Affinage

S1PR1

Sphingosine 1-phosphate receptor 1 · UniProt P21453

Length
382 aa
Mass
42.8 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

S1PR1 is a Gi-coupled GPCR for sphingosine-1-phosphate that orchestrates lymphocyte trafficking, vascular maturation, endothelial barrier function, and immune regulation by coupling extracellular S1P gradients to intracellular PI3K/Rac, MAPK, AKT/eNOS, and JAK2/STAT3 signaling cascades (PMID:9765227, PMID:11032855, PMID:21102457, PMID:31854513). Ligand recognition depends on Arg120 and Arg292 (ion-pairing with the S1P phosphate head group) and Glu121 (contacting the ammonium group), as confirmed by mutagenesis and cryo-EM structures that further revealed the mechanical activation switch and Gi-coupling interface (PMID:10982820, PMID:34526663). Agonist-induced internalization requires GRK2-mediated C-terminal phosphorylation, Tyr143 phosphorylation, moesin-dependent clathrin-coated vesicle formation, and dynamin-2-dependent endocytosis; this internalization is essential for lymphocyte egress from lymphoid organs, T cell survival via BCL2/JNK regulation, and suppression of type I interferon signaling (PMID:11741892, PMID:25588843, PMID:24358210, PMID:24638168, PMID:38194271, PMID:26787880). S1PR1 expression is transcriptionally driven by KLF2, STAT1, and STAT3, while CD69 functions as an unconventional protein agonist that contacts TM4 to allosterically activate Gi coupling and trigger receptor downregulation, thereby blocking lymphocyte egress (PMID:24162775, PMID:32006593, PMID:21102457, PMID:37039481).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Establishing that EDG-1 is a bona fide Gi/o-coupled S1P receptor resolved the orphan receptor's identity and defined its core signaling repertoire (PLC, Ca²⁺, MAPK, adenylate cyclase inhibition).

    Evidence Reconstitution in CHO/HEL cells with radioligand binding, pertussis toxin sensitivity, and multiple second-messenger assays

    PMID:9765227

    Open questions at the time
    • Downstream effectors beyond PLC/MAPK not yet mapped
    • In vivo relevance of S1PR1 signaling unknown
  2. 1999 High

    Demonstrating exclusive Gi coupling (versus Gq for EDG-3/EDG-5) and agonist-induced internalization with C-terminal dependence established the receptor's subtype-specific G-protein selectivity and trafficking behavior.

    Evidence Xenopus oocyte chimeric Gα reconstitution for coupling specificity; GFP-tagged receptor live imaging and C-terminal truncation in HEK293 for internalization

    PMID:10198065 PMID:10383399

    Open questions at the time
    • Kinase(s) mediating C-terminal phosphorylation unknown
    • Endosomal fate and recycling mechanism not defined
  3. 2000 High

    Knockout mice and mutagenesis revealed that S1PR1 mediates Rac activation via PI3K to drive cell migration and vascular maturation, and identified Arg120/Arg292/Glu121 as the ligand-binding triad, connecting receptor structure to developmental phenotype.

    Evidence Edg1−/− mouse embryonic cells (Rac/migration defects, vascular smooth muscle loss); site-directed mutagenesis with radioligand and GTPγS binding; reconstitution in CHO cells for PI3K-Rac-chemotaxis axis

    PMID:10982820 PMID:11032855 PMID:11094076

    Open questions at the time
    • Structural basis of Gi engagement not yet visualized
    • Tissue-specific roles beyond vasculature unexplored
  4. 2001 High

    Identification of GRK2 as the kinase driving agonist-induced internalization (distinct from PKC-mediated phosphorylation) and a single-residue determinant of S1P versus LPA selectivity established the mechanistic basis for receptor desensitization and ligand discrimination.

    Evidence In vitro GRK2 kinase assay and C-terminal truncation mutants; Glu/Gln interchange mutagenesis between S1P1 and LPA1

    PMID:11604399 PMID:11741892

    Open questions at the time
    • In vivo consequence of GRK2-dependent desensitization for lymphocyte trafficking not yet tested
    • Complete phosphorylation site map lacking
  5. 2002 High

    N-glycosylation at Asn30 was shown to be required for ligand-induced internalization and caveolar localization but dispensable for ligand binding and MAPK signaling, dissociating surface signaling from endocytic trafficking.

    Evidence N30D mutagenesis with sucrose gradient fractionation, internalization, binding, and MAPK assays

    PMID:12087059

    Open questions at the time
    • Role of caveolar versus clathrin-mediated endocytosis not resolved
    • Glycosylation impact on in vivo receptor function untested
  6. 2010 High

    Discovery of the S1PR1-STAT3 positive feedback loop — STAT3 transcribes S1PR1, and S1PR1 reciprocally sustains STAT3 via JAK2 upregulation — provided a mechanistic basis for persistent oncogenic STAT3 activation.

