera live imaging, C-terminal truncation, N30D glycosylation mutant with binding/MAPK/internalization assays","pmids":["10198065","12087059"],"confidence":"High","gaps":["Specific endocytic adaptors not identified at this stage","Functional consequence of recycling for signaling not yet defined"]},{"year":2010,"claim":"Revealed a STAT3–S1PR1 positive feedback loop that sustains persistent STAT3 activity, linking the receptor to tumor growth and metastasis.","evidence":"S1PR1 siRNA, STAT3 reporter, JAK2 kinase activity, IL-6 ELISA and in vivo tumor models","pmids":["21102457"],"confidence":"High","gaps":["Whether S1PR1-STAT3 coupling is direct or indirect via JAK2/IL-6","Generality across tumor types"]},{"year":2012,"claim":"Established endothelial S1PR1 as a brake on sprouting angiogenesis through VE-cadherin stabilization and VEGF antagonism, and showed it directs proplatelet shedding in megakaryocytes.","evidence":"Endothelial and megakaryocyte conditional S1pr1 deletion, VE-cadherin imaging, intravital bone marrow microscopy; c-Met/ITGB4 co-IP transactivation","pmids":["22975327","23148237","23212923"],"confidence":"High","gaps":["Quantitative balance between S1PR1 quiescence and VEGF sprouting cues unclear","Tissue-specific signaling differences not unified"]},{"year":2015,"claim":"Identified tyrosine-143 phosphorylation as the controller of internalization-recycling cycling in endothelial cells.","evidence":"Y143F/Y143D mutagenesis with flow cytometry internalization and barrier resistance assays","pmids":["25588843"],"confidence":"High","gaps":["Kinase responsible for Y143 phosphorylation unidentified","Relationship between Y143 and C-terminal serine phosphorylation"]},{"year":2016,"claim":"Showed that sustained S1PR1 signaling via dynamin 2-dependent internalization/recycling is the mechanistic basis for lymphocyte egress and that the receptor suppresses type I IFN amplification in pDCs.","evidence":"Dynamin 2 conditional KO with S1PR1 transgenic rescue, inducible T cell S1PR1 KO with intravital imaging, Tat-peptide internalization blockade and IFNAR1 turnover assays","pmids":["24638168","26862175","26787880","22334704","30877143"],"confidence":"High","gaps":["Precise signal duration required for egress not quantified","How CCR7 and S1PR1 signals are integrated at sinus entry"]},{"year":2017,"claim":"Connected endothelial S1PR1/eNOS signaling to blood pressure control and tissue repair, and revealed pro-tumor inflammasome signaling in macrophages.","evidence":"Endothelial-specific KO with eNOS/blood pressure measurement, FTY720 pharmacology, macrophage-specific S1pr1 KO with NLRP3/IL-1β and lymphangiogenesis readouts, ERK/CSF1 epistasis","pmids":["28607130","30877143","28739604","32091582"],"confidence":"High","gaps":["Cell-context determinants of pro- vs anti-tumor outcomes unresolved","Mechanism linking Gi to eNOS not fully detailed"]},{"year":2021,"claim":"Provided atomic-resolution structures of S1PR1-Gi complexes defining agonist binding and activation, and dissected an aPC/PAR1-β-arrestin2-SphK1-S1PR1-Akt survival axis and an anti-apoptotic JNK/BCL2 role.","evidence":"Cryo-EM of S1PR1-Gi with multiple agonists; endothelial siRNA epistasis for the aPC/PAR1 axis; receptor internalization-deficient mouse mutants with JNK/BCL2 and patient validation","pmids":["34526663","34873055","38194271"],"confidence":"High","gaps":["Structural basis of biased/β-arrestin signaling not captured","How internalization residues couple to JNK restraint mechanistically"]},{"year":2023,"claim":"Solved the structural and functional basis for CD69 acting as a cis transmembrane protein agonist that drives S1PR1 internalization to block egress, and confirmed direct S1PR1-STAT3 binding in carcinoma.","evidence":"Cryo-EM of CD69-S1PR1-Gi with interface mutagenesis, internalization and egress assays; S1PR1-STAT3 co-IP with KD/OE tumor assays; zebrafish s1pr1 loss in astrocytes","pmids":["37039481","31438989","38096817"],"confidence":"High","gaps":["Whether STAT3 binding is truly direct rests on single co-IP studies","CNS/glial roles characterized only in non-mammalian models"]},{"year":null,"claim":"How the multiple transcriptional inputs (STAT1, STAT3, KLF2, SMYD3/H3K4me3) and post-translational modifications are integrated to set S1PR1 surface density and signaling output in a given cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of receptor abundance control across tissues","Kinases for individual phosphosites incompletely identified","Biased signaling between Gi and β-arrestin arms not structurally defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,11,22]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,33,37]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,9,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,9,12,28]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,17,21]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,18,26,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,14,25,29]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[15]}],"complexes":[],"partners":["GNAI1","GNAI3","CAV1","AKT1","CD69","MET","ITGB4","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P21453","full_name":"Sphingosine 1-phosphate receptor 1","aliases":["Endothelial differentiation G-protein coupled receptor 1","Sphingosine 1-phosphate receptor Edg-1","S1P receptor Edg-1"],"length_aa":382,"mass_kda":42.8,"function":"G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury","subcellular_location":"Cell membrane; Endosome; Membrane raft","url":"https://www.uniprot.org/uniprotkb/P21453/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/S1PR1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/S1PR1","total_profiled":1310},"omim":[{"mim_id":"613492","title":"ALKALINE CERAMIDASE 2; ACER2","url":"https://www.omim.org/entry/613492"},{"mim_id":"612584","title":"SPHINGOLIPID TRANSPORTER 2; SPNS2","url":"https://www.omim.org/entry/612584"},{"mim_id":"608863","title":"PODOPLANIN; PDPN","url":"https://www.omim.org/entry/608863"},{"mim_id":"607092","title":"SPHINGOSINE KINASE 2; SPHK2","url":"https://www.omim.org/entry/607092"},{"mim_id":"606783","title":"C-TYPE LECTIN DOMAIN FAMILY 1, MEMBER B; CLEC1B","url":"https://www.omim.org/entry/606783"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/S1PR1"},"hgnc":{"alias_symbol":["edg-1","D1S3362","CD363"],"prev_symbol":["EDG1"]},"alphafold":{"accession":"P21453","domains":[{"cath_id":"1.20.1070.10","chopping":"31-330","consensus_level":"high","plddt":88.8441,"start":31,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21453","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21453-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21453-F1-predicted_aligned_error_v6.png","plddt_mean":81.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=S1PR1","jax_strain_url":"https://www.jax.org/strain/search?query=S1PR1"},"sequence":{"accession":"P21453","fasta_url":"https://rest.uniprot.org/uniprotkb/P21453.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21453/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21453"}},"corpus_meta":[{"pmid":"11032855","id":"PMC_11032855","title":"Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation.","date":"2000","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11032855","citation_count":978,"is_preprint":false},{"pmid":"9488656","id":"PMC_9488656","title":"Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1.","date":"1998","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9488656","citation_count":854,"is_preprint":false},{"pmid":"9660876","id":"PMC_9660876","title":"Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9660876","citation_count":427,"is_preprint":false},{"pmid":"11230698","id":"PMC_11230698","title":"Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility.","date":"2001","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11230698","citation_count":370,"is_preprint":false},{"pmid":"21102457","id":"PMC_21102457","title":"STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors.","date":"2010","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21102457","citation_count":342,"is_preprint":false},{"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":"22975327","id":"PMC_22975327","title":"The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2.","date":"2012","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22975327","citation_count":271,"is_preprint":false},{"pmid":"11583630","id":"PMC_11583630","title":"Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis.","date":"2001","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/11583630","citation_count":265,"is_preprint":false},{"pmid":"11150298","id":"PMC_11150298","title":"Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of alpha vbeta3- and beta1-containing integrins.