Affinage

GPR174

Probable G-protein coupled receptor 174 · UniProt Q9BXC1

Length
333 aa
Mass
38.5 kDa
Annotated
2026-06-10
24 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPR174 is an X-chromosome-encoded class A GPCR that functions as a lysophosphatidylserine (LysoPS) receptor governing immune cell activation, with a strong role in adaptive immunity (PMID:26077720, PMID:29017923). Upon LysoPS engagement it couples to Gαs and elevates intracellular cAMP, and cryo-EM structures show that the negatively charged LysoPS head group makes polar contacts within a positively charged pocket while the receptor accepts ligand laterally through a partially open TM4–TM5 portal in the membrane; co-purified endogenous LysoPS confers high constitutive Gs signaling, and a hydration-mediated network through the sodium pocket and the DRY/NPxxY motifs governs activation and selective engagement of Gs versus Gi (PMID:36823105, PMID:37737235, PMID:42096402). In CD4+ T cells GPR174 signaling suppresses IL-2 production and limits activation-marker upregulation in a Gαs-dependent manner, constrains regulatory T cell generation, and its deficiency reduces susceptibility to experimental autoimmune encephalomyelitis (PMID:26077720, PMID:29017923, PMID:29457279). GPR174 also acts as a receptor for CCL21 in B cells, where a testosterone-driven enhancement of GPR174–Gαi association preferentially promotes male B cell migration toward the T–B border and suppresses germinal centre formation, imparting sexual dimorphism to humoral immunity (PMID:31875850). In regulatory T cells, the Gαs/cAMP/PKA axis links GPR174 to downstream transcriptional control of CTLA-4, IL-10, and amphiregulin, shaping macrophage polarization and tissue responses to injury (PMID:30850582, PMID:36473866).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2012 Medium

    Established the molecular identity and signaling output of GPR174 by showing it is a LysoPS receptor with constitutive and ligand-stimulated cAMP elevation through Gαs.

    Evidence Stable expression in CHO cells with cAMP measurement, ligand screen, Erk phosphorylation, and NF449 Gαs inhibition

    PMID:23178570

    Open questions at the time
    • Single cell-based system without structural detail
    • Physiological cell type and in vivo relevance not addressed
  2. 2015 High

    Connected GPR174 signaling to an immunological role by showing LysoPS via GPR174 constrains Treg generation and modulates autoimmune susceptibility.

    Evidence Gpr174 knockout mice, in vitro T cell proliferation/Treg assays, and EAE model

    PMID:26077720

    Open questions at the time
    • Downstream transcriptional effectors of Treg suppression not yet defined
    • G protein dependence of the Treg phenotype not dissected here
  3. 2015 Medium

    Defined the structure-activity requirements of LysoPS for GPR174 potency and selectivity, enabling chemical tools.

    Evidence Synthetic chemistry and SAR of LysoPS analogues across receptor subtypes

    PMID:25970039

    Open questions at the time
    • Structural basis of selectivity not resolved at this stage
    • No in vivo validation of agonists
  4. 2017 Medium

    Identified IL-2 suppression as a concrete molecular output of GPR174 in CD4+ T cells and linked it to activation-induced LysoPS.

    Evidence Gpr174 KO splenocytes/T cells, anti-CD3/CD28 activation, IL-2 ELISA and RT-PCR, lipid profiling

    PMID:29017923

    Open questions at the time
    • G protein coupling responsible for IL-2 suppression not yet pinned down
    • Single lab
  5. 2018 High

    Established that GPR174-mediated T cell suppression operates through Gαs, tying the signaling axis to defined activation phenotypes in vivo.

    Evidence In vivo T cell proliferation models, Gαs inhibition in vitro, CD25/CD69 flow cytometry, Gpr174 KO comparison

    PMID:29457279

    Open questions at the time
    • Did not address Gαi contributions later seen in B cells
    • Transcriptional targets downstream of cAMP not mapped
  6. 2019 High

    Revealed a second ligand and a sex-dimorphic mechanism: GPR174 responds to CCL21 and, through testosterone-enhanced Gαi coupling, directs male B cell positioning and suppresses germinal centre formation.

    Evidence Ligand identification by fractionation, calcium flux, migration assays, GPR174–Gαi Co-IP, orchidectomy/testosterone models, conditional B cell KO, germinal centre analysis

    PMID:31875850

    Open questions at the time
    • Reconciliation of CCL21 versus LysoPS ligand usage not fully resolved
    • Mechanism of testosterone-driven Gαi bias unknown
  7. 2019 Medium

    Extended GPR174 function in Tregs to control of CTLA-4/IL-10 expression and macrophage polarization, linking the receptor to inflammatory tissue outcomes.