    Evidence ChIP for STAT3 on S1PR1 promoter, siRNA, reporter assays, JAK2/pSTAT3 Western blots, tumor xenografts

    PMID:21102457

    Open questions at the time
    • How S1PR1 upregulates JAK2 at the molecular level unclear
    • Whether feedback loop operates in all tumor types unknown
  7. 2011 High

    Genetic epistasis in conditional GRK2-knockout mice proved that GRK2-mediated S1PR1 desensitization on blood-exposed lymphocytes is required for lymphocyte entry into lymphoid tissues, connecting receptor desensitization to immune cell trafficking in vivo.

    Evidence Conditional GRK2 KO mice, adoptive transfer, rescue in S1P-deficient background, desensitization motif point mutant

    PMID:21960637

    Open questions at the time
    • Phosphorylation site specificity for desensitization versus internalization not resolved
    • Whether other GRKs contribute in vivo not excluded
  8. 2012 High

    Multiple conditional knockout studies expanded S1PR1's physiological roles to megakaryocyte-directed thrombopoiesis, endothelial vascular integrity (downstream of Smad2/3), and T cell trafficking regulated by CCR7-ERK5-KLF2 transcriptional control of S1PR1 expression.

    Evidence Megakaryocyte-specific S1PR1 KO with intravital imaging (thrombocytopenia); endothelial Smad2/3 double KO with reduced S1PR1; ERK5-conditional KO in T cells abolishing CCL19-stimulated S1PR1 upregulation

    PMID:22334704 PMID:22498737 PMID:23148237

    Open questions at the time
    • Signaling intermediates linking S1PR1 to proplatelet extension not mapped
    • Direct Smad2/3 binding to S1PR1 promoter not shown
  9. 2013 High

    KLF2 was identified as the key transcription factor driving S1PR1 expression in T cells, with TGF-β/IL-33/TNF suppressing KLF2 via PI3K/Akt to downregulate S1PR1, thereby enabling tissue-resident memory T cell formation; separately, moesin was shown to be required for clathrin-mediated S1PR1 internalization.

    Evidence Retroviral forced S1PR1 expression preventing TRM formation; moesin-KO mice with impaired clathrin-coated vesicle formation and S1PR1 internalization

    PMID:24162775 PMID:24358210

    Open questions at the time
    • Direct moesin-S1PR1 physical interaction not demonstrated
    • How moesin specifically enables clathrin coat assembly on S1PR1 unclear
  10. 2014 High

    Dynamin-2-dependent endocytosis was shown to sustain S1PR1 signaling at low S1P concentrations near lymphoid exit sites, establishing that endosomal signaling (not just surface signaling) is required for lymphocyte egress.

    Evidence T cell-specific dynamin-2 KO mice with defective egress rescued by S1PR1 overexpression

    PMID:24638168

    Open questions at the time
    • Endosomal signaling effectors downstream of internalized S1PR1 not identified
    • Whether signaling endosomes carry Gi or switch to other effectors unknown
  11. 2015 High

    Tyr143 phosphorylation was identified as a required step for agonist-induced S1PR1 internalization, with phospho-mimetic (Y143D) causing constitutive internalization and phospho-dead (Y143F) blocking it, adding a tyrosine phosphorylation checkpoint to the GRK2/serine-threonine mechanism.

    Evidence Y143F/Y143D mutagenesis with flow cytometry and TEER in endothelial cells

    PMID:25588843

    Open questions at the time
    • Kinase phosphorylating Y143 not identified
    • Relationship between Y143 phosphorylation and GRK2-mediated C-terminal phosphorylation unresolved
  12. 2016 High

    S1PR1 internalization was shown to suppress type I IFN signaling by accelerating IFNAR1 turnover independently of Gi (pertussis toxin-resistant), revealing an internalization-dependent immunomodulatory mechanism; simultaneously, KLF2-dependent S1PR1 expression downstream of miR302-367/ERK was linked to vascular stabilization.

    Evidence S1PR1 agonism with Tat-fusion peptide blocking internalization in pDCs; miR302-367 OE with S1PR1 conditional KO epistasis

    PMID:26787880 PMID:27756792

    Open questions at the time
    • Mechanism by which internalized S1PR1 promotes IFNAR1 degradation unknown
    • Whether miR302-367-KLF2-S1PR1 axis operates outside developmental angiogenesis unclear
  13. 2021 High

    Cryo-EM structures of S1PR1-Gi complexes provided atomic-level visualization of the ligand-binding pocket, the activation switch (TM5-6 rearrangement), and the Gi-coupling interface, validating decades of mutagenesis data; additionally, the S1PR1-STAT3 loop was extended to hypothalamic energy homeostasis and endothelial cardioprotection.

    Evidence Cryo-EM structures with diverse agonists; hypothalamic S1PR1 disruption altering food intake via STAT3; endothelial S1PR1-KO exacerbating cardiac remodeling with CSF1/macrophage and AKT/eNOS readouts

    PMID:25255053 PMID:31854513 PMID:32091582 PMID:34526663

    Open questions at the time
    • Dynamics of receptor activation in membrane environment not captured
    • How S1PR1-STAT3 loop integrates with canonical JAK-STAT kinetics in neurons versus tumor cells unclear
  14. 2023 High

    CD69 was revealed as an unprecedented protein agonist of S1PR1: its TM helix contacts S1PR1-TM4 to allosterically activate Gi and drive internalization/degradation, providing the structural mechanism for CD69-mediated lymphocyte retention in tissues.

