{"gene":"GPRC5B","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2000,"finding":"GPRC5B (RAIG-2) is a seven-transmembrane orphan receptor classified within the type 3/family C GPCR subfamily; it has only a short N-terminal extracellular domain (in contrast to other family C GPCRs), contains a signal peptide, and localizes to the cell surface when transiently transfected in HEK293T cells.","method":"Homology searching, sequence analysis, transient transfection with epitope-tagged constructs in HEK293T cells","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-surface localization confirmed by transfection in two independent papers (PMID:10945465, PMID:10783259) with consistent findings; no functional reconstitution or mutagenesis","pmids":["10945465","10783259"],"is_preprint":false},{"year":2002,"finding":"GPRC5B protein migrates at ~68 kDa on Western blot (close to predicted MW) and immunocytochemical analysis of GPRC5B-transfected cells confirmed cell-surface localization; immunohistochemical analysis in rat brain showed highest expression in neocortex, hippocampus, cerebellar granule cell layer, and spinal cord.","method":"Western blot with affinity-purified antisera, immunocytochemistry, immunohistochemistry","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-level localization confirmed by multiple methods in one paper; single lab","pmids":["12393273"],"is_preprint":false},{"year":2012,"finding":"GPRC5B is a lipid raft-associated transmembrane protein. It is phosphorylated on multiple tyrosine residues in its carboxyl terminus by the Src-family kinase Fyn, and this phosphorylation enables direct recruitment of Fyn through its SH2 domain. This GPRC5B–Fyn interaction is required to initiate and sustain a positive NF-κB–IKKε inflammatory signaling feedback loop in adipose tissue; a GPRC5B mutant lacking the Fyn-SH2 binding site fails to activate this loop. GPRC5B-deficient mice are protected from diet-induced obesity and insulin resistance.","method":"GPRC5B knockout mice (diet-induced obesity model), phosphorylation analysis, direct interaction assay (Fyn SH2 domain binding), site-directed mutant lacking Fyn-binding site, NF-κB/IKKε signaling assays, lipid raft fractionation","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mice, interaction mapping, mutagenesis, signaling assays) in one study, replicated in subsequent papers","pmids":["23169819"],"is_preprint":false},{"year":2013,"finding":"GPRC5B is present at the ventricular surface of cortical progenitors in the developing mouse neocortex; its depletion causes cortical progenitors to fail neuronal fate adoption and instead become astrocytes; GPRC5B-mediated signaling is required for proper β-catenin pathway regulation in progenitor fate decisions.","method":"GPRC5B depletion in developing mouse neocortex, neuronal fate analysis, β-catenin signaling assays","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype and pathway placement (β-catenin), single lab","pmids":["24089469"],"is_preprint":false},{"year":2013,"finding":"GPRC5B acts as a negative modulator of insulin secretion in pancreatic islets; lentiviral shRNA-mediated knockdown of Gprc5b in mouse islets strongly increased basal and glucose-stimulated insulin secretion and enhanced glutamate-potentiated secretion; knockdown also protected MIN6 β-cells against cytokine-induced apoptosis.","method":"Lentiviral shRNA knockdown of Gprc5b in intact murine islets, insulin secretion assays, MIN6 cytokine-induced apoptosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with specific secretion and apoptosis phenotypes, multiple readouts, single lab","pmids":["24404583"],"is_preprint":false},{"year":2014,"finding":"GPRC5B is packaged into exosomes by HGF-treated MDCK epithelial cysts and released into the cyst lumen; exosomal GPRC5B is taken up by nearby cells and, together with HGF, promotes ERK1/2 activation and tubulogenesis in 3D extracellular matrix gels under conditions where tubulogenesis would otherwise not occur.","method":"3D MDCK cyst model, exosome isolation and uptake assays, ERK1/2 phosphorylation assays, tubulogenesis assays","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exosome isolation, functional uptake, ERK activation and morphogenesis readouts; single lab","pmids":["24412205"],"is_preprint":false},{"year":2018,"finding":"GPRC5B mediates phosphorylation of sphingomyelin synthase 2 (SMS2) by Fyn. Lipid-induced metabolic stress augments GPRC5B–SMS2 interaction, leading to SMS2 phosphorylation that reduces its ubiquitination and increases its protein abundance. SMS2-generated DAG in sphingomyelin synthesis activates JNK, which impairs insulin signaling; phosphomimetic SMS2 is sufficient to impair insulin action in SMS2-KO MEFs under metabolic stress.","method":"Co-immunoprecipitation of GPRC5B–SMS2 complex, SMS2-KO MEFs, phosphomimetic SMS2 reconstitution, ubiquitination assays, JNK and insulin signaling readouts","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, KO cells, phosphomimetic reconstitution, ubiquitination, downstream signaling), single lab with rigorous controls","pmids":["30343189"],"is_preprint":false},{"year":2018,"finding":"GPRC5B promotes Purkinje cell (PC) axonal development and synapse formation with deep cerebellar nuclear (DCN) neurons; in Gprc5b-/- mice, PCs develop distal axonal swellings containing misshapen mitochondria with excessive reactive oxygen species (ROS); pharmacological reduction of ROS prevents these swellings in Gprc5b-/- PC cultures. LTP at mossy fiber–DCN synapses is attenuated and long-term motor learning is impaired in Gprc5b-/- mice.","method":"Gprc5b-/- mice, primary PC culture, ROS measurement, pharmacological ROS reduction, patch-clamp electrophysiology (LTD/LTP), rotarod and HOKR motor learning tests","journal":"Neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with multiple orthogonal cellular and physiological phenotypes, single lab","pmids":["29481883"],"is_preprint":false},{"year":2018,"finding":"Caveolin-1 (Cav1) directly interacts with the cytoplasmic tail of GPRC5B via Cav1's C-terminal domain (GPRC5B lacks a conventional caveolin-binding motif), and this interaction suppresses GPRC5B tyrosine phosphorylation, thereby reducing GPRC5B-mediated NF-κB signaling; cells lacking Cav1 show highly elevated GPRC5B phosphorylation, and exogenous Cav1 expression inhibits it.","method":"Co-immunoprecipitation, domain mapping, Cav1-deficient cell lines, exogenous Cav1 expression, NF-κB signaling assays under palmitate stress","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapped to specific domain, functional consequence demonstrated, single lab","pmids":["30086884"],"is_preprint":false},{"year":2019,"finding":"GPRC5B regulates inflammatory response in podocytes via NF-κB signaling; podocyte-specific Gprc5b knockout mice are partially protected from LPS-induced proteinuria and inflammatory cell recruitment. RNA-seq of knockout mice and in vitro podocyte experiments confirmed GPRC5B modulates NF-κB-dependent gene expression.","method":"Podocyte-specific Gprc5b KO mice, LPS-induced nephropathy model, proteinuria measurement, inflammatory cell quantification, RNA-seq, in vitro podocyte NF-κB assays","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with in vivo phenotype and mechanistic RNA-seq, single lab","pmids":["31285284"],"is_preprint":false},{"year":2020,"finding":"GPRC5B physically interacts with the prostacyclin receptor (IP) in vascular smooth muscle cells (SMCs), and GPRC5B knockdown increases membrane localization of IP, leading to enhanced IP-dependent cAMP production and SMC relaxation. SMC-specific Gprc5b-KO mice are protected from arterial hypertension, and this protection is abrogated by IP antagonists. GPRC5B deficiency also prevents SMC dedifferentiation during atherosclerosis, reducing plaque load.","method":"SMC-specific tamoxifen-inducible Gprc5b-KO mice, co-immunoprecipitation (GPRC5B–IP interaction), membrane fractionation of