    Evidence Gpr174 KO mice, LPS sepsis and CLP models, Treg–macrophage co-culture, flow cytometry and ELISA

    PMID:30850582

    Open questions at the time
    • Direct signaling pathway linking GPR174 loss to CTLA-4/IL-10 not dissected here
    • Single lab
  8. 2022 Medium

    Mapped a downstream transcriptional axis (Gαs/cAMP/PKA/EGR1/AREG) through which GPR174 in Tregs regulates angiogenesis and macrophage polarization.

    Evidence Treg-specific Gpr174 KO mice, hindlimb ischemia, AREG manipulation, EGR1 nuclear translocation, cAMP/PKA inhibition

    PMID:36473866

    Open questions at the time
    • Direct molecular link between PKA and EGR1 nuclear exclusion not fully resolved
    • Single lab
  9. 2023 High

    Provided the atomic basis for LysoPS recognition and Gs coupling, including lateral membrane ligand entry and confirmation of LysoPS as the constitutively bound endogenous ligand driving high basal signaling.

    Evidence Cryo-EM of LysoPS-bound and ligand-free GPR174-Gs complexes, mutagenesis, cAMP assays versus D1R, lipid specificity tests

    PMID:36823105 PMID:37737235 PMID:38048360

    Open questions at the time
    • Gi-bound conformation not resolved in these structures
    • Structural basis of constitutive activity versus regulated signaling not fully separated
  10. 2025 Medium

    Linked the LysoPS/GPR174 cAMP-PKA-CREB axis to a disease setting by showing it drives ESCC invasion and metastasis.

    Evidence LC-MS LysoPS measurement, migration/invasion assays, nuclear-cytoplasmic fractionation, nude mouse metastasis model, GPR174 overexpression

    PMID:40229851

    Open questions at the time
    • Causal requirement of endogenous GPR174 (vs overexpression) in patient tumors not established
    • Single lab
  11. 2026 High

    Resolved the mechanistic basis of Gs versus Gi selectivity by defining a continuous hydration network bridging the sodium pocket, conserved activation motifs, and the G protein interface.

    Evidence High-resolution cryo-EM of GPR174-Gs and GPR174-Gi complexes, molecular dynamics, and functional coupling assays

    PMID:42096402

    Open questions at the time
    • How physiological cues bias cells toward Gs versus Gi engagement not addressed
    • Link between hydration-network mutations and immune phenotypes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GPR174 integrates two ligands (LysoPS and CCL21) and switches between Gαs and Gαi outputs to produce context- and sex-specific immune outcomes remains unresolved.
  • Mechanism of ligand-dependent G protein switching in native cells unknown
  • Molecular basis of testosterone-driven Gαi bias undefined
  • Relative physiological contribution of constitutive versus ligand-driven signaling unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3
Partners
CCL21GNAIGNAS