    Evidence Cryo-EM structure of CD69-S1PR1-Gi complex, interface mutagenesis, internalization and egress assays

    PMID:37039481

    Open questions at the time
    • Whether other transmembrane proteins use a similar TM-contact agonism mechanism unknown
    • In vivo stoichiometry and regulation of CD69-S1PR1 interaction not defined
  15. 2024 Medium

    S1PR1 internalization was linked to T cell survival via BCL2 family balance and JNK restraint, with the same C-terminal residues required for internalization also necessary for anti-apoptotic function, unifying trafficking and survival signaling.

    Evidence Internalization-defective mutants, JNK/BCL2 assays, validation in ozanimod-treated ulcerative colitis patients

    PMID:38194271

    Open questions at the time
    • Direct endosomal signaling intermediates linking internalized S1PR1 to JNK suppression not identified
    • Whether anti-apoptotic function is Gi-dependent or Gi-independent not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the kinase phosphorylating Tyr143, the precise endosomal signaling complex composition after S1PR1 internalization, and whether the CD69 protein-agonist paradigm extends to other GPCRs.
  • Y143 kinase identity unknown
  • Endosomal signaling effectors of internalized S1PR1 not characterized
  • Structural basis of S1PR1-JAK2 upregulation mechanism undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
CD69DNM2GRK2KLF2MSNSPHK1STAT3