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11150298","citation_count":257,"is_preprint":false},{"pmid":"28739604","id":"PMC_28739604","title":"S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β.","date":"2017","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28739604","citation_count":236,"is_preprint":false},{"pmid":"9480864","id":"PMC_9480864","title":"Sphingosine 1-phosphate signalling through the G-protein-coupled receptor Edg-1.","date":"1998","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9480864","citation_count":233,"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 chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10383399","citation_count":226,"is_preprint":false},{"pmid":"10794715","id":"PMC_10794715","title":"Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10794715","citation_count":197,"is_preprint":false},{"pmid":"10198065","id":"PMC_10198065","title":"Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1.","date":"1999","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/10198065","citation_count":169,"is_preprint":false},{"pmid":"8626678","id":"PMC_8626678","title":"The inducible G protein-coupled receptor edg-1 signals via the G(i)/mitogen-activated protein kinase pathway.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8626678","citation_count":153,"is_preprint":false},{"pmid":"11557736","id":"PMC_11557736","title":"Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration.","date":"2001","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/11557736","citation_count":148,"is_preprint":false},{"pmid":"11726541","id":"PMC_11726541","title":"EDG-1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration.","date":"2001","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/11726541","citation_count":140,"is_preprint":false},{"pmid":"10921915","id":"PMC_10921915","title":"Agonist-modulated targeting of the EDG-1 receptor to plasmalemmal caveolae. eNOS activation by sphingosine 1-phosphate and the role of caveolin-1 in sphingolipid signal transduction.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10921915","citation_count":133,"is_preprint":false},{"pmid":"23148237","id":"PMC_23148237","title":"A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis.","date":"2012","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23148237","citation_count":128,"is_preprint":false},{"pmid":"28607130","id":"PMC_28607130","title":"S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure.","date":"2017","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/28607130","citation_count":114,"is_preprint":false},{"pmid":"9705355","id":"PMC_9705355","title":"Lysophosphatidic acid stimulates the G-protein-coupled receptor EDG-1 as a low affinity agonist.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9705355","citation_count":107,"is_preprint":false},{"pmid":"26856814","id":"PMC_26856814","title":"The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures.","date":"2016","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/26856814","citation_count":105,"is_preprint":false},{"pmid":"30877143","id":"PMC_30877143","title":"CD4 T cell sphingosine 1-phosphate receptor (S1PR)1 and S1PR4 and endothelial S1PR2 regulate afferent lymphatic migration.","date":"2019","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30877143","citation_count":81,"is_preprint":false},{"pmid":"37251708","id":"PMC_37251708","title":"Sphingosine-1-phosphate derived from PRP-Exos promotes angiogenesis in diabetic wound healing via the S1PR1/AKT/FN1 signalling pathway.","date":"2023","source":"Burns & trauma","url":"https://pubmed.ncbi.nlm.nih.gov/37251708","citation_count":77,"is_preprint":false},{"pmid":"29790626","id":"PMC_29790626","title":"Sphingosine-1-phosphate promotes the proliferation and attenuates apoptosis of Endothelial progenitor cells via S1PR1/S1PR3/PI3K/Akt pathway.","date":"2018","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/29790626","citation_count":71,"is_preprint":false},{"pmid":"34526663","id":"PMC_34526663","title":"Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition.","date":"2021","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34526663","citation_count":71,"is_preprint":false},{"pmid":"11673450","id":"PMC_11673450","title":"Sphingosine 1-phosphate activates nuclear factor-kappa B through Edg receptors. Activation through Edg-3 and Edg-5, but not Edg-1, in human embryonic kidney 293 cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11673450","citation_count":69,"is_preprint":false},{"pmid":"24631531","id":"PMC_24631531","title":"MicroRNA-363-mediated downregulation of S1PR1 suppresses the proliferation of hepatocellular carcinoma cells.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24631531","citation_count":67,"is_preprint":false},{"pmid":"12087059","id":"PMC_12087059","title":"N-glycans of sphingosine 1-phosphate receptor Edg-1 regulate ligand-induced receptor internalization.","date":"2002","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/12087059","citation_count":66,"is_preprint":false},{"pmid":"9226368","id":"PMC_9226368","title":"The mouse gene for the inducible G-protein-coupled receptor edg-1.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9226368","citation_count":65,"is_preprint":false},{"pmid":"26862175","id":"PMC_26862175","title":"T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26862175","citation_count":65,"is_preprint":false},{"pmid":"30083262","id":"PMC_30083262","title":"Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine.","date":"2018","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/30083262","citation_count":63,"is_preprint":false},{"pmid":"23969695","id":"PMC_23969695","title":"β1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: protective role of S1PR1 cardiac gene therapy.","date":"2013","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/23969695","citation_count":62,"is_preprint":false},{"pmid":"25255053","id":"PMC_25255053","title":"Hypothalamic S1P/S1PR1 axis controls energy homeostasis.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25255053","citation_count":61,"is_preprint":false},{"pmid":"28570482","id":"PMC_28570482","title":"Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation.","date":"2017","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/28570482","citation_count":61,"is_preprint":false},{"pmid":"31115798","id":"PMC_31115798","title":"S1PR1 as a Novel Promising Therapeutic Target in Cancer Therapy.","date":"2019","source":"Molecular diagnosis & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31115798","citation_count":60,"is_preprint":false},{"pmid":"32544090","id":"PMC_32544090","title":"S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling.","date":"2020","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/32544090","citation_count":59,"is_preprint":false},{"pmid":"10818441","id":"PMC_10818441","title":"Sphingosine 1-phosphate: a ligand for the EDG-1 family of G-protein-coupled receptors.","date":"2000","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/10818441","citation_count":57,"is_preprint":false},{"pmid":"15063179","id":"PMC_15063179","title":"Regulation of limb development by the sphingosine 1-phosphate receptor S1p1/EDG-1 occurs via the hypoxia/VEGF axis.","date":"2004","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15063179","citation_count":57,"is_preprint":false},{"pmid":"26787880","id":"PMC_26787880","title":"S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26787880","citation_count":55,"is_preprint":false},{"pmid":"30377291","id":"PMC_30377291","title":"Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30377291","citation_count":55,"is_preprint":false},{"pmid":"29377379","id":"PMC_29377379","title":"SPHK1-S1PR1-RANKL Axis Regulates the Interactions Between Macrophages and BMSCs in Inflammatory Bone Loss.","date":"2018","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/29377379","citation_count":53,"is_preprint":false},{"pmid":"15063151","id":"PMC_15063151","title":"Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1.","date":"2004","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15063151","citation_count":51,"is_preprint":false},{"pmid":"32091582","id":"PMC_32091582","title":"Vascular endothelial S1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction.","date":"2021","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/32091582","citation_count":51,"is_preprint":false},{"pmid":"26975859","id":"PMC_26975859","title":"PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis.","date":"2016","source":"Molecular imaging and biology","url":"https://pubmed.ncbi.nlm.nih.gov/26975859","citation_count":49,"is_preprint":false},{"pmid":"10971577","id":"PMC_10971577","title":"Expression and characterization of Edg-1 receptors in rat cardiomyocytes: calcium deregulation in response to sphingosine 1-phosphate.","date":"2000","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10971577","citation_count":47,"is_preprint":false},{"pmid":"31438989","id":"PMC_31438989","title":"S1PR1 promotes proliferation and inhibits apoptosis of esophageal squamous cell carcinoma through activating STAT3 pathway.