IP, cAMP assays, mesenteric artery ex vivo contractility, arterial hypertension model, atherosclerosis model","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mice in two disease models, direct co-IP, membrane localization, cAMP assay, pharmacological rescue), single lab with rigorous in vivo controls","pmids":["31941358"],"is_preprint":false},{"year":2021,"finding":"GPRC5B directly interacts with GlialCAM (validated by co-immunoprecipitation from brain interactome); reduction of GPRC5B in primary astrocytes downregulates MLC1 and GlialCAM proteins and impairs activation of the chloride channels ClC-2 and VRAC. The interaction between GPRC5B and MLC1 is dynamically regulated by changes in osmolarity and potassium concentration.","method":"GlialCAM interactome proteomics (MS), co-immunoprecipitation validation, siRNA knockdown in primary astrocytes, ClC-2 and VRAC electrophysiology, osmolarity/K+ modulation assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus co-IP validation plus functional channel assays; single lab","pmids":["34100078"],"is_preprint":false},{"year":2022,"finding":"GPRC5B overexpression in endothelial cells and VSMCs increases phosphorylation of ERK1/2 and activates NF-κB through a direct interaction with the tyrosine kinase Fyn; GPRC5B knockdown attenuates expression of pro-inflammatory cytokines (TNFα, IL-1β, IL-6) and adhesion molecules (ICAM-1, VCAM-1) and reduces MMP-9 expression/activity in response to high glucose and cytokines.","method":"Adenoviral/plasmid GPRC5B overexpression and siRNA knockdown in endothelial cells and VSMCs, ERK1/2 and NF-κB phosphorylation assays, co-immunoprecipitation with Fyn, cytokine and MMP-9 measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both overexpression and knockdown with direct Fyn interaction and signaling readouts; single lab","pmids":["35033869"],"is_preprint":false},{"year":2023,"finding":"GPRC5B is expressed in astrocyte endfeet in human brain; heterozygous de novo GPRC5B variants cause disrupted cell volume regulation (demonstrated in patient-derived lymphoblasts); GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation.","method":"Genetic identification of GPRC5B variants in MLC patients, immunohistochemistry of human brain, cell volume measurements in patient-derived lymphoblasts, electrophysiology","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional consequence in patient-derived cells with electrophysiology; single study with multiple orthogonal methods","pmids":["37143309"],"is_preprint":false},{"year":2025,"finding":"GPRC5B physically interacts with GPCRs of the prostanoid receptor family, particularly prostaglandin E receptor 2 (EP2), in macrophages, resulting in enhanced EP2-mediated cAMP signaling and anti-inflammatory effects; in GPRC5B-deficient macrophages, EP2 anti-inflammatory signaling is diminished, causing macrophage hyperactivity (increased migration and phagocytosis). In silico modelling identified residues mediating GPRC5B/EP2 dimerization, and their mutation abolishes facilitation of EP2 signaling; decoy peptides mimicking the interacting sequence reduce GPRC5B-mediated EP2-induced cAMP signaling.","method":"Myeloid-specific GPRC5B-KO mice, co-immunoprecipitation, in silico docking/modelling, site-directed mutagenesis of dimerization residues, cAMP assays, migration and phagocytosis assays, peritonitis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (KO mice, co-IP, mutagenesis, structural modelling with validation, decoy peptides, in vivo model) in a single rigorous study","pmids":["39920161"],"is_preprint":false},{"year":2025,"finding":"GPRC5B exhibits constitutive activity that is inhibited by MLC1, likely through interference with GPRC5B oligomerization. GlialCAM enhances β-arrestin 2 recruitment to GPRC5B, leading to GlialCAM mislocalization from cell-cell junctions. MLC-associated GPRC5B mutants show enhanced plasma membrane stability and increased affinity for GlialCAM but retain normal constitutive activity and responsiveness to MLC1; coexpression with these mutants does not induce GlialCAM mislocalization.","method":"Constitutive activity assays, β-arrestin 2 recruitment assays, domain/oligomerization analysis, localization studies of MLC-associated mutants, biochemical fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays establishing constitutive activity and modulation by MLC1/GlialCAM; single lab","pmids":["41314544"],"is_preprint":false},{"year":2025,"finding":"GPRC5B maintains mature β-cell function in obesity through cAMP/CREB-dependent regulation of MafA expression; β-cell-specific GPRC5B-KO mice on high-fat diet show reduced CREB phosphorylation (preceding MafA downregulation), decreased MafA mRNA and protein, reduced MafA target gene expression, loss of mature β-cell phenotype, and impaired insulin secretion and glucose tolerance.","method":"Tamoxifen-inducible β-cell-specific GPRC5B-KO mice, high-fat diet, flow cytometry, single-cell RNA-seq, CREB phosphorylation assays, Western blot and RT-PCR for MafA and targets, glucose tolerance tests, insulin secretion assays","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with temporal mechanistic ordering (CREB phosphorylation precedes MafA loss) and multiple orthogonal readouts; single lab","pmids":["40906536"],"is_preprint":false},{"year":2021,"finding":"GPRC5B expression in cardiac and lung myofibroblasts promotes collagen gene expression; Gprc5b knockdown reduces collagen gene expression in these cells, and Gprc5b expression is associated with and may depend on the actin-MRTF-SRF signaling pathway.","method":"siRNA knockdown of Gprc5b in cardiac and lung myofibroblasts, real-time RT-PCR for collagen genes, fibrosis mouse models (in vivo expression), actin-MRTF-SRF pathway analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway association inferred without direct mechanistic test of MRTF-SRF link","pmids":["34023784"],"is_preprint":false},{"year":2025,"finding":"GPRC5B loss in endothelial cells hyperactivates p38 MAPK signaling by increasing phosphorylation of upstream MKK3/6 kinases while concurrently suppressing the negative-feedback phosphatase DUSP1, resulting in enhanced endothelial proliferation, migration, and tube formation in vitro and accelerated tumor growth and neovascularization in vivo; these phenotypes are rescued by p38 inhibitor SB202190.","method":"Endothelial GPRC5B loss-of-function in vitro and in vivo, MKK3/6 and DUSP1 phosphorylation/expression assays, p38 inhibitor rescue, tube formation and migration assays, tumor xenograft model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissected with dual-mechanism (MKK3/6 and DUSP1) and pharmacological rescue in vivo; single lab","pmids":["41734845"],"is_preprint":false},{"year":2026,"finding":"NSUN2-mediated m5C RNA methylation upregulates GPRC5B mRNA expression in osteosarcoma; GPRC5B in turn suppresses apoptosis and promotes cell proliferation and migration. Knockdown of GPRC5B partially rescues the anti-apoptotic effects of NSUN2, establishing an NSUN2→m5C-GPRC5B anti-apoptotic regulatory axis.","method":"meRIP-seq and RNA-seq in osteosarcoma tissues, GPRC5B knockdown and NSUN2 knockdown functional experiments, apoptosis, proliferation, and migration assays","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect mechanism (m5C modification inferred from meRIP-seq; rescue experiment supports but does not fully reconstitute the axis)","pmids":["41846428"],"is_preprint":false},{"year":2023,"finding":"GPRC5B promotes cartilage homeostasis; Gprc5b-deficient chondrocytes upregulate catabolic genes and downregulate anabolic genes; Gprc5b-KO mice show more severe OA after destabilization of medial meniscus. Overexpression via lentiviral vectors alleviates cartilage degeneration. Mechanistically, GPRC5B acts through the AKT–mTOR–autophagy signaling pathway.","method":"Gprc5b-KO mice (DMM OA model), lentiviral GPRC5B overexpression, in vitro chondrocyte gene expression, AKT/mTOR/autophagy