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 EDG1/S1PR1 is a functional Gi/o-coupled GPCR for sphingosine-1-phosphate that activates phospholipase C, mobilizes intracellular Ca2+, activates Ras-MAPK, and inhibits adenylate cyclase; all responses are pertussis toxin-sensitive. Stable transfection in CHO and HEL cells, radioligand binding, pertussis toxin treatment, Ca2+ mobilization assay, IP production assay, MAPK activation assay, cAMP assay The Journal of biological chemistry High 9765227
1999 EDG1/S1PR1 couples preferentially to Gi (not Gq) as demonstrated in a Xenopus oocyte expression system; co-expression with chimeric Gαqi protein was required to confer S1P-responsive intracellular calcium transients, whereas EDG-3 and EDG-5 directly coupled to Gq pathway. Xenopus oocyte mRNA microinjection, chimeric G-protein co-expression, calcium transient recording The Journal of biological chemistry High 10383399
1999 Ligand-induced trafficking of EDG-1/S1PR1: SPP specifically induces reversible receptor translocation from the plasma membrane to perinuclear endocytic vesicles/lysosomes (t1/2 ~15 min internalization, ~30 min recycling); C-terminal truncation completely blocks internalization. EDG-1-GFP chimera live imaging in HEK293 cells, colocalization with endocytic markers, SPP dose-response, C-terminal truncation mutants Molecular biology of the cell High 10198065
2000 EDG1/S1PR1 mediates S1P-induced migration and Rac activation; Edg1-/- mouse embryonic cells fail to activate Rac in response to S1P and exhibit defective migration, leading to vascular maturation defects due to loss of vascular smooth muscle cells/pericytes. Germline knockout mouse model, vascular phenotyping, Rac GTPase activation assay, cell migration assay The Journal of clinical investigation High 11032855
2000 EDG1/S1PR1 (but not EDG5) signals via PI3-kinase and Rac to promote chemotaxis and membrane ruffling; EDG5 instead inhibits Rac by stimulating Rac-GTPase-activating protein activity, establishing receptor subtype-specific regulation of Rac. CHO cells stably expressing EDG1, EDG3, or EDG5; chemotaxis assay, membrane ruffle quantification, GTP-Rac pulldown, PI3K assay, pertussis toxin and dominant-negative Cdc42/Rho constructs Molecular and cellular biology High 11094076
2000 Computational modeling and site-directed mutagenesis identified Arg120, Arg292 (ion-pairing with the phosphate of S1P), and Glu121 (ion-pairing with the ammonium group) as critical ligand-recognition residues of EDG-1/S1PR1. Computational homology modeling, site-directed mutagenesis, radioligand binding, [35S]GTPγS binding, receptor internalization assay The Journal of biological chemistry High 10982820
2001 A single residue difference (Glu vs. Gln at the homologous position) determines ligand specificity between S1P1/EDG1 (Glu required for S1P recognition) and LPA1/EDG2; Glu/Gln interchange point mutants confirmed this prediction. Computational modeling, site-directed mutagenesis of S1P1 and LPA1, ligand-binding assays The Journal of biological chemistry High 11604399
2001 EDG1/S1PR1 phosphorylation and internalization are regulated by two independent mechanisms: agonist-induced GRK2 phosphorylation (on C-terminal serine/threonine residues) drives internalization, whereas PKC/PMA-induced phosphorylation causes surface loss via a distinct pathway; removal of 12 C-terminal residues specifically blocks agonist-mediated internalization but not PMA-mediated phosphorylation. Phosphoamino acid analysis, in vitro GRK2 kinase assay, C-terminal truncation mutants, surface expression assay in intact cells The Journal of biological chemistry High 11741892
2001 EDG-1/S1PR1 mediates S1P-induced cardiac myocyte hypertrophy primarily via Gi, activating ERK, p38 MAPK, JNK, PI3K/Akt, and Rho/actin stress fiber pathways; anti-EDG1 antibodies blocked S1P-induced hypertrophy in neonatal rat cardiomyocytes. Neonatal rat cardiomyocyte culture, anti-EDG1 antibody blocking, phospho-Western blot, kinase inhibitors, [3H]-phenylalanine incorporation, cell size measurement Journal of molecular and cellular cardiology Medium 11549339
2002 EDG-1/S1PR1 is N-glycosylated at Asn30 in its extracellular N-terminus; this glycosylation is required for ligand-induced receptor internalization and for localization to caveolae microdomains, but not for ligand binding or MAPK activation. N30D mutagenesis, sucrose density gradient fractionation, ligand binding assay, MAPK activation assay, internalization assay FASEB journal High 12087059
2010 STAT3 directly transcribes the S1PR1 gene; S1PR1 reciprocally activates STAT3 by upregulating JAK2 tyrosine kinase activity, and S1P-S1PR1-induced STAT3 activation is persistent (vs. transient IL-6-induced activation), forming a positive feedback loop for sustained STAT3 activity in tumor cells. ChIP assay, siRNA knockdown, reporter assay, Western blot for JAK2/pSTAT3, tumor xenograft models Nature medicine High 21102457
2011 GRK2 mediates agonist-induced S1PR1 desensitization on blood-exposed lymphocytes; GRK2 deficiency impairs lymphocyte movement from blood into lymphoid tissues, and this block is rescued in S1P-deficient mice. B cell movement between marginal zone and follicles requires GRK2-dependent S1PR1 desensitization. Conditional GRK2 knockout mice, adoptive transfer experiments, S1P-deficient mouse rescue, S1PR1 desensitization motif point mutant Science High 21960637