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31438989","citation_count":45,"is_preprint":false},{"pmid":"20844107","id":"PMC_20844107","title":"The sphingosine 1-phosphate receptor, S1PR₁, plays a prominent but not exclusive role in enhancing the excitability of sensory neurons.","date":"2010","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/20844107","citation_count":45,"is_preprint":false},{"pmid":"10818438","id":"PMC_10818438","title":"Sphingosine-1-phosphate signaling via the EDG-1 family of G-protein-coupled receptors.","date":"2000","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/10818438","citation_count":42,"is_preprint":false},{"pmid":"11146117","id":"PMC_11146117","title":"Differential roles of Edg-1 and Edg-5, sphingosine 1-phosphate receptors, in the signaling pathways in C6 glioma cells.","date":"2000","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/11146117","citation_count":42,"is_preprint":false},{"pmid":"27756792","id":"PMC_27756792","title":"A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability.","date":"2016","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/27756792","citation_count":42,"is_preprint":false},{"pmid":"11709084","id":"PMC_11709084","title":"The sphingosine-1-phosphate receptor EDG-1 is essential for platelet-derived growth factor-induced cell motility.","date":"2001","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/11709084","citation_count":41,"is_preprint":false},{"pmid":"24638168","id":"PMC_24638168","title":"Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling.","date":"2014","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24638168","citation_count":41,"is_preprint":false},{"pmid":"31854513","id":"PMC_31854513","title":"Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31854513","citation_count":40,"is_preprint":false},{"pmid":"27881715","id":"PMC_27881715","title":"S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization.","date":"2016","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/27881715","citation_count":40,"is_preprint":false},{"pmid":"36068200","id":"PMC_36068200","title":"S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36068200","citation_count":38,"is_preprint":false},{"pmid":"30814488","id":"PMC_30814488","title":"S1PR1 regulates the switch of two angiogenic modes by VE-cadherin phosphorylation in breast cancer.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30814488","citation_count":36,"is_preprint":false},{"pmid":"23212923","id":"PMC_23212923","title":"Critical role of S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23212923","citation_count":36,"is_preprint":false},{"pmid":"31293578","id":"PMC_31293578","title":"S1P-S1PR1 Signaling: the \"Sphinx\" in Osteoimmunology.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31293578","citation_count":35,"is_preprint":false},{"pmid":"29608575","id":"PMC_29608575","title":"Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29608575","citation_count":35,"is_preprint":false},{"pmid":"30476824","id":"PMC_30476824","title":"S1P promotes inflammation-induced tube formation by HLECs via the S1PR1/NF-κB pathway.","date":"2018","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30476824","citation_count":34,"is_preprint":false},{"pmid":"36071219","id":"PMC_36071219","title":"S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission.","date":"2022","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36071219","citation_count":33,"is_preprint":false},{"pmid":"34516079","id":"PMC_34516079","title":"InVitro and In Vivo Investigation of S1PR1 Expression in the Central Nervous System Using [3H]CS1P1 and [11C]CS1P1.","date":"2021","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/34516079","citation_count":33,"is_preprint":false},{"pmid":"32585303","id":"PMC_32585303","title":"Post-translational modifications of S1PR1 and endothelial barrier regulation.","date":"2020","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/32585303","citation_count":31,"is_preprint":false},{"pmid":"30918324","id":"PMC_30918324","title":"Combination of sphingosine-1-phosphate receptor 1 (S1PR1) agonist and antiviral drug: a potential therapy against pathogenic influenza virus.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30918324","citation_count":31,"is_preprint":false},{"pmid":"7959012","id":"PMC_7959012","title":"Cloning of the rat edg-1 immediate-early gene: expression pattern suggests diverse functions.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7959012","citation_count":31,"is_preprint":false},{"pmid":"37039481","id":"PMC_37039481","title":"Transmembrane protein CD69 acts as an S1PR1 agonist.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37039481","citation_count":30,"is_preprint":false},{"pmid":"34873055","id":"PMC_34873055","title":"aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34873055","citation_count":29,"is_preprint":false},{"pmid":"32562552","id":"PMC_32562552","title":"Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy.","date":"2020","source":"Clinical pharmacology and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32562552","citation_count":28,"is_preprint":false},{"pmid":"34109517","id":"PMC_34109517","title":"Blocking SphK1/S1P/S1PR1 Signaling Pathway Alleviates Lung Injury Caused by Sepsis in Acute Ethanol Intoxication Mice.","date":"2021","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34109517","citation_count":28,"is_preprint":false},{"pmid":"25588843","id":"PMC_25588843","title":"S1PR1 Tyr143 phosphorylation downregulates endothelial cell surface S1PR1 expression and responsiveness.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25588843","citation_count":26,"is_preprint":false},{"pmid":"22334704","id":"PMC_22334704","title":"CCR7/CCL19 controls expression of EDG-1 in T cells.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22334704","citation_count":26,"is_preprint":false},{"pmid":"37012886","id":"PMC_37012886","title":"Dexmedetomidine alleviates oxidative stress and mitochondrial dysfunction in diabetic peripheral neuropathy via the microRNA-34a/SIRT2/S1PR1 axis.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37012886","citation_count":26,"is_preprint":false},{"pmid":"25188412","id":"PMC_25188412","title":"Sphingosine-1-phosphate promotes extravillous trophoblast cell invasion by activating MEK/ERK/MMP-2 signaling pathways via S1P/S1PR1 axis activation.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25188412","citation_count":26,"is_preprint":false},{"pmid":"28399143","id":"PMC_28399143","title":"Sphingosine 1-phosphate receptor 1 (S1PR1) agonist CYM5442 inhibits expression of intracellular adhesion molecule 1 (ICAM1) in endothelial cells infected with influenza A viruses.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28399143","citation_count":26,"is_preprint":false},{"pmid":"32602083","id":"PMC_32602083","title":"In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation.","date":"2020","source":"Molecular imaging and biology","url":"https://pubmed.ncbi.nlm.nih.gov/32602083","citation_count":25,"is_preprint":false},{"pmid":"26597451","id":"PMC_26597451","title":"S1PR1 expression correlates with inflammatory responses to Newcastle disease virus infection.","date":"2015","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/26597451","citation_count":24,"is_preprint":false},{"pmid":"38823539","id":"PMC_38823539","title":"Kaempferol mitigates sepsis-induced acute lung injury by modulating the SphK1/S1P/S1PR1/MLC2 signaling pathway to restore the integrity of the pulmonary endothelial cell barrier.","date":"2024","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/38823539","citation_count":24,"is_preprint":false},{"pmid":"24740542","id":"PMC_24740542","title":"Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth.","date":"2014","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24740542","citation_count":24,"is_preprint":false},{"pmid":"28878352","id":"PMC_28878352","title":"S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.","date":"2017","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/28878352","citation_count":24,"is_preprint":false},{"pmid":"34301921","id":"PMC_34301921","title":"SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34301921","citation_count":23,"is_preprint":false},{"pmid":"37379683","id":"PMC_37379683","title":"S1P/S1PR1 axis promotes macrophage M1 polarization through NLRP3 inflammasome activation in Lupus nephritis.","date":"2023","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37379683","citation_count":23,"is_preprint":false},{"pmid":"38096817","id":"PMC_38096817","title":"Astrocyte growth is driven by the Tre1/S1pr1 phospholipid-binding G protein-coupled receptor.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/38096817","citation_count":22,"is_preprint":false},{"pmid":"32424937","id":"PMC_32424937","title":"Coinhibition of S1PR1 and GP130 by siRNA-loaded alginate-conjugated trimethyl chitosan nanoparticles robustly blocks development of cancer cells.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32424937","citation_count":22,"is_preprint":false},{"pmid":"26238015","id":"PMC_26238015","title":"Sphingosine-1-phosphate receptor 1 (S1PR1) expression in non-muscle invasive urothelial carcinoma: Association with poor clinical outcome and potential therapeutic target.","date":"2015","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/26238015","citation_count":22,"is_preprint":false},{"pmid":"38194271","id":"PMC_38194271","title":"S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/38194271","citation_count":21,"is_preprint":false},{"pmid":"37735908","id":"PMC_37735908","title":"Force-Loaded Cementocytes Regulate Osteoclastogenesis via S1P/S1PR1/Rac1 Axis.","date":"2023","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/37735908","citation_count":21,"is_preprint":false},{"pmid":"36204852","id":"PMC_36204852","title":"Siponimod exerts neuroprotective effects on the retina and higher visual pathway through neuronal S1PR1 in experimental glaucoma.","date":"2023","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/36204852","citation_count":21,"is_preprint":false},{"pmid":"37828220","id":"PMC_37828220","title":"S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37828220","citation_count":20,"is_preprint":false},{"pmid":"36600310","id":"PMC_36600310","title":"S1PR1/S1PR3-YAP signaling and S1P-ALOX15 signaling contribute to an aggressive behavior in obesity-lymphoma.