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 GPR174 expression in CHO cells constitutively elevates intracellular cAMP, and LysoPS stimulation further increases cAMP and phosphorylates Erk; these responses are blocked by NF449, an inhibitor of Gαs protein, establishing GPR174 as a LysoPS receptor that couples to Gαs/adenylyl cyclase signaling. Stable expression in CHO cells, intracellular cAMP measurement, cholera toxin comparison, lipid/nucleotide ligand screen, Erk phosphorylation assay, pharmacological inhibition with NF449 Biochemical and biophysical research communications Medium 23178570
2015 GPR174 functions as a LysoPS receptor that constrains regulatory T cell (Treg) generation in the thymus and reduces the fraction of CD103+ peripheral Tregs; LysoPS acting via GPR174 suppresses T cell proliferation and Treg generation in vitro, and GPR174 deficiency reduces susceptibility to experimental autoimmune encephalomyelitis. Gpr174 knockout mice (X-linked gene deletion), in vitro T cell proliferation assay with LysoPS, flow cytometry of thymic/peripheral Treg populations, in vivo EAE model, genetic complementation with Treg-specific deletion The Journal of experimental medicine High 26077720
2015 Structure-activity relationship analysis of synthetic LysoPS analogues identified structural requirements of the fatty acid, glycerol, and L-serine modules for potency and receptor subtype selectivity at GPR174 (LPS3), yielding potent and selective GPR174 agonists. Synthetic chemistry, SAR analysis of LysoPS analogues in receptor activation assays Journal of medicinal chemistry Medium 25970039
2017 GPR174 (LPS3) mediates LysoPS-induced suppression of IL-2 production in CD4+ T cells at both mRNA and protein levels; LysoPS-stimulated suppression is absent in LPS3-deficient splenocytes and CD4+ T cells, and LysoPS with various fatty acids is upregulated upon T cell activation. Gpr174 (LPS3) knockout mice, anti-CD3/anti-CD28 T cell activation assay, ELISA and RT-PCR for IL-2, lipid profiling of activated T cells Biochemical and biophysical research communications Medium 29017923
2018 LysoPS/GPR174-mediated suppression of T cell activation requires Gαs proteins; mechanistically, GPR174 signals through Gαs to suppress IL-2 production and limit upregulation of activation markers CD25 and CD69 on naive T cells in vitro and in vivo. In vivo T cell proliferation models (sublethal irradiation, Treg depletion), Gαs inhibition experiments in vitro, CD25/CD69 flow cytometry, IL-2 measurement, Gpr174 KO comparison Immunology and cell biology High 29457279
2019 GPR174, encoded on the X chromosome, acts as a receptor for CCL21 in B cells; CCL21 triggers calcium flux and preferentially induces migration of male B cells via GPR174, which associates more with Gαi protein in male than female B cells. Testosterone drives this sex difference: orchidectomy impairs GPR174-mediated CCL21 migration and testosterone treatment of female B cells confers male-like GPR174-Gαi association and migration. GPR174 suppresses germinal centre formation in males by positioning B cells towards the T-B border rather than follicular centre. Biochemical fractionation of conditioned media to identify CCL21 ligand, calcium flux assay, B cell migration assay, Co-IP of GPR174 with Gαi, orchidectomy and testosterone treatment models, Gpr174 conditional KO in B cells, germinal centre analysis by flow cytometry and histology, EAE model Nature High 31875850
2019 GPR174 deficiency in Tregs promotes CTLA-4 and IL-10 expression in Tregs, which drives anti-inflammatory M2 macrophage polarization and protects against sepsis-induced lung damage; Gpr174-deficient Tregs also directly suppress pro-inflammatory cytokines (IL-6, TNF-α) in macrophages in vitro. Gpr174 KO mice, LPS-induced sepsis and CLP models, flow cytometry, ELISA, in vitro Treg–macrophage co-culture assays Cell death & disease Medium 30850582
2022 GPR174 in Tregs negatively regulates angiogenesis after ischemic injury; GPR174 deficiency upregulates amphiregulin (AREG) expression in Tregs by inhibiting nuclear accumulation of EGR1 via the Gαs/cAMP/PKA signaling pathway, thereby enhancing endothelial cell function and reducing pro-inflammatory macrophage polarization. Treg-specific Gpr174 KO mice, hindlimb ischemia model, blood flow recovery measurement, AREG overexpression/KD, EGR1 nuclear translocation assay, cAMP/PKA pathway inhibition Nature communications Medium 36473866
2023 Cryo-EM structure of LysoPS-bound human GPR174 in complex with Gs protein reveals: (1) negatively charged LysoPS head group forms extensive polar interactions with ligand binding pocket residues; (2) the L-serine moiety inserts deeply into a positively charged cavity; (3) a partially open pocket on TM4–TM5 allows lateral ligand entry from the membrane; (4) Gs coupling involves deep insertion of the αH5 helix with extensive polar interactions. Cryo-EM structure determination, structural analysis, functional mutagenesis (implied by ligand binding pocket characterization) Nature communications High 36823105
2023 Cryo-EM structures of GPR174 without exogenous ligand reveal endogenous LysoPS co-purified with the receptor, conferring high constitutive Gs signaling comparable to fully activated D1R; GPR174 mutants with reduced ligand-binding affinity can be dose-dependently activated by exogenous LysoPS (but not other lipids), confirming LysoPS as the specific endogenous ligand. GPR174 adopts a non-canonical Gs coupling mode. Cryo-EM structure determination of GPR174-Gs complex without exogenous ligand, cAMP assay comparing GPR174 to D1R, site-directed mutagenesis of ligand-binding residues, LysoPS dose-response in GPR174 mutants, lipid specificity assays Nature communications High 37737235
2023 Cryo-EM structures of human GPR34 and GPR174 in complex with LysoPS and G protein elucidate the lipid-binding modes and structural features of these receptors in the active state, providing comparative insights into LysoPS receptor ligand recognition. Cryo-EM structure determination, structural analysis and comparison, functional studies of ligand binding PLoS biology High 38048360
2025 The LysoPS/GPR174 axis drives ESCC metastasis via the cAMP-PKA-CREB signaling pathway: LysoPS upregulates GPR174 expression, which activates cAMP-PKA, causing the catalytic subunit of PKA to translocate into the nucleus and phosphorylate CREB, promoting invasion and metastasis in vitro and in vivo. LC-MS for LysoPS measurement, Western blotting, wound healing and Transwell migration assays, nuclear-cytoplasmic fractionation, CCK-8 proliferation assay, nude mouse metastasis model, GPR174 overexpression Journal of translational medicine Medium 40229851
2026 High-resolution cryo-EM structures (2.0 Å) of LysoPS-activated GPR174 bound to Gs and Gi reveal a continuous hydration-mediated signal transduction network bridging the sodium-binding pocket, NPxxY and DRY motifs, and G protein-binding interface. This water network stabilizes the active state and differentially reshapes the intracellular cavity to enable selective engagement of Gs versus Gi. Molecular dynamics and functional assays confirm the hydration network is essential for activation and G protein selectivity. Cryo-EM structure determination (2.0 Å GPR174-Gs, 3.4 Å GPR174-Gi), molecular dynamics simulations, functional assays (cAMP/G protein coupling), sequence alignment across class A GPCRs PLoS biology High 42096402
2025 Molecular dynamics simulations of GPR174 bound to an antagonist (mPS, modified LysoPS) versus LysoPS show that mPS inactivates GPR174 by reducing conformational dynamics, disrupting the PIF, DRY, and N/DPxxY conserved activation motifs, and blocking signal transduction to the G protein interface, whereas LysoPS engages these motifs to couple the binding site to Gs. Membrane lipids including PIP2 modulate ligand dynamics and receptor conformational states. Molecular dynamics simulations in heterogeneous lipid bilayer, network analysis of signaling pathways, protein-lipid interaction analysis bioRxivpreprint Low 41000684