2012 S1PR1 on megakaryocytes directs proplatelet extension into bone marrow sinusoids by sensing the S1P gradient; conditional S1PR1-deficient mice develop severe thrombocytopenia due to aberrant extravascular proplatelet formation and defective intravascular shedding. Conditional knockout mice, intravital multiphoton microscopy, platelet counts, bone marrow histology The Journal of experimental medicine High 23148237
2012 Smad2/3 signaling in endothelial cells maintains vascular integrity by regulating S1PR1 and N-cadherin expression; endothelial-specific Smad2/3 double KO results in reduced S1PR1 expression, gaps between ECs and mural cells, and embryonic hemorrhage. Tie2-Cre conditional double knockout mice, immunostaining, Western blot for S1PR1 and adhesion proteins Blood Medium 22498737
2012 S1PR1-STAT3 signaling in myeloid cells enables intravasation and formation of premetastatic niches; targeting S1PR1 or STAT3 in myeloid cells disrupts existing premetastatic niches. Myeloid-specific conditional knockouts, flow cytometry, tumor metastasis models Cancer cell Medium 22624714
2013 KLF2 transcriptionally drives S1PR1 expression in T cells; TGF-β, IL-33, and TNF suppress KLF2 via PI3K/Akt signaling, thereby downregulating S1PR1 and enabling tissue-resident memory CD8+ T cell establishment. Forced S1PR1 expression prevents TRM cell formation. Retroviral forced expression of S1PR1 in T cells, cytokine treatment, transcription factor knockdown, mouse adoptive transfer models Nature immunology High 24162775
2013 S1PR1 forms a complex with c-Met and integrin β4 in caveolin-enriched lipid rafts; HGF-induced c-Met activation leads to S1PR1 transactivation and Rac1 activation, which are rate-limiting for endothelial barrier enhancement. Co-immunoprecipitation, siRNA knockdown of S1PR1 and ITGB4, transendothelial electrical resistance measurement, c-Met inhibitor XL880 The Journal of biological chemistry Medium 23212923
2014 Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling in T cells at low S1P concentrations near lymphoid organ exit sites; dynamin 2-deficient T cells can only generate a transient pulse of S1PR1 signaling insufficient for egress. T cell-specific dynamin 2 knockout mice, transgenic S1PR1 rescue, lymphocyte egress assay, thymus and lymph node cellularity The Journal of experimental medicine High 24638168
2015 Tyrosine 143 phosphorylation of S1PR1 is required for agonist-induced receptor internalization in endothelial cells; Y143F (phospho-defective) fails to internalize, Y143D (phospho-mimicking) shows constitutive internalization; S1PR1 dephosphorylation at Y143 accompanies receptor recycling to the plasma membrane. Site-directed mutagenesis (Y143F, Y143D), flow cytometry for surface S1PR1, TEER measurement, phospho-specific analysis Journal of cell science High 25588843
2016 S1PR1 agonism accelerates IFNAR1 turnover and suppresses STAT1 phosphorylation in plasmacytoid dendritic cells, thereby inhibiting the type I IFN autoamplification loop; this suppression is pertussis toxin-resistant but blocked by a C-terminal S1PR1 peptide that prevents receptor internalization, indicating internalization is required for the immunosuppressive mechanism. Pharmacological S1PR1 agonism and antagonism, Tat-fusion peptide blocking internalization, IFNAR1 turnover assay, pSTAT1 Western blot, in vivo CpG-A IFN-α induction Proceedings of the National Academy of Sciences High 26787880
2016 T cell-intrinsic S1PR1 is the master regulator of effector T cell sinus entry and egress from draining lymph nodes during infection; S1PR1-deficient effector T cells migrate normally within the paracortex but fail to enter lymphatic sinuses. Inducible T cell-specific S1PR1 knockout mice, two-photon intravital microscopy, adoptive transfer Proceedings of the National Academy of Sciences High 26862175
2013 Moesin controls clathrin-mediated S1PR1 internalization in T cells; moesin-deficient T cells fail to form clathrin-coated vesicles and internalize S1PR1 upon S1P stimulation, resulting in delayed lymphopenia after FTY720 treatment and persistent S1P chemotaxis ex vivo. Moesin-deficient mice, FTY720 treatment, clathrin inhibitor, colocalization of S1PR1 with clathrin-coated vesicles/early endosomes, chemotaxis assay PloS one High 24358210
2017 S1PR1 in tumor-associated macrophages promotes lymphangiogenesis and pulmonary metastasis via NLRP3 inflammasome activation and IL-1β production; conditional S1PR1 deletion in CD11bhi CD206+ TAMs reduces Nlrp3 expression and prevents metastasis. Myeloid-specific S1PR1 conditional knockout mice, transcriptome analysis of isolated TAMs, in vitro macrophage-lymphangiogenesis assay, inflammasome activation The Journal of experimental medicine High 28739604
2021 Cryo-EM structures of S1PR1 and S1PR5 bound to diverse agonists and heterotrimeric Gi protein reveal: (1) distinct binding modes of chemically different agonists, (2) the mechanical switch that activates these receptors, and (3) the structural basis of G protein coupling and ligand selectivity. Cryo-electron microscopy structure determination, functional signaling assays Cell research High 34526663