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36600310","citation_count":20,"is_preprint":false},{"pmid":"31357710","id":"PMC_31357710","title":"Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31357710","citation_count":20,"is_preprint":false},{"pmid":"30083186","id":"PMC_30083186","title":"Sphingosine 1 phosphate receptor-1 (S1PR1) signaling protects cardiac function by inhibiting cardiomyocyte autophagy.","date":"2018","source":"Journal of geriatric cardiology : JGC","url":"https://pubmed.ncbi.nlm.nih.gov/30083186","citation_count":20,"is_preprint":false},{"pmid":"33797381","id":"PMC_33797381","title":"SphK1 Promotes Cancer Progression through Activating JAK/STAT Pathway and Up-Regulating S1PR1 Expression in Colon Cancer Cells.","date":"2022","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33797381","citation_count":20,"is_preprint":false},{"pmid":"37699301","id":"PMC_37699301","title":"Aralia saponin A isolated from Achyranthes bidentata Bl. ameliorates LPS/D-GalN induced acute liver injury via SPHK1/S1P/S1PR1 pathway in vivo and in vitro.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37699301","citation_count":19,"is_preprint":false},{"pmid":"30712389","id":"PMC_30712389","title":"Potential involvement of S1PR1/STAT3 signaling pathway in cardiac valve damage due to rheumatic heart disease.","date":"2019","source":"Biotechnic & histochemistry : official publication of the Biological Stain Commission","url":"https://pubmed.ncbi.nlm.nih.gov/30712389","citation_count":19,"is_preprint":false},{"pmid":"27073467","id":"PMC_27073467","title":"miR-133b, a microRNA targeting S1PR1, suppresses nasopharyngeal carcinoma cell proliferation.","date":"2016","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27073467","citation_count":18,"is_preprint":false},{"pmid":"33931142","id":"PMC_33931142","title":"S1PR1 signaling in cancer: A current perspective.","date":"2021","source":"Advances in protein chemistry and structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/33931142","citation_count":17,"is_preprint":false},{"pmid":"32045395","id":"PMC_32045395","title":"S1PR1-Associated Molecular Signature Predicts Survival in Patients with Sepsis.","date":"2020","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/32045395","citation_count":16,"is_preprint":false},{"pmid":"32006593","id":"PMC_32006593","title":"STAT1 transcriptionally regulates the expression of S1PR1 by binding its promoter region.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32006593","citation_count":16,"is_preprint":false},{"pmid":"33715582","id":"PMC_33715582","title":"miR-145-5p exerts anti-tumor effects in diffuse large B-cell lymphoma by regulating S1PR1/STAT3/AKT pathway.","date":"2021","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/33715582","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53807,"output_tokens":11670,"usd":0.168236,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22618,"output_tokens":4801,"usd":0.116557,"stage2_stop_reason":"end_turn"},"total_usd":0.284793,"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\": 1998,\n      \"finding\": \"Sphingosine-1-phosphate (S1P/SPP) was identified as a high-affinity ligand for the orphan GPCR EDG-1 (S1PR1), binding with Kd ~8.1 nM; receptor overexpression induced cell-cell aggregation, cadherin upregulation, and adherens junction formation in an S1P- and Rho-dependent manner.\",\n      \"method\": \"Radioligand binding assay, receptor overexpression in HEK293 cells, morphological and biochemical assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay with Kd determination, functional validation, foundational ligand identification replicated in subsequent studies\",\n      \"pmids\": [\"9488656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"EDG-1 (S1PR1) couples exclusively to the Gi pathway: binding of S1P to EDG-1 inhibits forskolin-stimulated cAMP accumulation in a pertussis toxin-sensitive manner; S1P-induced mitogenesis and anti-apoptosis were independent of EDG-1 and correlated with intracellular S1P uptake.\",\n      \"method\": \"cAMP assay with pertussis toxin inhibition, intracellular microinjection of S1P, antisense and receptor expression studies\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods, pertussis toxin dissection of pathway, replicated in other papers\",\n      \"pmids\": [\"9660876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The third cytosolic loop (i3) of EDG-1 (S1PR1) physically associates with Giα and Goα polypeptides in a GTPγS-sensitive manner; immunoprecipitation of EDG-1 co-precipitates Giα1 and Giα3; EDG-1 overexpression leads to sustained, pertussis toxin-sensitive MAP kinase activation.\",\n      \"method\": \"Co-immunoprecipitation, GTPγS competition assay, MAP kinase activity assay with pertussis toxin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP with GTPγS competition, functional pertussis toxin studies, replicated across multiple labs\",\n      \"pmids\": [\"8626678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EDG-1 (S1PR1) activates only Gi family members (not Gs, Gq, G12, or G13), as established by subunit-selective [35S]GTPγS binding in Sf9 and HEK293 cells; in contrast, EDG-3 and H218/EDG-5 additionally couple to Gq and G13.\",\n      \"method\": \"Subunit-selective [35S]GTPγS 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, two cell systems, clearly distinguished receptor coupling profiles\",\n      \"pmids\": [\"10488065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"S1P ligand binding specifically induces reversible trafficking of EDG-1 (S1PR1) from the plasma membrane to perinuclear endosomal/lysosomal vesicles (t1/2 ~15 min internalization, t1/2 ~30 min recycling); truncation of the C-terminus completely blocks internalization; C-terminal domain is essential for ligand-induced trafficking.\",\n      \"method\": \"EDG-1-GFP chimera live-cell imaging, subcellular colocalization with endocytic/lysosomal markers, C-terminal truncation mutant analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GFP-chimera live imaging, organelle colocalization, domain deletion mutant, multiple methods in one study\",\n      \"pmids\": [\"10198065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Genetic deletion of Edg-1 (S1PR1) in mice caused embryonic hemorrhage and death at E12.5–E14.5 due to deficient vascular smooth muscle cell/pericyte coverage; EDG-1-null cells failed to activate the small GTPase Rac in response to S1P, which is required for migration.\",\n      \"method\": \"Gene knockout in mice (Edg1−/− embryos), histology, Rac activation assay in mutant cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined vascular phenotype, biochemical Rac assay, replicated/cited widely\",\n      \"pmids\": [\"11032855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"S1P-induced endothelial cell migration requires Akt-mediated phosphorylation of EDG-1 (S1PR1) at the T236 residue in the third intracellular loop; activated Akt binds to EDG-1, and T236A mutant EDG-1 acts as a dominant-negative that sequesters Akt and blocks Rac activation, cortical actin assembly, and chemotaxis without affecting Gi-dependent signaling.\",\n      \"method\": \"Akt-EDG-1 binding assay, site-directed mutagenesis (T236A), in vitro migration/chemotaxis assay, Rac activation assay, dominant-negative analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis of specific phosphorylation site, in vitro kinase assay, dominant-negative approach, multiple orthogonal readouts\",\n      \"pmids\": [\"11583630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-induced cell motility depends on EDG-1 (S1PR1): PDGF activates sphingosine kinase, raising intracellular S1P levels, which transactivates EDG-1 as demonstrated by β-arrestin translocation and EDG-1 phosphorylation; EDG-1-null or kinase-inhibited cells fail to activate Rac or migrate toward PDGF.\",\n      \"method\": \"EDG-1 knockout fibroblasts, β-arrestin translocation assay (GPCR transactivation), sphingosine kinase inhibition, chemotaxis assay, Rac activation\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, multiple functional assays, receptor transactivation measured directly\",\n      \"pmids\": [\"11230698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SPP-induced HUVEC migration requires signaling via EDG-1 and EDG-3 receptors through Rho activation (blocked by C3 exotoxin), leading to Rho-dependent integrin clustering (αvβ3 and β1) into focal contacts; Rac activation was dispensable for adhesion but EDG-1 and EDG-3 were both required for Rho activation.\",\n      \"method\": \"Antisense oligonucleotide knockdown of EDG-1 and EDG-3, C3 exotoxin treatment, integrin blocking antibodies, Rho activation assay, cell adhesion/migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antisense knockdown + toxin inhibition + integrin blockade, multiple orthogonal approaches\",\n      \"pmids\": [\"11150298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EDG-1 (S1PR1) localizes to caveolin-1-enriched plasmalemmal caveolae (~55% of protein); co-immunoprecipitation shows direct EDG-1/caveolin-1 interaction; S1P treatment increases EDG-1 targeting to caveolae (~93%); caveolin-1 overexpression inhibits S1P-mediated eNOS activation and attenuates agonist-induced EDG-1 phosphorylation by >90%.