pathway assays","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in vivo with pathway identification; single lab","pmids":["37521864"],"is_preprint":false},{"year":2025,"finding":"GPRC5B mediates retinoic acid (RA)-induced suppression of adult hippocampal neurogenesis and depressive-like behaviors; Gprc5b-KO mice are resilient to RA-induced behavioral effects and show a larger pool of proliferative neuronal stem cells, with RA failing to inhibit neurogenesis in the absence of GPRC5B. RA increases GPRC5B expression specifically in the hippocampal neurogenic subgranular zone.","method":"Gprc5b-KO mice, RA treatment, behavioral assays, BrdU/EdU-based neurogenesis quantification, hippocampal SGZ expression analysis","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific behavioral and cellular phenotypes linking GPRC5B to RA-dependent neurogenesis; single lab","pmids":["41204039"],"is_preprint":false}],"current_model":"GPRC5B is a constitutively active, lipid raft-associated orphan family C GPCR that transduces signals primarily by recruiting Src-family kinase Fyn via phosphorylation of its C-terminal tyrosine residues, activating downstream NF-κB–IKKε and ERK inflammatory pathways; it physically interacts with and modulates the signaling of partner GPCRs (prostacyclin receptor IP and prostaglandin E receptor EP2), with MLC1 inhibiting its constitutive activity (likely by disrupting oligomerization) and caveolin-1 suppressing its phosphorylation, while GPRC5B-mediated Fyn activity also drives SMS2 phosphorylation to promote DAG-dependent JNK activation and insulin resistance; additionally, GPRC5B is transferred intercellularly via exosomes to promote ERK-dependent tubulogenesis, is required for β-catenin-regulated neuronal fate determination in cortical progenitors, and maintains mature β-cell identity in obesity through cAMP/CREB-dependent MafA expression."},"narrative":{"mechanistic_narrative":"GPRC5B is a constitutively active, lipid raft-associated orphan family C GPCR with only a short extracellular domain that broadly couples membrane lipid and inflammatory state to intracellular signaling across metabolic, vascular, and neural tissues [PMID:10945465, PMID:10783259, PMID:23169819]. Its core signaling output depends on tyrosine phosphorylation of its cytoplasmic C-terminus by the Src-family kinase Fyn, which then binds the phosphorylated tail through its SH2 domain to drive a self-sustaining NF-κB–IKKε inflammatory feedback loop and ERK1/2 activation; a mutant lacking the Fyn-SH2 binding site cannot initiate this loop, and GPRC5B-deficient mice are protected from diet-induced obesity and insulin resistance [PMID:23169819, PMID:35033869]. This phosphorylation node is negatively gated by caveolin-1, which binds the GPRC5B cytoplasmic tail and suppresses its tyrosine phosphorylation and downstream NF-κB signaling [PMID:30086884]. Fyn activity downstream of GPRC5B also phosphorylates sphingomyelin synthase 2 (SMS2), stabilizing it against ubiquitination and driving DAG-dependent JNK activation that impairs insulin action under lipid stress [PMID:30343189]. Beyond its own signaling, GPRC5B physically associates with and modulates partner GPCRs: it sequesters the prostacyclin receptor IP in vascular smooth muscle to restrain cAMP-driven relaxation and dedifferentiation [PMID:31941358], and dimerizes with the prostaglandin E receptor EP2 in macrophages to enhance EP2-mediated cAMP anti-inflammatory signaling [PMID:39920161]. GPRC5B has additional cell-type-specific roles, including maintenance of mature β-cell identity through cAMP/CREB-dependent MafA expression [PMID:40906536] and a constitutive activity that is inhibited by MLC1 and coupled to GlialCAM/β-arrestin 2 in astrocyte volume regulation [PMID:34100078, PMID:41314544]; heterozygous de novo GPRC5B variants disrupting astrocyte cell-volume regulation cause a megalencephalic leukoencephalopathy (MLC)-related disorder [PMID:37143309]. Its developmental and tissue-homeostatic functions, including cortical neuronal fate determination via β-catenin [PMID:24089469] and cartilage homeostasis via AKT–mTOR–autophagy [PMID:37521864], extend the receptor's reach but are less mechanistically resolved.","teleology":[{"year":2000,"claim":"Established GPRC5B as a structurally distinct orphan family C GPCR, defining its molecular identity and cell-surface disposition before any function was known.","evidence":"Homology searching and transient transfection of epitope-tagged constructs in HEK293T cells","pmids":["10945465","10783259"],"confidence":"Medium","gaps":["No ligand identified","No signaling activity demonstrated","Function entirely unknown at this stage"]},{"year":2002,"claim":"Confirmed endogenous protein expression and CNS-enriched distribution, anchoring later neural phenotypes to a real expression pattern.","evidence":"Western blot, immunocytochemistry, and immunohistochemistry in rat brain","pmids":["12393273"],"confidence":"Medium","gaps":["No functional assay","Brain-region expression does not establish cell-type-specific roles"]},{"year":2012,"claim":"Defined the central signaling mechanism: Fyn phosphorylates the GPRC5B C-terminal tyrosines and is recruited via its SH2 domain to sustain an NF-κB–IKKε inflammatory loop, linking the receptor to obesity-associated insulin resistance.","evidence":"Knockout mice in diet-induced obesity, Fyn SH2-domain interaction mapping, Fyn-binding-site mutant, NF-κB/IKKε assays, lipid raft fractionation","pmids":["23169819"],"confidence":"High","gaps":["Upstream activating signal/ligand undefined","Mechanism connecting raft localization to Fyn phosphorylation not detailed"]},{"year":2013,"claim":"Extended GPRC5B function into development and pancreatic physiology, showing it directs cortical progenitor neuronal fate via β-catenin and negatively modulates islet insulin secretion.","evidence":"GPRC5B depletion in mouse neocortex with fate analysis; lentiviral shRNA knockdown in murine islets and MIN6 cells with secretion and apoptosis assays","pmids":["24089469","24404583"],"confidence":"Medium","gaps":["Molecular link between GPRC5B and β-catenin not resolved","Mechanism of insulin-secretion modulation not defined"]},{"year":2014,"claim":"Demonstrated intercellular transfer of GPRC5B via exosomes that promotes ERK-dependent tubulogenesis, revealing a non-cell-autonomous mode of action.","evidence":"3D MDCK cyst model, exosome isolation and uptake, ERK1/2 phosphorylation and tubulogenesis assays","pmids":["24412205"],"confidence":"Medium","gaps":["How exosomal GPRC5B activates ERK in recipient cells unknown","Single epithelial model"]},{"year":2018,"claim":"Resolved how GPRC5B-Fyn signaling reaches lipid metabolism and identified caveolin-1 as a negative regulator, building a two-sided control of the phosphorylation node.","evidence":"Co-IP of GPRC5B–SMS2, SMS2-KO MEFs with phosphomimetic reconstitution, ubiquitination and JNK/insulin readouts; Cav1 co-IP, domain mapping, Cav1-deficient cells under palmitate stress","pmids":["30343189","30086884"],"confidence":"High","gaps":["How metabolic stress augments GPRC5B–SMS2 interaction unknown","Stoichiometry of Cav1 regulation not quantified"]},{"year":2018,"claim":"Showed a cerebellar developmental role, with GPRC5B required for Purkinje cell axonal/synaptic integrity, mitochondrial ROS control, synaptic plasticity, and motor learning.","evidence":"Gprc5b-/- mice, primary PC culture, ROS measurement and pharmacological reduction, patch-clamp LTP/LTD, rotarod and HOKR tests","pmids":["29481883"],"confidence":"Medium","gaps":["Molecular link between GPRC5B and mitochondrial ROS unknown","Whether this uses the Fyn/NF-κB axis untested"]},{"year":2019,"claim":"Generalized the NF-κB inflammatory role beyond adipose to kidney podocytes, with cell-type-specific knockout protecting against inflammatory nephropathy.","evidence":"Podocyte-specific Gprc5b KO mice, LPS nephropathy model, proteinuria, inflammatory cell quantification, RNA-seq, in