2023 CD69 acts as a protein agonist of S1PR1 in cis: cryo-EM structure of CD69-S1PR1-Gi complex shows the CD69 transmembrane helix contacts S1PR1-TM4, allosterically inducing TM5-6 movement to activate Gi coupling and promote receptor internalization and degradation, inhibiting lymphocyte egress. Cryo-EM structure determination, mutagenesis of interface residues, S1PR1 internalization assay, lymphocyte egress assay eLife High 37039481
2021 Endothelial S1PR1 activates ERK signaling and upregulates CSF1 expression, promoting Ly6clow reparative macrophage proliferation via cell-contact manner, thereby ameliorating post-myocardial infarction cardiac remodeling. Endothelial-specific S1pr1 knockout mice, pharmacological S1PR1 activation, CSF1 blockade, flow cytometry, in vitro co-culture Cardiovascular research Medium 32091582
2019 Endothelial S1PR1 activates AKT/eNOS signaling, increasing NO production which inhibits cardiomyocyte hypertrophy and cardiac fibroblast activation; endothelial-specific S1pr1 deletion aggravates pressure overload-induced cardiac dysfunction. Endothelial-specific S1pr1 conditional KO mice, transverse aortic constriction model, in vitro AKT/eNOS pathway inhibition, NO measurement Journal of cellular and molecular medicine Medium 31854513
2014 Hypothalamic S1PR1 in POMC neurons activates STAT3 and the melanocortin system to reduce food intake and increase energy expenditure; STAT3 in turn upregulates S1PR1 expression in a positive feedback loop; selective disruption of hypothalamic S1PR1 increases food intake. Intracerebroventricular S1P injection, selective hypothalamic S1PR1 disruption, STAT3 phosphorylation assay, food intake and energy expenditure measurement in rodents Nature communications Medium 25255053
2016 miR302-367 reduces Erk1/2 in endothelial cells, which increases KLF2 expression, which in turn upregulates S1PR1 and VE-cadherin; genetic or pharmacological S1PR1 deletion reverses the anti-angiogenic and vascular-stabilizing effects of miR302-367. Endothelial-specific miR302-367 overexpression, S1PR1 conditional KO mice, pharmacological S1PR1 blockade, in vitro and in vivo angiogenesis assays Circulation research Medium 27756792
2021 aPC activates PAR1 to recruit β-arrestin-2, which activates SphK1 independent of Dvl2; SphK1 then transactivates S1PR1 to activate Akt and protect endothelial cells from apoptosis. S1PR1 co-associates with caveolin-1, and aPC increases S1PR1/Cav1 association; this pathway is distinct from the PAR1-β-arr2-ERK1/2 pathway. siRNA knockdown of PAR1, S1PR1, SphK1, β-arrestin-2, Cav1; co-immunoprecipitation; apoptosis assay in human endothelial cells Proceedings of the National Academy of Sciences Medium 34873055
2024 S1PR1 limits T cell apoptosis by maintaining BCL2 family balance via restraint of JNK activity; the same C-terminal residues required for receptor internalization are necessary for this anti-apoptotic function, linking internalization to survival signaling. S1PR1 internalization-defective mutants, JNK activity assay, BCL2 family protein expression, apoptosis assay, validation in ozanimod-treated ulcerative colitis patients The Journal of clinical investigation Medium 38194271
2023 S1PR1 (ortholog of Drosophila Tre1) is required for astrocyte process elaboration; loss of s1pr1 in zebrafish disrupts astrocyte process extension/retraction dynamics during growth, leading to defects in motor behavior. s1pr1 zebrafish knockout, live imaging of astrocyte process dynamics, pharmacological treatment, Drosophila Tre1 mutant analysis Neuron Medium 38096817
2020 STAT1 transcription factor binds to the -29 to -12 bp minimal promoter region of S1PR1, directly stimulating S1PR1 expression; STAT1 knockdown reduces S1PR1 and overexpression or IFN-γ activation of STAT1 increases S1PR1 levels. EMSA, ChIP assay, promoter-reporter truncation analysis, STAT1 siRNA knockdown, IFN-γ stimulation Gene Medium 32006593
2012 CCR7/CCL19 signaling upregulates EDG-1/S1PR1 expression in T cells via an ERK5-KLF2 pathway; ERK5 conditional deletion in T cells abolishes CCL19-stimulated S1PR1 upregulation and migration toward S1P. ERK5flox/flox/Lck-Cre conditional KO mice, human T cell line CCR7 stimulation, KLF2 and S1PR1 expression analysis, chemotaxis assay The Journal of biological chemistry Medium 22334704
2012 IL-10 stimulation induces S1PR1 expression in lymph node T cells via STAT3-dependent signaling, promoting CD4+ T cell egress and peripheral nerve infiltration in autoimmune neuropathy. IL-10-deficient mice, IL-10 in vitro stimulation of lymph node cells, STAT3 inhibition, S1PR1 expression analysis, histological nerve infiltration assessment Journal of immunology Medium 29367208
2022 S1PR1/S1P/Sphk1 pathway differentially modulates CD4+ vs. CD8+ T cell alloreactivity by augmenting mitochondrial fission and increasing mitochondrial mass specifically in allogeneic CD4+ T cells via AMPK/AKT/mTOR/Drp1 signaling. Sphk1 and S1PR1 conditional knockouts, pharmacological inhibitors, GVHD mouse model, mitochondrial mass and fission assays, flow cytometry Cellular & molecular immunology Medium 36071219