\",\n      \"method\": \"Sucrose gradient ultracentrifugation fractionation, co-immunoprecipitation with anti-caveolin-1 antibody, eNOS activity assay, caveolin-1 overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, subcellular fractionation, functional eNOS assay, multiple methods\",\n      \"pmids\": [\"10921915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"EDG-1 (S1PR1) expression in vascular smooth muscle cells (VSMCs) enhances S1P-induced proliferation via Gi-dependent p70 S6 kinase activation and cyclin D1 expression (blocked by pertussis toxin and rapamycin), and enhances migration via Gi activation but independently of p70 S6 kinase.\",\n      \"method\": \"Stable transfection of EDG-1 into adult VSMCs, pertussis toxin treatment, rapamycin treatment, p70 S6 kinase assay, cyclin D1 western blot, migration assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor overexpression with pharmacological dissection, multiple downstream readouts in single study\",\n      \"pmids\": [\"11557736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"EDG-1 (S1PR1) couples to Gi but not Gq: EDG-1 mRNA expression in Xenopus oocytes did not confer S1P-responsive intracellular calcium transients unless co-expressed with the chimeric Gαqi protein; in contrast, EDG-3 and EDG-5 alone conferred calcium responses to S1P, demonstrating differential Gq/Gi coupling among S1P receptors.\",\n      \"method\": \"Xenopus oocyte expression system, microinjection of receptor mRNA ± chimeric G-protein constructs, electrophysiological calcium transient recording\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in Xenopus oocytes, chimeric G-protein complementation, directly compared receptor subtypes\",\n      \"pmids\": [\"10383399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EDG-1 (S1PR1) is N-glycosylated at asparagine-30 in its extracellular N-terminus; non-glycosylated mutant N30D-Edg-1 shows normal plasma membrane expression, ligand binding, and MAP kinase activation, but markedly reduced ligand-induced internalization and is not associated with caveolae membrane fractions.\",\n      \"method\": \"Site-directed mutagenesis (N30D), sucrose density gradient fractionation, radioligand binding assay, MAP kinase assay, internalization assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis + multiple functional and localization assays in same study\",\n      \"pmids\": [\"12087059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"STAT3 transcriptionally drives S1PR1 expression; reciprocally, S1PR1 activates STAT3 by upregulating JAK2 tyrosine kinase activity and IL-6 gene expression, forming a positive feedback loop that sustains persistent STAT3 activation in cancer cells; silencing S1PR1 inhibits STAT3 activity, tumor growth, and metastasis.\",\n      \"method\": \"S1PR1 siRNA knockdown in tumor/immune cells, STAT3 reporter assay, JAK2 kinase activity measurement, IL-6 ELISA, in vivo tumor models\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA in vitro and in vivo, kinase activity assay, cytokine measurement, multiple cell types and tumor models\",\n      \"pmids\": [\"21102457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S1PR1 signaling restricts sprouting angiogenesis by inhibiting VEGF-A-induced signaling and stabilizing VE-cadherin localization at endothelial junctions; loss of S1PR1 in endothelial cells leads to increased sprouting and ectopic vessel branching.\",\n      \"method\": \"S1PR1 loss-of-function in endothelial cells (genetic deletion), VE-cadherin localization by immunofluorescence, VEGF-A signaling assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelial-specific genetic deletion with defined molecular phenotype, VE-cadherin localization and VEGF signaling as readouts\",\n      \"pmids\": [\"22975327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"S1PR1 (S1pr1) on megakaryocytes functions as a directional cue receptor for S1P gradients, guiding proplatelet extensions into bone marrow sinusoids; conditional S1pr1 deletion causes severe thrombocytopenia due to aberrant extravascular proplatelet formation and defective intravascular shedding.\",\n      \"method\": \"Conditional mouse mutants, intravital multiphoton microscopy of bone marrow, platelet counts\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with intravital imaging and defined platelet phenotype\",\n      \"pmids\": [\"23148237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"S1P activates NF-κB in a receptor-dependent fashion through EDG-3 and EDG-5 (which couple to Gi, Gq, and G13), but not through EDG-1 (S1PR1, which couples to Gi only); NF-κB activation requires protein kinase C and Ca2+ downstream of Gq; Rho activation alone by S1P was insufficient for NF-κB activation.\",\n      \"method\": \"HEK293 cells overexpressing individual Edg receptors, NF-κB reporter assay, PKC and Ca2+ inhibitor studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor subtype comparison with specific pharmacological inhibitors, clear negative result for S1PR1\",\n      \"pmids\": [\"11673450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling and T cell egress: in low S1P concentrations, dynamin 2 enables S1PR1 internalization/recycling which sustains signaling sufficient for egress; dynamin 2 deficiency limits T cells to a single pulse of S1PR1 signaling, insufficient for egress; transgenic S1PR1 overexpression rescues egress in dynamin 2 KO mice.\",\n      \"method\": \"T cell-specific dynamin 2 conditional KO mouse, S1PR1 transgenic rescue, T cell egress assay from thymus and lymph nodes\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with transgenic rescue, mechanistic epistasis established\",\n      \"pmids\": [\"24638168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S1PR1 signaling suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells by accelerating IFNAR1 turnover/degradation and downregulating STAT1 phosphorylation; this suppression is pertussis toxin-resistant and requires S1PR1 internalization (blocked by a C-terminal Tat-peptide); endogenous S1P-S1PR1 signaling sets pDC sensitivity for IFN-α amplification.\",\n      \"method\": \"S1PR1 agonist treatment of pDCs, Tat-fusion receptor internalization blocking peptide, IFNAR1 turnover measurement, STAT1 phosphorylation assay, in vivo Ex26 antagonist, pertussis toxin studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pharmacological and peptide tools, protein turnover assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"26787880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structures of S1PR1 and S1PR5 in complex with heterotrimeric Gi protein and diverse agonists (including drugs) were determined; structures reveal the binding modes of chemically distinct agonists, a mechanical switch activating the receptors, and the basis for ligand selectivity and G-protein coupling.\",\n      \"method\": \"Cryo-electron microscopy structure determination, functional assays for ligand activation and G-protein coupling\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM with functional validation, multiple structures and ligands\",\n      \"pmids\": [\"34526663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD69, a transmembrane protein expressed on activated lymphocytes, acts as a protein agonist of S1PR1 in cis: cryo-EM structure shows the transmembrane helix of one CD69 homodimer protomer contacts S1PR1-TM4, allosterically inducing movement of S1PR1-TMs 5-6 to activate receptor and engage heterotrimeric Gi; mutations at the CD69-S1PR1 interface reduce receptor internalization; CD69 promotes Gi-dependent S1PR1 internalization, loss of S1P gradient sensing, and inhibition of lymphocyte egress.\",\n      \"method\": \"Cryo-EM structure of CD69-S1PR1-Gi complex, mutagenesis of interface residues, receptor internalization assay, lymphocyte egress assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis and functional validation, novel mechanism established\",\n      \"pmids\": [\"37039481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Phosphorylation of S1PR1 at tyrosine-143 (Y143) is required for S1P-induced receptor internalization in endothelial cells; Y143 phosphorylation correlates with maximal receptor internalization at 20 min and Y143 dephosphorylation accompanies receptor recycling to the cell surface at ~1 h; phospho-defective Y143F mutant fails to internalize while phospho-mimicking Y143D shows constitutive high internalization; C-terminal serine phosphorylation did not modulate Y143-dependent internalization.\",\n      \"method\": \"Site-directed mutagenesis (Y143F, Y143D), flow cytometry/immunofluorescence internalization assay, endothelial barrier resistance measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific residue with multiple phosphorylation mutants, internalization and barrier function readouts\",\n      \"pmids\": [\"25588843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Edg-1 (S1PR1) expression in Sf9 and COS-7 cells confers S1P-induced adenylate cyclase inhibition and MAP kinase activation (Gi-mediated), but not Ca2+ mobilization; LPA does not activate EDG-1 and Vzg-1/Edg-2 cannot substitute for Edg-1.