vitro NF-κB assays","pmids":["31285284"],"confidence":"Medium","gaps":["Whether the same Fyn-SH2 mechanism operates in podocytes not directly tested"]},{"year":2020,"claim":"Established GPRC5B as a direct modulator of partner GPCR signaling, sequestering the prostacyclin receptor IP to restrain cAMP-driven vasorelaxation and SMC dedifferentiation in hypertension and atherosclerosis.","evidence":"SMC-specific inducible Gprc5b-KO mice, GPRC5B–IP co-IP, IP membrane fractionation, cAMP assays, ex vivo contractility, hypertension and atherosclerosis models with IP antagonist rescue","pmids":["31941358"],"confidence":"High","gaps":["Structural basis of GPRC5B–IP interaction not defined here","Relationship to Fyn signaling in this context unclear"]},{"year":2021,"claim":"Connected GPRC5B to the astrocyte volume-regulation machinery through direct GlialCAM and MLC1 interactions controlling ClC-2/VRAC channel activity, framing its relevance to leukoencephalopathy.","evidence":"GlialCAM interactome MS with co-IP validation, siRNA in primary astrocytes, ClC-2 and VRAC electrophysiology, osmolarity/K+ modulation","pmids":["34100078"],"confidence":"Medium","gaps":["Whether GPRC5B regulates channels directly or via MLC1/GlialCAM abundance unclear","No structural interaction map"]},{"year":2022,"claim":"Confirmed in vascular endothelium and VSMCs that GPRC5B drives ERK1/2 and NF-κB activation via Fyn, promoting pro-inflammatory cytokine and adhesion-molecule expression under hyperglycemic/cytokine stress.","evidence":"Overexpression and siRNA knockdown in endothelial cells and VSMCs, ERK/NF-κB assays, Fyn co-IP, cytokine and MMP-9 measurements","pmids":["35033869"],"confidence":"Medium","gaps":["Causal ordering of ERK vs NF-κB activation not resolved","Single lab"]},{"year":2023,"claim":"Provided human genetic and functional evidence linking GPRC5B to a megalencephalic leukoencephalopathy-spectrum disorder via disrupted astrocyte cell-volume regulation.","evidence":"Genetic identification of de novo GPRC5B variants in MLC patients, human brain IHC, cell-volume measurements in patient-derived lymphoblasts, electrophysiology","pmids":["37143309"],"confidence":"Medium","gaps":["Whether variants are gain- or loss-of-function not fully resolved at this stage","Genotype–phenotype correlation limited"]},{"year":2023,"claim":"Identified a protective role in cartilage homeostasis acting through AKT–mTOR–autophagy signaling, expanding GPRC5B's tissue-homeostatic functions.","evidence":"Gprc5b-KO mice in DMM osteoarthritis model, lentiviral overexpression, chondrocyte gene expression, AKT/mTOR/autophagy assays","pmids":["37521864"],"confidence":"Medium","gaps":["How GPRC5B engages AKT-mTOR not mechanistically defined","Receptor activation trigger in chondrocytes unknown"]},{"year":2025,"claim":"Resolved a second partner-GPCR mechanism in macrophages, with GPRC5B-EP2 dimerization (mapped by modelling and mutagenesis) enhancing anti-inflammatory cAMP signaling and restraining macrophage activity.","evidence":"Myeloid-specific GPRC5B-KO mice, co-IP, in silico docking, dimerization-residue mutagenesis, decoy peptides, cAMP/migration/phagocytosis assays, peritonitis model","pmids":["39920161"],"confidence":"High","gaps":["Whether GPRC5B modulates EP2 oppositely to IP across tissues not reconciled","No experimental structure of the dimer"]},{"year":2025,"claim":"Defined GPRC5B's constitutive activity and its regulation by MLC1 (via oligomerization) and GlialCAM/β-arrestin 2, and characterized how MLC-associated mutants alter membrane stability and GlialCAM localization.","evidence":"Constitutive activity and β-arrestin 2 recruitment assays, oligomerization/domain analysis, MLC-mutant localization, biochemical fractionation","pmids":["41314544"],"confidence":"Medium","gaps":["Endogenous ligand or stimulus controlling constitutive activity unknown","Downstream effectors of β-arrestin recruitment not mapped"]},{"year":2025,"claim":"Showed GPRC5B sustains mature β-cell identity in obesity via cAMP/CREB-dependent MafA expression, with temporal ordering placing CREB phosphorylation upstream of MafA loss.","evidence":"Tamoxifen-inducible β-cell-specific GPRC5B-KO mice on high-fat diet, scRNA-seq, CREB phosphorylation, MafA Western/RT-PCR, glucose tolerance and insulin secretion","pmids":["40906536"],"confidence":"Medium","gaps":["How GPRC5B couples to cAMP/CREB in β-cells not defined","Apparent contrast with earlier islet knockdown phenotype unreconciled"]},{"year":2025,"claim":"Implicated GPRC5B as a brake on endothelial p38 MAPK signaling by restraining MKK3/6 and maintaining DUSP1, with loss accelerating angiogenesis and tumor growth.","evidence":"Endothelial loss-of-function in vitro and in vivo, MKK3/6 and DUSP1 assays, p38 inhibitor rescue, tube formation, migration, tumor xenograft","pmids":["41734845"],"confidence":"Medium","gaps":["Mechanism by which GPRC5B regulates DUSP1 and MKK3/6 unknown","Relationship to the pro-inflammatory ERK/NF-κB role unresolved"]},{"year":2025,"claim":"Linked RA signaling to GPRC5B in suppression of adult hippocampal neurogenesis and depressive-like behavior, with KO mice resistant to RA effects.","evidence":"Gprc5b-KO mice, RA treatment, behavioral assays, BrdU/EdU neurogenesis quantification, SGZ expression analysis","pmids":["41204039"],"confidence":"Medium","gaps":["Downstream signaling mediating neurogenesis suppression undefined","Whether RA directly regulates GPRC5B transcription unclear"]},{"year":null,"claim":"The endogenous ligand or activating stimulus of GPRC5B and the structural basis for how its constitutive activity, partner-GPCR dimerization, and Fyn-dependent versus cAMP-dependent outputs are selected across tissues remain unresolved.","evidence":"No timeline discovery identifies a ligand or reconciles the divergent (pro- vs anti-inflammatory, secretory) outputs mechanistically","pmids":[],"confidence":"Low","gaps":["No endogenous ligand identified","No experimental structure of GPRC5B or its GPCR heterodimers","Context-dependent output selection (NF-κB/ERK vs cAMP/CREB vs p38) not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,14,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,10,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,9,12,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,21]}],"complexes":[],"partners":["FYN","CAV1","SMS2","PTGIR","PTGER2","GLIALCAM","MLC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZH0","full_name":"G-protein coupled receptor family C group 5 member B","aliases":["A-69G12.1","Retinoic acid-induced gene 2 protein","RAIG-2"],"length_aa":403,"mass_kda":44.8,"function":"G-protein coupled receptor involved in the regulation of cell volume","subcellular_location":"Cell membrane; Cytoplasmic vesicle 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1; BMIQ1","url":"https://www.omim.org/entry/606641"},{"mim_id":"605949","title":"G PROTEIN-COUPLED RECEPTOR, FAMILY C, GROUP 5, MEMBER C; GPRC5C","url":"https://www.omim.org/entry/605949"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":213.2}],"url":"https://www.proteinatlas.org/search/GPRC5B"},"hgnc":{"alias_symbol":["RAIG-2"],"prev_symbol":[]},"alphafold":{"accession":"Q9NZH0","domains":[{"cath_id":"1.20.1070.10","chopping":"43-297","consensus_level":"medium","plddt":89.4322,"start":43,"end":297}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZH0-F1-predicted_aligned_error_v6.png","plddt_mean":74.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPRC5B","jax_strain_url":"https://www.jax.org/strain/search?query=GPRC5B"},"sequence":{"accession":"Q9NZH0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZH0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZH0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZH0"}},"corpus_meta":[{"pmid":"10945465","id":"PMC_10945465","title":"Molecular 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(RAIG-2) is a seven-transmembrane orphan receptor classified within the type 3/family C GPCR subfamily; it has only a short N-terminal extracellular domain (in contrast to other family C GPCRs), contains a signal peptide, and localizes to the cell surface when transiently transfected in HEK293T cells.