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity. Nature 94 31875850
2015 The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function. The Journal of experimental medicine 67 26077720
2013 An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease. Journal of medical genetics 52 23667180
2019 Gpr174-deficient regulatory T cells decrease cytokine storm in septic mice. Cell death & disease 45 30850582
2015 Structure-activity relationships of lysophosphatidylserine analogs as agonists of G-protein-coupled receptors GPR34, P2Y10, and GPR174. Journal of medicinal chemistry 42 25970039
2017 Lysophosphatidylserine suppresses IL-2 production in CD4 T cells through LPS3/GPR174. Biochemical and biophysical research communications 41 29017923
2018 Lysophosphatidylserine suppression of T-cell activation via GPR174 requires Gαs proteins. Immunology and cell biology 38 29457279
2022 GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression. Nature communications 32 36473866
2015 Role of the X-linked gene GPR174 in autoimmune Addison's disease. The Journal of clinical endocrinology and metabolism 29 25295623
2023 Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation. Nature communications 26 36823105
2012 Expression of orphan G-protein coupled receptor GPR174 in CHO cells induced morphological changes and proliferation delay via increasing intracellular cAMP. Biochemical and biophysical research communications 26 23178570
2022 Gpr174 Knockout Alleviates DSS-Induced Colitis via Regulating the Immune Function of Dendritic Cells. Frontiers in immunology 24 35669778
2013 rs3827440, a nonsynonymous single nucleotide polymorphism within GPR174 gene in X chromosome, is associated with Graves' disease in Polish Caucasian population. Tissue antigens 22 24289805
2023 Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling. Nature communications 16 37737235
2019 GPR174 suppression attenuates retinopathy in angiotensin II (Ang II)-treated mice by reducing inflammation via PI3K/AKT signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 14 31918274
2023 Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174. PLoS biology 12 38048360
2020 GPR174 and ITM2A Gene Polymorphisms rs3827440 and rs5912838 on the X chromosome in Korean Children with Autoimmune Thyroid Disease. Genes 11 32727090
2019 The increased marginal zone B cells attenuates early inflammatory responses during sepsis in Gpr174 deficient mice. International immunopharmacology 11 31786099
2017 RNASET2, GPR174, and PTPN22 gene polymorphisms are related to the risk of liver damage associated with the hyperthyroidism in patients with Graves' disease. Journal of clinical laboratory analysis 10 28568286
2012 Genetic map of lps3: a new short petiole gene in soybeans. Genome 8 22276917
2022 Activation of CCL21-GPR174/CCR7 on cardiac fibroblasts underlies myocardial ischemia/reperfusion injury. Frontiers in genetics 3 36159993
2025 The LysoPS/GPR174 axis drives metastatic progression in esophageal squamous cell carcinoma through cAMP-PKA-CREB signaling activation. Journal of translational medicine 2 40229851
2026 Structured water molecules drive activation and G protein selectivity in the GPR174 receptor. PLoS biology 0 42096402
2025 GPR174 Antagonism: Structure, Function, and Dynamics. bioRxiv : the preprint server for biology 0 41000684

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