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. The Journal of clinical investigation 977 11032855
2013 Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nature immunology 680 24162775
2010 STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors. Nature medicine 339 21102457
2000 Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3. Molecular and cellular biology 275 11094076
1998 EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. The Journal of biological chemistry 245 9765227
2017 S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. The Journal of experimental medicine 236 28739604
1999 Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. The Journal of biological chemistry 225 10383399
2012 S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites. Cancer cell 209 22624714
2018 Targeting the SphK1/S1P/S1PR1 Axis That Links Obesity, Chronic Inflammation, and Breast Cancer Metastasis. Cancer research 187 29351902
2011 GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood. Science (New York, N.Y.) 170 21960637
1999 Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1. Molecular biology of the cell 169 10198065
1999 EDG3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with signaling characteristics distinct from EDG1 and AGR16. Biochemical and biophysical research communications 142 10381367
2000 Identification of Edg1 receptor residues that recognize sphingosine 1-phosphate. The Journal of biological chemistry 133 10982820
2012 A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis. The Journal of experimental medicine 126 23148237
2016 The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures. Journal of neuroinflammation 103 26856814
2011 Sphingosine kinase 1 promotes tumour cell migration and invasion via the S1P/EDG1 axis in hepatocellular carcinoma. Liver international : official journal of the International Association for the Study of the Liver 89 22098666
2001 A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors. The Journal of biological chemistry 89 11604399
2001 EDG1 receptor stimulation leads to cardiac hypertrophy in rat neonatal myocytes. Journal of molecular and cellular cardiology 83 11549339
2015 miR-155 Deficiency Ameliorates Autoimmune Inflammation of Systemic Lupus Erythematosus by Targeting S1pr1 in Faslpr/lpr Mice. Journal of immunology (Baltimore, Md. : 1950) 80 25911753
2012 S1PR1 is an effective target to block STAT3 signaling in activated B cell-like diffuse large B-cell lymphoma. Blood 78 22745305
2001 Dual regulation of EDG1/S1P(1) receptor phosphorylation and internalization by protein kinase C and G-protein-coupled receptor kinase 2. The Journal of biological chemistry 76 11741892
2018 Wnt/β-catenin signaling regulates VE-cadherin-mediated anastomosis of brain capillaries by counteracting S1pr1 signaling. Nature communications 71 30451830
2023 Sphingosine-1-phosphate derived from PRP-Exos promotes angiogenesis in diabetic wound healing via the S1PR1/AKT/FN1 signalling pathway. Burns & trauma 69 37251708
2001 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. The Journal of biological chemistry 69 11673450
2014 MicroRNA-363-mediated downregulation of S1PR1 suppresses the proliferation of hepatocellular carcinoma cells. Cellular signalling 66 24631531
2021 Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition. Cell research 65 34526663
2002 N-glycans of sphingosine 1-phosphate receptor Edg-1 regulate ligand-induced receptor internalization. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 65 12087059
1997 The mouse gene for the inducible G-protein-coupled receptor edg-1. Genomics 65 9226368
2016 T cell-intrinsic S1PR1 regulates endogenous effector T-cell egress dynamics from lymph nodes during infection. Proceedings of the National Academy of Sciences of the United States of America 64 26862175
2018 Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine. Theranostics 61 30083262
2017 Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain 61 28570482
2014 Hypothalamic S1P/S1PR1 axis controls energy homeostasis. Nature communications 61 25255053
2012 Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions. Blood 61 22498737
2019 The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1-STAT3 signaling pathway. Cell death & disease 60 31534132
2019 S1PR1 as a Novel Promising Therapeutic Target in Cancer Therapy. Molecular diagnosis & therapy 58 31115798
2000 Sphingosine 1-phosphate: a ligand for the EDG-1 family of G-protein-coupled receptors. Annals of the New York Academy of Sciences 56 10818441
2018 Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway. Cell death & disease 55 30377291
2013 An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 55 23554499
2016 S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification. Proceedings of the National Academy of Sciences of the United States of America 54 26787880
2018 SPHK1-S1PR1-RANKL Axis Regulates the Interactions Between Macrophages and BMSCs in Inflammatory Bone Loss. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 52 29377379
2021 Vascular endothelial S1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction. Cardiovascular research 50 32091582
2016 PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis. Molecular imaging and biology 49 26975859
2010 The sphingosine 1-phosphate receptor, S1PR₁, plays a prominent but not exclusive role in enhancing the excitability of sensory neurons. Journal of neurophysiology 45 20844107
2008 beta-Arrestin recruitment assay for the identification of agonists of the sphingosine 1-phosphate receptor EDG1. Journal of biomolecular screening 45 19036707
2000 Sphingosine-1-phosphate signaling via the EDG-1 family of G-protein-coupled receptors. Annals of the New York Academy of Sciences 42 10818438
2016 A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability. Circulation research 41 27756792
2019 Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway. Journal of cellular and molecular medicine 40 31854513
2014 Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling. The Journal of experimental medicine 40 24638168
2022 S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression. Cell death & disease 36 36068200
2012 Critical role of S1PR1 and integrin β4 in HGF/c-Met-mediated increases in vascular integrity. The Journal of biological chemistry 36 23212923
2019 S1P-S1PR1 Signaling: the "Sphinx" in Osteoimmunology. Frontiers in immunology 34 31293578
2018 Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus. PloS one 34 29608575
2018 S1P promotes inflammation-induced tube formation by HLECs via the S1PR1/NF-κB pathway. International immunopharmacology 33 30476824