\",\n      \"method\": \"Homology searching, sequence analysis, transient transfection with epitope-tagged constructs in HEK293T cells\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-surface localization confirmed by transfection in two independent papers (PMID:10945465, PMID:10783259) with consistent findings; no functional reconstitution or mutagenesis\",\n      \"pmids\": [\"10945465\", \"10783259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"GPRC5B protein migrates at ~68 kDa on Western blot (close to predicted MW) and immunocytochemical analysis of GPRC5B-transfected cells confirmed cell-surface localization; immunohistochemical analysis in rat brain showed highest expression in neocortex, hippocampus, cerebellar granule cell layer, and spinal cord.\",\n      \"method\": \"Western blot with affinity-purified antisera, immunocytochemistry, immunohistochemistry\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-level localization confirmed by multiple methods in one paper; single lab\",\n      \"pmids\": [\"12393273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GPRC5B is a lipid raft-associated transmembrane protein. It is phosphorylated on multiple tyrosine residues in its carboxyl terminus by the Src-family kinase Fyn, and this phosphorylation enables direct recruitment of Fyn through its SH2 domain. This GPRC5B–Fyn interaction is required to initiate and sustain a positive NF-κB–IKKε inflammatory signaling feedback loop in adipose tissue; a GPRC5B mutant lacking the Fyn-SH2 binding site fails to activate this loop. GPRC5B-deficient mice are protected from diet-induced obesity and insulin resistance.\",\n      \"method\": \"GPRC5B knockout mice (diet-induced obesity model), phosphorylation analysis, direct interaction assay (Fyn SH2 domain binding), site-directed mutant lacking Fyn-binding site, NF-κB/IKKε signaling assays, lipid raft fractionation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mice, interaction mapping, mutagenesis, signaling assays) in one study, replicated in subsequent papers\",\n      \"pmids\": [\"23169819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPRC5B is present at the ventricular surface of cortical progenitors in the developing mouse neocortex; its depletion causes cortical progenitors to fail neuronal fate adoption and instead become astrocytes; GPRC5B-mediated signaling is required for proper β-catenin pathway regulation in progenitor fate decisions.\",\n      \"method\": \"GPRC5B depletion in developing mouse neocortex, neuronal fate analysis, β-catenin signaling assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype and pathway placement (β-catenin), single lab\",\n      \"pmids\": [\"24089469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GPRC5B acts as a negative modulator of insulin secretion in pancreatic islets; lentiviral shRNA-mediated knockdown of Gprc5b in mouse islets strongly increased basal and glucose-stimulated insulin secretion and enhanced glutamate-potentiated secretion; knockdown also protected MIN6 β-cells against cytokine-induced apoptosis.\",\n      \"method\": \"Lentiviral shRNA knockdown of Gprc5b in intact murine islets, insulin secretion assays, MIN6 cytokine-induced apoptosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with specific secretion and apoptosis phenotypes, multiple readouts, single lab\",\n      \"pmids\": [\"24404583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPRC5B is packaged into exosomes by HGF-treated MDCK epithelial cysts and released into the cyst lumen; exosomal GPRC5B is taken up by nearby cells and, together with HGF, promotes ERK1/2 activation and tubulogenesis in 3D extracellular matrix gels under conditions where tubulogenesis would otherwise not occur.\",\n      \"method\": \"3D MDCK cyst model, exosome isolation and uptake assays, ERK1/2 phosphorylation assays, tubulogenesis assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exosome isolation, functional uptake, ERK activation and morphogenesis readouts; single lab\",\n      \"pmids\": [\"24412205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPRC5B mediates phosphorylation of sphingomyelin synthase 2 (SMS2) by Fyn. Lipid-induced metabolic stress augments GPRC5B–SMS2 interaction, leading to SMS2 phosphorylation that reduces its ubiquitination and increases its protein abundance. SMS2-generated DAG in sphingomyelin synthesis activates JNK, which impairs insulin signaling; phosphomimetic SMS2 is sufficient to impair insulin action in SMS2-KO MEFs under metabolic stress.\",\n      \"method\": \"Co-immunoprecipitation of GPRC5B–SMS2 complex, SMS2-KO MEFs, phosphomimetic SMS2 reconstitution, ubiquitination assays, JNK and insulin signaling readouts\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, KO cells, phosphomimetic reconstitution, ubiquitination, downstream signaling), single lab with rigorous controls\",\n      \"pmids\": [\"30343189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GPRC5B promotes Purkinje cell (PC) axonal development and synapse formation with deep cerebellar nuclear (DCN) neurons; in Gprc5b-/- mice, PCs develop distal axonal swellings containing misshapen mitochondria with excessive reactive oxygen species (ROS); pharmacological reduction of ROS prevents these swellings in Gprc5b-/- PC cultures. LTP at mossy fiber–DCN synapses is attenuated and long-term motor learning is impaired in Gprc5b-/- mice.\",\n      \"method\": \"Gprc5b-/- mice, primary PC culture, ROS measurement, pharmacological ROS reduction, patch-clamp electrophysiology (LTD/LTP), rotarod and HOKR motor learning tests\",\n      \"journal\": \"Neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with multiple orthogonal cellular and physiological phenotypes, single lab\",\n      \"pmids\": [\"29481883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Caveolin-1 (Cav1) directly interacts with the cytoplasmic tail of GPRC5B via Cav1's C-terminal domain (GPRC5B lacks a conventional caveolin-binding motif), and this interaction suppresses GPRC5B tyrosine phosphorylation, thereby reducing GPRC5B-mediated NF-κB signaling; cells lacking Cav1 show highly elevated GPRC5B phosphorylation, and exogenous Cav1 expression inhibits it.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, Cav1-deficient cell lines, exogenous Cav1 expression, NF-κB signaling assays under palmitate stress\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapped to specific domain, functional consequence demonstrated, single lab\",\n      \"pmids\": [\"30086884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GPRC5B regulates inflammatory response in podocytes via NF-κB signaling; podocyte-specific Gprc5b knockout mice are partially protected from LPS-induced proteinuria and inflammatory cell recruitment. RNA-seq of knockout mice and in vitro podocyte experiments confirmed GPRC5B modulates NF-κB-dependent gene expression.\",\n      \"method\": \"Podocyte-specific Gprc5b KO mice, LPS-induced nephropathy model, proteinuria measurement, inflammatory cell quantification, RNA-seq, in vitro podocyte NF-κB assays\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with in vivo phenotype and mechanistic RNA-seq, single lab\",\n      \"pmids\": [\"31285284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPRC5B physically interacts with the prostacyclin receptor (IP) in vascular smooth muscle cells (SMCs), and GPRC5B knockdown increases membrane localization of IP, leading to enhanced IP-dependent cAMP production and SMC relaxation. SMC-specific Gprc5b-KO mice are protected from arterial hypertension, and this protection is abrogated by IP antagonists. GPRC5B deficiency also prevents SMC dedifferentiation during atherosclerosis, reducing plaque load.