\",\n      \"method\": \"Heterologous expression in Sf9 and COS-7 cells, adenylate cyclase assay, MAP kinase assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct heterologous expression with multiple signaling readouts, receptor specificity confirmed by negative controls\",\n      \"pmids\": [\"9480864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S1PR1 signaling in endothelial cells activates the ERK/CSF1 pathway, enhancing CSF1 expression in a cell-contact-dependent manner, which promotes Ly6clow reparative macrophage proliferation after myocardial infarction; endothelial S1pr1-specific deletion reduces reparative macrophage accumulation and worsens cardiac remodeling; pharmacological S1pr1 activation ameliorates post-MI cardiac remodeling.\",\n      \"method\": \"Endothelial-specific S1pr1 KO mouse model, pharmacological S1pr1 activation, flow cytometry for macrophage subsets, CSF1 signaling blockade, ERK activation assay\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelial-specific KO + pharmacological rescue + CSF1 blockade epistasis, mechanistic pathway defined\",\n      \"pmids\": [\"32091582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In T lymphocytes, CCR7/CCL19 signaling upregulates S1PR1 (EDG-1) expression via ERK5 activation and induction of the KLF2 transcription factor; CCR7/CCL19-stimulated T cells show increased S1PR1-ligand-directed migration at 48 h, which is abolished in ERK5-deficient T cells.\",\n      \"method\": \"ERK5 conditional KO mouse (ERK5flox/flox/Lck-Cre), primary murine T cell stimulation, migration assay to S1PR1 ligands, KLF2 and S1PR1 expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with functional migration readout, pathway placement established by epistasis, single lab\",\n      \"pmids\": [\"22334704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"S1P1 (S1PR1) signaling in the developing vasculature regulates limb development non-cell-autonomously: loss of S1P1 in endothelium causes HIF-1α and VEGF induction in limbs (but not in embryonic fibroblasts), leading to hyperplastic vasculature and defective digit/chondrocyte morphogenesis; endothelium-specific S1P1 null mice recapitulate limb defects.\",\n      \"method\": \"Whole-body and endothelium-specific S1p1 KO mice, HIF-1α/VEGF immunostaining, limb histology\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO, non-cell-autonomous mechanism demonstrated by comparison of whole-body vs. endothelial KO\",\n      \"pmids\": [\"15063179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"T cell-intrinsic S1PR1 is required for effector T cell entry into lymphatic sinuses and egress from draining lymph nodes during infection; using inducible T cell-specific S1PR1 KO, WT and S1PR1-deficient effector T cells both migrate to sinus-adjacent positions but only WT T cells enter sinuses, even when CCR7 retention signals are downregulated.\",\n      \"method\": \"Inducible T cell-specific S1PR1 gene deletion, intravital two-photon microscopy of lymph node, viral infection model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible conditional KO with direct intravital imaging, mechanistic epistasis with CCR7\",\n      \"pmids\": [\"26862175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD4 T cell S1PR1 and S1PR4, and endothelial cell S1PR2, are each required for T cell migration across lymphatic endothelial cells (LECs) and into afferent lymphatic vessels and draining lymph nodes; S1PR1 and S1PR4 differentially regulate T cell motility and VCAM-1 binding; S1PR2 in LECs regulates VE-cadherin, occludin, and zonulin-1 expression via ERK.\",\n      \"method\": \"Receptor-specific KO and blockade, transwell migration assay across LECs, intravital imaging, VCAM-1 binding assay, VE-cadherin/occludin/ZO-1 immunostaining\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple receptor-specific KO models, functional migration assay, junction molecule mechanistic readouts\",\n      \"pmids\": [\"30877143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HGF activates S1PR1 transactivation via c-Met: c-Met, S1PR1, and integrin β4 (ITGB4) are recruited to caveolin-enriched lipid rafts upon HGF treatment; co-immunoprecipitation shows direct c-Met interaction with both S1PR1 and ITGB4; S1PR1 siRNA attenuates ITGB4 and Rac1 activation, c-Met/ITGB4 interaction, and transendothelial electrical resistance.\",\n      \"method\": \"Co-immunoprecipitation, lipid raft fractionation, siRNA knockdown of S1PR1 and ITGB4, Rac1 activation assay, transendothelial electrical resistance measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP demonstrating protein complex, siRNA knockdown with multiple functional readouts\",\n      \"pmids\": [\"23212923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S1PR1 regulates lymphatic vascular quiescence by antagonizing laminar shear stress (LSS)-mediated VEGF-C/VEGFR3 signaling; S1PR1 inhibits RhoA activity to promote membrane localization of claudin-5 (tight junction molecule); S1pr1 loss in LECs induces hypersprouting rescued by reducing Vegfr3 gene dosage in vivo.\",\n      \"method\": \"LEC-specific S1pr1 KO, Vegfr3 heterozygous rescue genetics, in vitro LSS experiments, RhoA activation assay, claudin-5 membrane localization\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue epistasis in vivo, biochemical RhoA assay, junction protein localization\",\n      \"pmids\": [\"32544090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S1PR1 signaling in tumor-associated macrophages (TAMs) promotes lymphangiogenesis and pulmonary metastasis via NLRP3 inflammasome activation and IL-1β production; macrophage-specific S1pr1 deletion reduces Nlrp3 expression in TAMs and prevents tumor lymphangiogenesis and metastasis; macrophage-dependent lymphangiogenesis in vitro requires both S1PR1 signaling and IL-1β production.\",\n      \"method\": \"CD11b+ macrophage-specific S1pr1 KO mouse, transcriptome analysis of isolated TAMs, in vitro lymphangiogenesis assay, inflammasome activation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO, transcriptomic + in vitro mechanistic validation, two tumor model systems\",\n      \"pmids\": [\"28739604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"S1PR1 limits apoptosis in T cells by maintaining BCL2 family member balance via restraint of JNK activity; the same intracellular residues enabling S1PR1 internalization are required to prevent the proapoptotic cascade; this is distinct from S1PR1's role in directing egress.\",\n      \"method\": \"Mouse genetic models (S1PR1 internalization-deficient mutants), JNK activity assay, BCL2 family member expression, T cell survival assay; findings confirmed in ozanimod-treated ulcerative colitis patients\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mutagenesis of receptor internalization residues, JNK pathway dissection, murine and human patient validation\",\n      \"pmids\": [\"38194271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"β1-adrenergic receptor (β1AR) and S1PR1 physically interact and show reciprocal cross-regulation: S1PR1 agonist (S1P) can induce β1AR downregulation, and β-AR agonist (isoproterenol) can induce S1PR1 downregulation; G-protein-coupled receptor kinase-2 (GRK2) is involved; this cross-talk is observed in mouse hearts under chronic β-AR stimulation and in a rat heart failure model.\",\n      \"method\": \"HEK293 cells overexpressing both receptors, receptor downregulation assays, co-immunoprecipitation, in vivo mouse cardiac model, rat heart failure model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP + cross-stimulation experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"23969695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Lysophosphatidic acid (LPA) is a low-affinity agonist for EDG-1 (S1PR1): LPA binds with Kd ~2.3 μM (vs ~8 nM for S1P), induces receptor phosphorylation, MAP kinase activation, and Rho-dependent morphogenesis.\",\n      \"method\": \"Radioligand binding assay, receptor phosphorylation assay, MAP kinase assay, morphological analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding with Kd measurement, functional signaling assays, single lab\",\n      \"pmids\": [\"9705355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-induced focal adhesion formation and activation of FAK, Src, and p38 are dysregulated in EDG-1-null fibroblasts; PDGF-induced lamellipodia extension and cell motility are abrogated in EDG-1-null cells; in contrast, mitogenesis, survival responses, and ERK1/2 activation by PDGF or S1P are unaffected by EDG-1 deletion, indicating EDG-1 is required for cytoskeletal integration but not growth signals.\",\n      \"method\": \"EDG-1-null fibroblasts, FAK/Src/p38 kinase activation assays, lamellipodia observation, cell motility assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with biochemical and morphological readouts, clear separation of cytoskeletal vs. growth signaling outputs\",\n      \"pmids\": [\"11726541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR302-367 elevation in endothelial cells promotes vascular stability and reduces sprouting angiogenesis via an Erk1/2-Klf2-S1pr1 pathway: downregulation of Erk1/2 increases Klf2, which induces S1pr1 and its target VE-cadherin; pharmacological blockade or genetic deletion of S1pr1 in ECs reverses the antiangiogenic effect of miR302-367.