2012 Knockdown of the sphingosine-1-phosphate receptor S1PR1 reduces pain behaviors induced by local inflammation of the rat sensory ganglion. Neuroscience letters 31 22445889
2021 The CAGE-MiR-181b-5p-S1PR1 Axis Regulates Anticancer Drug Resistance and Autophagy in Gastric Cancer Cells. Frontiers in cell and developmental biology 29 34113619
2020 Post-translational modifications of S1PR1 and endothelial barrier regulation. Biochimica et biophysica acta. Molecular and cell biology of lipids 29 32585303
2017 bFGF Protects Against Oxygen Glucose Deprivation/Reoxygenation-Induced Endothelial Monolayer Permeability via S1PR1-Dependent Mechanisms. Molecular neurobiology 29 28466272
2022 S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission. Cellular & molecular immunology 28 36071219
2020 Genomewide Meta-Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent-Induced Sensory Peripheral Neuropathy. Clinical pharmacology and therapeutics 28 32562552
2023 Transmembrane protein CD69 acts as an S1PR1 agonist. eLife 26 37039481
2021 aPC/PAR1 confers endothelial anti-apoptotic activity via a discrete, β-arrestin-2-mediated SphK1-S1PR1-Akt signaling axis. Proceedings of the National Academy of Sciences of the United States of America 26 34873055
2018 S1PR1 predicts patient survival and promotes chemotherapy drug resistance in gastric cancer cells through STAT3 constitutive activation. EBioMedicine 26 30316864
2015 S1PR1 Tyr143 phosphorylation downregulates endothelial cell surface S1PR1 expression and responsiveness. Journal of cell science 26 25588843
2014 Sphingosine-1-phosphate promotes extravillous trophoblast cell invasion by activating MEK/ERK/MMP-2 signaling pathways via S1P/S1PR1 axis activation. PloS one 26 25188412
2012 CCR7/CCL19 controls expression of EDG-1 in T cells. The Journal of biological chemistry 26 22334704
2021 Blocking SphK1/S1P/S1PR1 Signaling Pathway Alleviates Lung Injury Caused by Sepsis in Acute Ethanol Intoxication Mice. Inflammation 25 34109517
2020 In vivo Characterization of Four 18F-Labeled S1PR1 Tracers for Neuroinflammation. Molecular imaging and biology 24 32602083
2020 Coix Seed Oil Exerts an Anti-Triple-Negative Breast Cancer Effect by Disrupting miR-205/S1PR1 Axis. Frontiers in pharmacology 24 33101013
2017 S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells. Leukemia 24 28878352
2014 Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth. American journal of physiology. Cell physiology 24 24740542
2023 Dexmedetomidine alleviates oxidative stress and mitochondrial dysfunction in diabetic peripheral neuropathy via the microRNA-34a/SIRT2/S1PR1 axis. International immunopharmacology 23 37012886
2021 SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters. Cell death & disease 22 34301921
2020 Coinhibition of S1PR1 and GP130 by siRNA-loaded alginate-conjugated trimethyl chitosan nanoparticles robustly blocks development of cancer cells. Journal of cellular physiology 22 32424937
2018 Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents. European journal of medicinal chemistry 22 29604582
2018 MiR-125b-1-3p Exerts Antitumor Functions in Lung Carcinoma Cells by Targeting S1PR1. Chinese medical journal 22 30082521
2012 B cell-specific S1PR1 deficiency blocks prion dissemination between secondary lymphoid organs. Journal of immunology (Baltimore, Md. : 1950) 22 22504650
2023 Siponimod exerts neuroprotective effects on the retina and higher visual pathway through neuronal S1PR1 in experimental glaucoma. Neural regeneration research 21 36204852
2020 LncRNA KCNQ1OT1 regulates the invasion and migration of hepatocellular carcinoma by acting on S1PR1 through miR-149. Cancer gene therapy 21 32753631
2024 S1PR1 inhibition induces proapoptotic signaling in T cells and limits humoral responses within lymph nodes. The Journal of clinical investigation 20 38194271
2024 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. Chemico-biological interactions 20 38823539
2023 Study on the action mechanism of Buyang Huanwu Decoction against ischemic stroke based on S1P/S1PR1/PI3K/Akt signaling pathway. Journal of ethnopharmacology 20 37030556
2016 Hypothalamic S1P/S1PR1 axis controls energy homeostasis in Middle-Aged Rodents: the reversal effects of physical exercise. Aging 20 28039439
2013 Moesin controls clathrin-mediated S1PR1 internalization in T cells. PloS one 20 24358210
2023 Inhibitory Effect of Astragalus Polysaccharide on Premetastatic Niche of Lung Cancer through the S1PR1-STAT3 Signaling Pathway. Evidence-based complementary and alternative medicine : eCAM 19 36714534
2023 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. International immunopharmacology 19 37699301
2020 BATF3 promotes malignant phenotype of colorectal cancer through the S1PR1/p-STAT3/miR-155-3p/WDR82 axis. Cancer gene therapy 19 33057139
2019 Potential involvement of S1PR1/STAT3 signaling pathway in cardiac valve damage due to rheumatic heart disease. Biotechnic & histochemistry : official publication of the Biological Stain Commission 19 30712389
2019 Sphk1/S1P/S1PR1 Signaling is Involved in the Development of Autoimmune Thyroiditis in Patients and NOD.H-2h4 Mice. Thyroid : official journal of the American Thyroid Association 19 30963819
2019 Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation. Cells 19 31357710
2023 Force-Loaded Cementocytes Regulate Osteoclastogenesis via S1P/S1PR1/Rac1 Axis. Journal of dental research 18 37735908
2023 Astrocyte growth is driven by the Tre1/S1pr1 phospholipid-binding G protein-coupled receptor. Neuron 18 38096817
2018 IL-10 Paradoxically Promotes Autoimmune Neuropathy through S1PR1-Dependent CD4+ T Cell Migration. Journal of immunology (Baltimore, Md. : 1950) 18 29367208
2023 S1PR1/S1PR3-YAP signaling and S1P-ALOX15 signaling contribute to an aggressive behavior in obesity-lymphoma. Journal of experimental & clinical cancer research : CR 17 36600310
2023 S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway. Oncogene 17 37828220
2023 Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease. Neuroscience letters 17 38101611
2018 Syntheses and in vitro biological evaluation of S1PR1 ligands and PET studies of four F-18 labeled radiotracers in the brain of nonhuman primates. Organic & biomolecular chemistry 17 30462126
2021 miR-145-5p exerts anti-tumor effects in diffuse large B-cell lymphoma by regulating S1PR1/STAT3/AKT pathway. Leukemia & lymphoma 16 33715582
2021 S1PR1 signaling in cancer: A current perspective. Advances in protein chemistry and structural biology 16 33931142
2020 STAT1 transcriptionally regulates the expression of S1PR1 by binding its promoter region. Gene 16 32006593
2016 miR-133b, a microRNA targeting S1PR1, suppresses nasopharyngeal carcinoma cell proliferation. Experimental and therapeutic medicine 16 27073467