\",\n      \"method\": \"SMC-specific tamoxifen-inducible Gprc5b-KO mice, co-immunoprecipitation (GPRC5B–IP interaction), membrane fractionation of IP, cAMP assays, mesenteric artery ex vivo contractility, arterial hypertension model, atherosclerosis model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mice in two disease models, direct co-IP, membrane localization, cAMP assay, pharmacological rescue), single lab with rigorous in vivo controls\",\n      \"pmids\": [\"31941358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPRC5B directly interacts with GlialCAM (validated by co-immunoprecipitation from brain interactome); reduction of GPRC5B in primary astrocytes downregulates MLC1 and GlialCAM proteins and impairs activation of the chloride channels ClC-2 and VRAC. The interaction between GPRC5B and MLC1 is dynamically regulated by changes in osmolarity and potassium concentration.\",\n      \"method\": \"GlialCAM interactome proteomics (MS), co-immunoprecipitation validation, siRNA knockdown in primary astrocytes, ClC-2 and VRAC electrophysiology, osmolarity/K+ modulation assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus co-IP validation plus functional channel assays; single lab\",\n      \"pmids\": [\"34100078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPRC5B overexpression in endothelial cells and VSMCs increases phosphorylation of ERK1/2 and activates NF-κB through a direct interaction with the tyrosine kinase Fyn; GPRC5B knockdown attenuates expression of pro-inflammatory cytokines (TNFα, IL-1β, IL-6) and adhesion molecules (ICAM-1, VCAM-1) and reduces MMP-9 expression/activity in response to high glucose and cytokines.\",\n      \"method\": \"Adenoviral/plasmid GPRC5B overexpression and siRNA knockdown in endothelial cells and VSMCs, ERK1/2 and NF-κB phosphorylation assays, co-immunoprecipitation with Fyn, cytokine and MMP-9 measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both overexpression and knockdown with direct Fyn interaction and signaling readouts; single lab\",\n      \"pmids\": [\"35033869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPRC5B is expressed in astrocyte endfeet in human brain; heterozygous de novo GPRC5B variants cause disrupted cell volume regulation (demonstrated in patient-derived lymphoblasts); GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation.\",\n      \"method\": \"Genetic identification of GPRC5B variants in MLC patients, immunohistochemistry of human brain, cell volume measurements in patient-derived lymphoblasts, electrophysiology\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional consequence in patient-derived cells with electrophysiology; single study with multiple orthogonal methods\",\n      \"pmids\": [\"37143309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPRC5B physically interacts with GPCRs of the prostanoid receptor family, particularly prostaglandin E receptor 2 (EP2), in macrophages, resulting in enhanced EP2-mediated cAMP signaling and anti-inflammatory effects; in GPRC5B-deficient macrophages, EP2 anti-inflammatory signaling is diminished, causing macrophage hyperactivity (increased migration and phagocytosis). In silico modelling identified residues mediating GPRC5B/EP2 dimerization, and their mutation abolishes facilitation of EP2 signaling; decoy peptides mimicking the interacting sequence reduce GPRC5B-mediated EP2-induced cAMP signaling.\",\n      \"method\": \"Myeloid-specific GPRC5B-KO mice, co-immunoprecipitation, in silico docking/modelling, site-directed mutagenesis of dimerization residues, cAMP assays, migration and phagocytosis assays, peritonitis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (KO mice, co-IP, mutagenesis, structural modelling with validation, decoy peptides, in vivo model) in a single rigorous study\",\n      \"pmids\": [\"39920161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPRC5B exhibits constitutive activity that is inhibited by MLC1, likely through interference with GPRC5B oligomerization. GlialCAM enhances β-arrestin 2 recruitment to GPRC5B, leading to GlialCAM mislocalization from cell-cell junctions. MLC-associated GPRC5B mutants show enhanced plasma membrane stability and increased affinity for GlialCAM but retain normal constitutive activity and responsiveness to MLC1; coexpression with these mutants does not induce GlialCAM mislocalization.\",\n      \"method\": \"Constitutive activity assays, β-arrestin 2 recruitment assays, domain/oligomerization analysis, localization studies of MLC-associated mutants, biochemical fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays establishing constitutive activity and modulation by MLC1/GlialCAM; single lab\",\n      \"pmids\": [\"41314544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPRC5B maintains mature β-cell function in obesity through cAMP/CREB-dependent regulation of MafA expression; β-cell-specific GPRC5B-KO mice on high-fat diet show reduced CREB phosphorylation (preceding MafA downregulation), decreased MafA mRNA and protein, reduced MafA target gene expression, loss of mature β-cell phenotype, and impaired insulin secretion and glucose tolerance.\",\n      \"method\": \"Tamoxifen-inducible β-cell-specific GPRC5B-KO mice, high-fat diet, flow cytometry, single-cell RNA-seq, CREB phosphorylation assays, Western blot and RT-PCR for MafA and targets, glucose tolerance tests, insulin secretion assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with temporal mechanistic ordering (CREB phosphorylation precedes MafA loss) and multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"40906536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPRC5B expression in cardiac and lung myofibroblasts promotes collagen gene expression; Gprc5b knockdown reduces collagen gene expression in these cells, and Gprc5b expression is associated with and may depend on the actin-MRTF-SRF signaling pathway.\",\n      \"method\": \"siRNA knockdown of Gprc5b in cardiac and lung myofibroblasts, real-time RT-PCR for collagen genes, fibrosis mouse models (in vivo expression), actin-MRTF-SRF pathway analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway association inferred without direct mechanistic test of MRTF-SRF link\",\n      \"pmids\": [\"34023784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPRC5B loss in endothelial cells hyperactivates p38 MAPK signaling by increasing phosphorylation of upstream MKK3/6 kinases while concurrently suppressing the negative-feedback phosphatase DUSP1, resulting in enhanced endothelial proliferation, migration, and tube formation in vitro and accelerated tumor growth and neovascularization in vivo; these phenotypes are rescued by p38 inhibitor SB202190.\",\n      \"method\": \"Endothelial GPRC5B loss-of-function in vitro and in vivo, MKK3/6 and DUSP1 phosphorylation/expression assays, p38 inhibitor rescue, tube formation and migration assays, tumor xenograft model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissected with dual-mechanism (MKK3/6 and DUSP1) and pharmacological rescue in vivo; single lab\",\n      \"pmids\": [\"41734845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NSUN2-mediated m5C RNA methylation upregulates GPRC5B mRNA expression in osteosarcoma; GPRC5B in turn suppresses apoptosis and promotes cell proliferation and migration. Knockdown of GPRC5B partially rescues the anti-apoptotic effects of NSUN2, establishing an NSUN2→m5C-GPRC5B anti-apoptotic regulatory axis.\",\n      \"method\": \"meRIP-seq and RNA-seq in osteosarcoma tissues, GPRC5B knockdown and NSUN2 knockdown functional experiments, apoptosis, proliferation, and migration assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect mechanism (m5C modification inferred from meRIP-seq; rescue experiment supports but does not fully reconstitute the axis)\",\n      \"pmids\": [\"41846428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPRC5B promotes cartilage homeostasis; Gprc5b-deficient chondrocytes upregulate catabolic genes and downregulate anabolic genes; Gprc5b-KO mice show more severe OA after destabilization of medial meniscus. Overexpression via lentiviral vectors alleviates cartilage degeneration. Mechanistically, GPRC5B acts through the AKT–mTOR–autophagy signaling pathway.