\",\n      \"method\": \"miRNA overexpression in ECs, retinal vascular assay, endothelial-specific S1pr1 deletion, ERK/KLF2/S1PR1/VE-cadherin expression and function assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis validated by genetic S1pr1 deletion rescue + pharmacological blockade, pathway defined by multiple manipulations\",\n      \"pmids\": [\"27756792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S1PR1 signaling in endothelial cells controls blood pressure and flow-mediated mechanotransduction: endothelial-specific S1PR1 deletion decreases basal and stimulated eNOS-derived nitric oxide and elevates baseline blood pressure; FTY720 (functional S1PR1 antagonist) markedly decreases endothelial S1PR1, increases blood pressure in control mice, and exacerbates angiotensin II-induced hypertension.\",\n      \"method\": \"Endothelial-specific S1PR1 KO mice, eNOS activity assay, blood pressure measurement, FTY720 pharmacological treatment, angiotensin II hypertension model\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelial-specific KO + pharmacological validation in multiple models, mechanistic eNOS assay\",\n      \"pmids\": [\"28607130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S1P in HDL promotes physical interaction between SR-BI and S1PR1 on the plasma membrane; HDL-derived S1P initiates S1PR1 internalization and intracellular calcium flux; HDL without supplemented S1P did not trigger these responses, establishing S1P as the active component mediating HDL-induced S1PR1 activation and SR-BI/S1PR1 interaction.\",\n      \"method\": \"Protein-fragment complementation assay (SR-BI/S1PR1 interaction), confocal microscopy, calcium flux assay, recombinant HDL particles ± S1P, primary vascular smooth muscle cells and HEK293 cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementation assay + calcium flux + confocal colocalization, single lab\",\n      \"pmids\": [\"27881715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"aPC/PAR1 anti-apoptotic signaling is mediated by a discrete β-arrestin-2-SphK1-S1PR1-Akt axis in endothelial cells: aPC activates PAR1 to engage β-arr2, which activates SphK1 independent of Dvl2, leading to S1PR1 transactivation and Akt-dependent cell survival; endogenous PAR1 and S1PR1 co-reside in caveolin-1-rich microdomains, and Cav1 is required for this pathway.\",\n      \"method\": \"Endothelial cell siRNA knockdown of β-arr2, SphK1, S1PR1, Cav1; co-immunoprecipitation; Akt phosphorylation; cell apoptosis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple siRNA knockdowns with functional apoptosis readout, co-IP, pathway epistasis established\",\n      \"pmids\": [\"34873055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"S1P/S1PR1 signaling in hypothalamic POMC neurons activates STAT3 and the melanocortin system to reduce food intake and increase energy expenditure; STAT3 controls S1PR1 expression in neurons via a positive feedback; selective disruption of hypothalamic S1PR1 increases food intake and reduces respiratory exchange ratio.\",\n      \"method\": \"Intracerebroventricular S1P injection, hypothalamic S1PR1-selective disruption in rodents, STAT3 activity assay, food intake and energy expenditure measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct CNS injection, regional gene disruption, STAT3 pathway validation, multiple physiological readouts\",\n      \"pmids\": [\"25255053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STAT1 transcriptionally regulates S1PR1 expression by binding its promoter in the region -29 to -12 bp upstream of TSS; STAT1 knockdown reduces S1PR1 expression, STAT1 overexpression upregulates it, and IFN-γ activation of STAT1 increases S1PR1 mRNA and protein; confirmed by EMSA and ChIP assays.\",\n      \"method\": \"STAT1 siRNA knockdown, STAT1 overexpression, EMSA, ChIP assay at S1PR1 promoter, luciferase reporter assay with truncated promoter fragments, IFN-γ stimulation\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EMSA + ChIP + functional promoter reporter + gain- and loss-of-function in single study\",\n      \"pmids\": [\"32006593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMYD3 promotes S1PR1 expression in hepatocellular carcinoma by methylating histone H3 at lysine 4 (H3K4me3) at the S1PR1 promoter; SMYD3 expression is positively correlated with S1PR1 in HCC and promotes HCC cell growth and migration in a manner partially dependent on S1PR1 upregulation.\",\n      \"method\": \"Chromatin immunoprecipitation (H3K4me3 at S1PR1 promoter), SMYD3 overexpression/knockdown, S1PR1 promoter activity assay, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with histone mark at S1PR1 promoter, gain/loss of function, single lab\",\n      \"pmids\": [\"34301921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"S1PR1 directly activates STAT3 in esophageal squamous cell carcinoma cells: co-immunoprecipitation demonstrates direct binding of S1PR1 and STAT3; S1PR1 silencing reduces STAT3 phosphorylation (p-STAT3), while S1PR1 overexpression increases p-STAT3 and promotes proliferation and suppresses apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (S1PR1-STAT3 interaction), siRNA knockdown, S1PR1 overexpression, STAT3 phosphorylation western blot, in vitro and in vivo tumor assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single co-IP + functional KD/OE readouts, single lab\",\n      \"pmids\": [\"31438989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, loss of s1pr1 disrupts astrocyte process elaboration and extension/retraction dynamics; pharmacological modulation of S1pr1 balances astrocyte process growth; functional analog of Drosophila Tre1, with loss of either causing motor behavioral defects.\",\n      \"method\": \"s1pr1 loss-of-function in zebrafish, live imaging of astrocyte process dynamics, pharmacological S1PR1 modulation, behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in zebrafish with live imaging and pharmacology; ortholog evidence but not in mammalian cells\",\n      \"pmids\": [\"38096817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Endothelial S1PR1 activates the AKT/eNOS signaling pathway, producing nitric oxide that inhibits cardiomyocyte hypertrophy and cardiac fibroblast transformation; endothelial-specific S1pr1 deletion aggravates pressure overload-induced cardiac hypertrophy and fibrosis; inhibition of AKT/eNOS reverses S1pr1-overexpression-mediated protection.\",\n      \"method\": \"Endothelial-specific S1pr1 KO (TAC model), S1pr1 overexpression, AKT/eNOS phosphorylation assay, NO production measurement, AKT inhibitor epistasis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endothelial KO + overexpression + pathway inhibitor epistasis, multiple cardiac phenotype readouts\",\n      \"pmids\": [\"31854513\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"S1PR1 (EDG-1) is a Gi-coupled GPCR that binds sphingosine-1-phosphate with high affinity (~8 nM Kd) and signals exclusively through Gi (not Gq, G12/13) to activate MAP kinase, inhibit cAMP, and promote Rac-dependent cytoskeletal rearrangements required for cell migration, vascular maturation, and lymphocyte egress; receptor activity is regulated by Akt-mediated phosphorylation at T236 (enabling Rac activation and chemotaxis), tyrosine-143 phosphorylation (controlling receptor internalization/recycling), N-glycosylation at Asn30 (required for internalization and caveolae association), and interaction with CD69 (a transmembrane protein agonist that activates S1PR1-Gi to drive internalization and block lymphocyte egress); the receptor forms a positive feedback loop with STAT3 (STAT3 drives S1PR1 transcription, S1PR1 sustains STAT3 via JAK2), localizes to caveolin-1-enriched caveolae where it is subject to caveolin-1 inhibitory interactions, and in endothelial cells activates eNOS via AKT to regulate vascular tone and blood pressure.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"S1PR1 (EDG-1) is a high-affinity (~8 nM Kd) G protein-coupled receptor for sphingosine-1-phosphate that signals exclusively through the Gi family to control cell migration, vascular integrity, and lymphocyte trafficking [#0, #3]. Its third intracellular loop binds Giα/Goα in a GTPγS-sensitive manner, and ligand engagement inhibits adenylate cyclase and drives sustained, pertussis toxin-sensitive MAP kinase activation without coupling to Gq, G12, or G13 [#1, #2, #11]. A defining output is Gi-dependent activation of the small GTPase Rac, which is required for cortical actin assembly, lamellipodia formation, and chemotaxis; Rac activation additionally requires Akt-mediated phosphorylation of the receptor at T236, while cytoskeletal integration of growth factor cues (PDGF, HGF, aPC/PAR1) proceeds through S1PR1 transactivation downstream of sphingosine kinase and β-arrestin [#5, #6, #7, #28, #38]. Genetic deletion is embryonic lethal from vascular hemorrhage due to defective mural-cell coverage, and in endothelium S1PR1 stabilizes VE-cadherin junctions, restrains VEGF/VEGFR3-driven sprouting via RhoA inhibition, and activates AKT/eNOS to set vascular tone and blood pressure [#5, #14, #29, #36, #44]. In the immune system, S1PR1 senses S1P gradients to drive lymphocyte egress from thymus and lymph nodes, a function dependent on dynamin 2-mediated internalization/recycling that sustains signaling [#17, #26]. Receptor trafficking is governed by an essential C-terminal domain, N-glycosylation at Asn30 (required for internalization and caveolae targeting), and tyrosine-143 phosphorylation; CD69 acts as a cis transmembrane protein agonist contacting TM4 to allosterically activate the receptor and drive internalization that blocks egress [#4, #12, #21, #20]. S1PR1 resides in caveolin-1-enriched caveolae where caveolin-1 inhibits its signaling, and it forms a STAT3-driven positive feedback loop (via JAK2/IL-6) that sustains STAT3 activity in tumors and hypothalamic neurons [#9, #13, #39]. Cryo-EM structures of S1PR1-Gi complexes define agonist binding modes and the activation switch [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the orphan receptor EDG-1 engages inhibitory G proteins through a defined cytosolic interface, providing the first mechanistic link to a signaling output.