\",\n      \"method\": \"Gprc5b-KO mice (DMM OA model), lentiviral GPRC5B overexpression, in vitro chondrocyte gene expression, AKT/mTOR/autophagy pathway assays\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in vivo with pathway identification; single lab\",\n      \"pmids\": [\"37521864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPRC5B mediates retinoic acid (RA)-induced suppression of adult hippocampal neurogenesis and depressive-like behaviors; Gprc5b-KO mice are resilient to RA-induced behavioral effects and show a larger pool of proliferative neuronal stem cells, with RA failing to inhibit neurogenesis in the absence of GPRC5B. RA increases GPRC5B expression specifically in the hippocampal neurogenic subgranular zone.\",\n      \"method\": \"Gprc5b-KO mice, RA treatment, behavioral assays, BrdU/EdU-based neurogenesis quantification, hippocampal SGZ expression analysis\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific behavioral and cellular phenotypes linking GPRC5B to RA-dependent neurogenesis; single lab\",\n      \"pmids\": [\"41204039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPRC5B is a constitutively active, lipid raft-associated orphan family C GPCR that transduces signals primarily by recruiting Src-family kinase Fyn via phosphorylation of its C-terminal tyrosine residues, activating downstream NF-κB–IKKε and ERK inflammatory pathways; it physically interacts with and modulates the signaling of partner GPCRs (prostacyclin receptor IP and prostaglandin E receptor EP2), with MLC1 inhibiting its constitutive activity (likely by disrupting oligomerization) and caveolin-1 suppressing its phosphorylation, while GPRC5B-mediated Fyn activity also drives SMS2 phosphorylation to promote DAG-dependent JNK activation and insulin resistance; additionally, GPRC5B is transferred intercellularly via exosomes to promote ERK-dependent tubulogenesis, is required for β-catenin-regulated neuronal fate determination in cortical progenitors, and maintains mature β-cell identity in obesity through cAMP/CREB-dependent MafA expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPRC5B is a constitutively active, lipid raft-associated orphan family C GPCR with only a short extracellular domain that broadly couples membrane lipid and inflammatory state to intracellular signaling across metabolic, vascular, and neural tissues [#0, #2]. Its core signaling output depends on tyrosine phosphorylation of its cytoplasmic C-terminus by the Src-family kinase Fyn, which then binds the phosphorylated tail through its SH2 domain to drive a self-sustaining NF-\\u03baB\\u2013IKK\\u03b5 inflammatory feedback loop and ERK1/2 activation; a mutant lacking the Fyn-SH2 binding site cannot initiate this loop, and GPRC5B-deficient mice are protected from diet-induced obesity and insulin resistance [#2, #12]. This phosphorylation node is negatively gated by caveolin-1, which binds the GPRC5B cytoplasmic tail and suppresses its tyrosine phosphorylation and downstream NF-\\u03baB signaling [#8]. Fyn activity downstream of GPRC5B also phosphorylates sphingomyelin synthase 2 (SMS2), stabilizing it against ubiquitination and driving DAG-dependent JNK activation that impairs insulin action under lipid stress [#6]. Beyond its own signaling, GPRC5B physically associates with and modulates partner GPCRs: it sequesters the prostacyclin receptor IP in vascular smooth muscle to restrain cAMP-driven relaxation and dedifferentiation [#10], and dimerizes with the prostaglandin E receptor EP2 in macrophages to enhance EP2-mediated cAMP anti-inflammatory signaling [#14]. GPRC5B has additional cell-type-specific roles, including maintenance of mature \\u03b2-cell identity through cAMP/CREB-dependent MafA expression [#16] and a constitutive activity that is inhibited by MLC1 and coupled to GlialCAM/\\u03b2-arrestin 2 in astrocyte volume regulation [#11, #15]; heterozygous de novo GPRC5B variants disrupting astrocyte cell-volume regulation cause a megalencephalic leukoencephalopathy (MLC)-related disorder [#13]. Its developmental and tissue-homeostatic functions, including cortical neuronal fate determination via \\u03b2-catenin [#3] and cartilage homeostasis via AKT\\u2013mTOR\\u2013autophagy [#20], extend the receptor's reach but are less mechanistically resolved.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established GPRC5B as a structurally distinct orphan family C GPCR, defining its molecular identity and cell-surface disposition before any function was known.\",\n      \"evidence\": \"Homology searching and transient transfection of epitope-tagged constructs in HEK293T cells\",\n      \"pmids\": [\"10945465\", \"10783259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand identified\", \"No signaling activity demonstrated\", \"Function entirely unknown at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Confirmed endogenous protein expression and CNS-enriched distribution, anchoring later neural phenotypes to a real expression pattern.\",\n      \"evidence\": \"Western blot, immunocytochemistry, and immunohistochemistry in rat brain\",\n      \"pmids\": [\"12393273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay\", \"Brain-region expression does not establish cell-type-specific roles\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the central signaling mechanism: Fyn phosphorylates the GPRC5B C-terminal tyrosines and is recruited via its SH2 domain to sustain an NF-\\u03baB\\u2013IKK\\u03b5 inflammatory loop, linking the receptor to obesity-associated insulin resistance.\",\n      \"evidence\": \"Knockout mice in diet-induced obesity, Fyn SH2-domain interaction mapping, Fyn-binding-site mutant, NF-\\u03baB/IKK\\u03b5 assays, lipid raft fractionation\",\n      \"pmids\": [\"23169819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activating signal/ligand undefined\", \"Mechanism connecting raft localization to Fyn phosphorylation not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended GPRC5B function into development and pancreatic physiology, showing it directs cortical progenitor neuronal fate via \\u03b2-catenin and negatively modulates islet insulin secretion.\",\n      \"evidence\": \"GPRC5B depletion in mouse neocortex with fate analysis; lentiviral shRNA knockdown in murine islets and MIN6 cells with secretion and apoptosis assays\",\n      \"pmids\": [\"24089469\", \"24404583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between GPRC5B and \\u03b2-catenin not resolved\", \"Mechanism of insulin-secretion modulation not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated intercellular transfer of GPRC5B via exosomes that promotes ERK-dependent tubulogenesis, revealing a non-cell-autonomous mode of action.\",\n      \"evidence\": \"3D MDCK cyst model, exosome isolation and uptake, ERK1/2 phosphorylation and tubulogenesis assays\",\n      \"pmids\": [\"24412205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How exosomal GPRC5B activates ERK in recipient cells unknown\", \"Single epithelial model\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how GPRC5B-Fyn signaling reaches lipid metabolism and identified caveolin-1 as a negative regulator, building a two-sided control of the phosphorylation node.\",\n      \"evidence\": \"Co-IP of GPRC5B\\u2013SMS2, SMS2-KO MEFs with phosphomimetic reconstitution, ubiquitination and JNK/insulin readouts; Cav1 co-IP, domain mapping, Cav1-deficient cells under palmitate stress\",\n      \"pmids\": [\"30343189\", \"30086884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How metabolic stress augments GPRC5B\\u2013SMS2 interaction unknown\", \"Stoichiometry of Cav1 regulation not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed a cerebellar developmental role, with GPRC5B required for Purkinje cell axonal/synaptic integrity, mitochondrial ROS control, synaptic plasticity, and motor learning.\",\n      \"evidence\": \"Gprc5b-/- mice, primary PC culture, ROS measurement and pharmacological reduction, patch-clamp LTP/LTD, rotarod and HOKR tests\",\n      \"pmids\": [\"29481883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between GPRC5B and mitochondrial ROS unknown\", \"Whether this uses the Fyn/NF-\\u03baB axis untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the NF-\\u03baB inflammatory role beyond adipose to kidney podocytes, with cell-type-specific knockout protecting against inflammatory nephropathy.\",\n      \"evidence\": \"Podocyte-specific Gprc5b KO mice, LPS nephropathy model, proteinuria, inflammatory cell quantification, RNA-seq, in vitro NF-\\u03baB assays\",\n      \"pmids\": [\"31285284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the same Fyn-SH2 mechanism operates in podocytes not directly tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established GPRC5B as a direct modulator of partner GPCR signaling, sequestering the prostacyclin receptor IP to restrain cAMP-driven vasorelaxation and SMC dedifferentiation in hypertension and atherosclerosis.\",\n      \"evidence\": \"SMC-specific inducible Gprc5b-KO mice, GPRC5B\\u2013IP co-IP, IP membrane fractionation, cAMP assays, ex vivo contractility, hypertension and atherosclerosis models with IP antagonist rescue\",\n      \"pmids\": [\"31941358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GPRC5B\\u2013IP interaction not defined here\", \"Relationship to Fyn signaling in this context unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected GPRC5B to the astrocyte volume-regulation machinery through direct GlialCAM and MLC1 interactions controlling ClC-2/VRAC channel activity, framing its relevance to leukoencephalopathy.\",\n      \"evidence\": \"GlialCAM interactome MS with co-IP validation, siRNA in primary astrocytes, ClC-2 and VRAC electrophysiology, osmolarity/K+ modulation\",\n      \"pmids\": [\"34100078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GPRC5B regulates channels directly or via MLC1/GlialCAM abundance unclear\", \"No structural interaction map\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed in vascular endothelium and VSMCs that GPRC5B drives ERK1/2 and NF-\\u03baB activation via Fyn, promoting pro-inflammatory cytokine and adhesion-molecule expression under hyperglycemic/cytokine stress.\",\n      \"evidence\": \"Overexpression and siRNA knockdown in endothelial cells and VSMCs, ERK/NF-\\u03baB assays, Fyn co-IP, cytokine and MMP-9 measurements\",\n      \"pmids\": [\"35033869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal ordering of ERK vs NF-\\u03baB activation not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided human genetic and functional evidence linking GPRC5B to a megalencephalic leukoencephalopathy-spectrum disorder via disrupted astrocyte cell-volume regulation.\",\n      \"evidence\": \"Genetic identification of de novo GPRC5B variants in MLC patients, human brain IHC, cell-volume measurements in patient-derived lymphoblasts, electrophysiology\",\n      \"pmids\": [\"37143309\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether variants are gain- or loss-of-function not fully resolved at this stage\", \"Genotype\\u2013phenotype correlation limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a protective role in cartilage homeostasis acting through AKT\\u2013mTOR\\u2013autophagy signaling, expanding GPRC5B's tissue-homeostatic functions.\",\n      \"evidence\": \"Gprc5b-KO mice in DMM osteoarthritis model, lentiviral overexpression, chondrocyte gene expression, AKT/mTOR/autophagy assays\",\n      \"pmids\": [\"37521864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GPRC5B engages AKT-mTOR not mechanistically defined\", \"Receptor activation trigger in chondrocytes unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a second partner-GPCR mechanism in macrophages, with GPRC5B-EP2 dimerization (mapped by modelling and mutagenesis) enhancing anti-inflammatory cAMP signaling and restraining macrophage activity.\",\n      \"evidence\": \"Myeloid-specific GPRC5B-KO mice, co-IP, in silico docking, dimerization-residue mutagenesis, decoy peptides, cAMP/migration/phagocytosis assays, peritonitis model\",\n      \"pmids\": [\"39920161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPRC5B modulates EP2 oppositely to IP across tissues not reconciled\", \"No experimental structure of the dimer\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined GPRC5B's constitutive activity and its regulation by MLC1 (via oligomerization) and GlialCAM/\\u03b2-arrestin 2, and characterized how MLC-associated mutants alter membrane stability and GlialCAM localization.\",\n      \"evidence\": \"Constitutive activity and \\u03b2-arrestin 2 recruitment assays, oligomerization/domain analysis, MLC-mutant localization, biochemical fractionation\",\n      \"pmids\": [\"41314544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous ligand or stimulus controlling constitutive activity unknown\", \"Downstream effectors of \\u03b2-arrestin recruitment not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed GPRC5B sustains mature \\u03b2-cell identity in obesity via cAMP/CREB-dependent MafA expression, with temporal ordering placing CREB phosphorylation upstream of MafA loss.\",\n      \"evidence\": \"Tamoxifen-inducible \\u03b2-cell-specific GPRC5B-KO mice on high-fat diet, scRNA-seq, CREB phosphorylation, MafA Western/RT-PCR, glucose tolerance and insulin secretion\",\n      \"pmids\": [\"40906536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GPRC5B couples to cAMP/CREB in \\u03b2-cells not defined\", \"Apparent contrast with earlier islet knockdown phenotype unreconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated GPRC5B as a brake on endothelial p38 MAPK signaling by restraining MKK3/6 and maintaining DUSP1, with loss accelerating angiogenesis and tumor growth.\",\n      \"evidence\": \"Endothelial loss-of-function in vitro and in vivo, MKK3/6 and DUSP1 assays, p38 inhibitor rescue, tube formation, migration, tumor xenograft\",\n      \"pmids\": [\"41734845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which GPRC5B regulates DUSP1 and MKK3/6 unknown\", \"Relationship to the pro-inflammatory ERK/NF-\\u03baB role unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked RA signaling to GPRC5B in suppression of adult hippocampal neurogenesis and depressive-like behavior, with KO mice resistant to RA effects.\",\n      \"evidence\": \"Gprc5b-KO mice, RA treatment, behavioral assays, BrdU/EdU neurogenesis quantification, SGZ expression analysis\",\n      \"pmids\": [\"41204039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling mediating neurogenesis suppression undefined\", \"Whether RA directly regulates GPRC5B transcription unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous ligand or activating stimulus of GPRC5B and the structural basis for how its constitutive activity, partner-GPCR dimerization, and Fyn-dependent versus cAMP-dependent outputs are selected across tissues remain unresolved.\",\n      \"evidence\": \"No timeline discovery identifies a ligand or reconciles the divergent (pro- vs anti-inflammatory, secretory) outputs mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No endogenous ligand identified\", \"No experimental structure of GPRC5B or its GPCR heterodimers\", \"Context-dependent output selection (NF-\\u03baB/ERK vs cAMP/CREB vs p38) not mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 14, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 10, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 9, 12, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FYN\", \"CAV1\", \"SMS2\", \"PTGIR\", \"PTGER2\", \"GlialCAM\", \"MLC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}