\",\n      \"evidence\": \"Co-IP and GTPγS competition mapping i3 loop association with Giα/Goα plus pertussis toxin-sensitive MAPK assays\",\n      \"pmids\": [\"8626678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand not yet known at this point\", \"No structural detail of coupling\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified S1P as the high-affinity physiological ligand and showed receptor engagement drives Gi-restricted cAMP inhibition and Rho-dependent morphogenesis, defining EDG-1 as the S1P receptor.\",\n      \"evidence\": \"Radioligand binding (Kd ~8 nM), heterologous expression with cAMP/MAPK assays, pertussis toxin dissection\",\n      \"pmids\": [\"9488656\", \"9660876\", \"9480864\", \"9705355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LPA acts only as a low-affinity agonist; physiological relevance unclear\", \"Selectivity among Gi members not yet resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved that S1PR1 couples exclusively to Gi (not Gq/G12/G13), distinguishing it from sibling S1P receptors and explaining its calcium-silent, migration-centric signaling.\",\n      \"evidence\": \"Subunit-selective [35S]GTPγS binding in Sf9/HEK293 and Xenopus oocyte chimeric Gαqi complementation\",\n      \"pmids\": [\"10488065\", \"10383399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of Gi not fully enumerated\", \"Does not address receptor trafficking\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated S1PR1 is essential for vascular maturation in vivo and links receptor activity to Rac-dependent migration, defining its developmental role.\",\n      \"evidence\": \"Edg1-/- mouse knockout with vascular histology and Rac activation assays; caveolae fractionation showing caveolin-1 interaction\",\n      \"pmids\": [\"11032855\", \"10921915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions not separated\", \"How caveolin-1 inhibits signaling mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined Akt phosphorylation at T236 as a switch enabling Rac activation and chemotaxis, and established S1PR1 as the obligatory transactivation node for PDGF-driven cytoskeletal remodeling.\",\n      \"evidence\": \"Site-directed mutagenesis (T236A dominant-negative), Akt-receptor binding, β-arrestin translocation, EDG-1-null fibroblast chemotaxis and FAK/Src/p38 assays\",\n      \"pmids\": [\"11583630\", \"11230698\", \"11726541\", \"11150298\", \"11557736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether T236 phosphorylation is direct in vivo across cell types\", \"Integration of Rho vs Rac outputs context-dependent\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapped receptor trafficking determinants — C-terminus and Asn30 N-glycosylation — required for ligand-induced internalization and caveolae targeting.\",\n      \"evidence\": \"GFP-chimera live imaging, C-terminal truncation, N30D glycosylation mutant with binding/MAPK/internalization assays\",\n      \"pmids\": [\"10198065\", \"12087059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific endocytic adaptors not identified at this stage\", \"Functional consequence of recycling for signaling not yet defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a STAT3–S1PR1 positive feedback loop that sustains persistent STAT3 activity, linking the receptor to tumor growth and metastasis.\",\n      \"evidence\": \"S1PR1 siRNA, STAT3 reporter, JAK2 kinase activity, IL-6 ELISA and in vivo tumor models\",\n      \"pmids\": [\"21102457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S1PR1-STAT3 coupling is direct or indirect via JAK2/IL-6\", \"Generality across tumor types\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established endothelial S1PR1 as a brake on sprouting angiogenesis through VE-cadherin stabilization and VEGF antagonism, and showed it directs proplatelet shedding in megakaryocytes.\",\n      \"evidence\": \"Endothelial and megakaryocyte conditional S1pr1 deletion, VE-cadherin imaging, intravital bone marrow microscopy; c-Met/ITGB4 co-IP transactivation\",\n      \"pmids\": [\"22975327\", \"23148237\", \"23212923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance between S1PR1 quiescence and VEGF sprouting cues unclear\", \"Tissue-specific signaling differences not unified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified tyrosine-143 phosphorylation as the controller of internalization-recycling cycling in endothelial cells.\",\n      \"evidence\": \"Y143F/Y143D mutagenesis with flow cytometry internalization and barrier resistance assays\",\n      \"pmids\": [\"25588843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Y143 phosphorylation unidentified\", \"Relationship between Y143 and C-terminal serine phosphorylation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that sustained S1PR1 signaling via dynamin 2-dependent internalization/recycling is the mechanistic basis for lymphocyte egress and that the receptor suppresses type I IFN amplification in pDCs.\",\n      \"evidence\": \"Dynamin 2 conditional KO with S1PR1 transgenic rescue, inducible T cell S1PR1 KO with intravital imaging, Tat-peptide internalization blockade and IFNAR1 turnover assays\",\n      \"pmids\": [\"24638168\", \"26862175\", \"26787880\", \"22334704\", \"30877143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise signal duration required for egress not quantified\", \"How CCR7 and S1PR1 signals are integrated at sinus entry\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected endothelial S1PR1/eNOS signaling to blood pressure control and tissue repair, and revealed pro-tumor inflammasome signaling in macrophages.\",\n      \"evidence\": \"Endothelial-specific KO with eNOS/blood pressure measurement, FTY720 pharmacology, macrophage-specific S1pr1 KO with NLRP3/IL-1β and lymphangiogenesis readouts, ERK/CSF1 epistasis\",\n      \"pmids\": [\"28607130\", \"30877143\", \"28739604\", \"32091582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-context determinants of pro- vs anti-tumor outcomes unresolved\", \"Mechanism linking Gi to eNOS not fully detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided atomic-resolution structures of S1PR1-Gi complexes defining agonist binding and activation, and dissected an aPC/PAR1-β-arrestin2-SphK1-S1PR1-Akt survival axis and an anti-apoptotic JNK/BCL2 role.\",\n      \"evidence\": \"Cryo-EM of S1PR1-Gi with multiple agonists; endothelial siRNA epistasis for the aPC/PAR1 axis; receptor internalization-deficient mouse mutants with JNK/BCL2 and patient validation\",\n      \"pmids\": [\"34526663\", \"34873055\", \"38194271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of biased/β-arrestin signaling not captured\", \"How internalization residues couple to JNK restraint mechanistically\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Solved the structural and functional basis for CD69 acting as a cis transmembrane protein agonist that drives S1PR1 internalization to block egress, and confirmed direct S1PR1-STAT3 binding in carcinoma.\",\n      \"evidence\": \"Cryo-EM of CD69-S1PR1-Gi with interface mutagenesis, internalization and egress assays; S1PR1-STAT3 co-IP with KD/OE tumor assays; zebrafish s1pr1 loss in astrocytes\",\n      \"pmids\": [\"37039481\", \"31438989\", \"38096817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3 binding is truly direct rests on single co-IP studies\", \"CNS/glial roles characterized only in non-mammalian models\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple transcriptional inputs (STAT1, STAT3, KLF2, SMYD3/H3K4me3) and post-translational modifications are integrated to set S1PR1 surface density and signaling output in a given cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of receptor abundance control across tissues\", \"Kinases for individual phosphosites incompletely identified\", \"Biased signaling between Gi and β-arrestin arms not structurally defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 11, 22]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 33, 37]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 9, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 9, 12, 28]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 17, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 18, 26, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 14, 25, 29]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GNAI1\", \"GNAI3\", \"CAV1\", \"AKT1\", \"CD69\", \"MET\", \"ITGB4\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}