{"gene":"NPTXR","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2015,"finding":"NPTXR and NPTX2 are required for clustering of GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin fast-spiking interneurons (PVFSIs). In NPTX2(-/-)/NPTXR(-/-) double knockout mice, GluA4 is dramatically reduced at PVFSI synapses, AMPAR-mediated currents are diminished, and the circuit exhibits delayed maturation, prolonged critical period, reduced feedforward inhibition, and epileptiform discharges.","method":"Double knockout mouse model (NPTX2-/-/NPTXR-/-), electrophysiology, immunofluorescence, GluA4 quantification","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean double-KO with multiple orthogonal readouts (receptor quantification, electrophysiology, circuit-level phenotype); replicated across developmental timepoints in same study","pmids":["25754824"],"is_preprint":false},{"year":2021,"finding":"C1QL3 mediates formation of a novel trans-synaptic adhesion complex involving NPTXR (and NPTX1) with the postsynaptic adhesion GPCR ADGRB3/BAI3. The complex was identified by in vivo interactome study (co-immunoprecipitation/pulldown), and single-cell RNA-seq confirmed co-expression of C1ql3, Nptx1, and Nptxr in the same excitatory neurons, consistent with presynaptic secretion and postsynaptic ADGRB3 binding.","method":"In vivo interactome study (co-immunoprecipitation/pulldown), single-cell RNA-seq co-expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP/pulldown in vivo plus co-expression corroboration, single lab, functional consequence of complex inferred but not directly tested by mutagenesis or reconstitution","pmids":["33337553"],"is_preprint":false},{"year":2026,"finding":"The conserved C-terminal pentraxin (PTX) domain of NPTXR (NPTXRPTX) was produced as uniformly 15N,13C-labeled recombinant protein and near-complete backbone NMR resonance assignments were obtained, providing the first structural characterization of this domain and a foundation for studying NPTXR–ligand interactions that drive synapse organization.","method":"NMR spectroscopy (backbone resonance assignment of uniformly 15N,13C-labeled NPTXRPTX)","journal":"Biomolecular NMR assignments","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structural characterization (assignments only, no functional mutagenesis validation yet), single lab, first structural data on this domain","pmids":["41495486"],"is_preprint":false},{"year":2020,"finding":"In gastric cancer cells, NPTXR regulates activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. siRNA-mediated NPTXR silencing promoted caspase-mediated apoptosis and attenuated proliferation, cell cycle progression, migration, invasion, adhesion, and stem cell-like properties in vitro, and inhibited tumorigenicity in mouse xenograft models. Anti-NPTXR monoclonal antibody inhibited peritoneal metastasis in mice.","method":"siRNA knockdown, in vitro functional assays (proliferation, apoptosis, migration, invasion, adhesion), mouse xenograft model, anti-NPTXR monoclonal antibody treatment, signaling pathway analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD with defined cellular phenotypes plus in vivo validation and antibody intervention, single lab, multiple orthogonal readouts","pmids":["32847597"],"is_preprint":false},{"year":2024,"finding":"In esophageal squamous cell carcinoma (ESCC) cells, siRNA-mediated NPTXR knockdown reduced cell proliferation, increased apoptosis, and decreased cell adhesion. An anti-NPTXR monoclonal antibody significantly inhibited ESCC cell proliferation in vitro, consistent with findings in gastric cancer.","method":"siRNA knockdown, cell proliferation assay, apoptosis assay, adhesion assay, anti-NPTXR monoclonal antibody treatment in vitro","journal":"Annals of surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple defined cellular phenotypes plus antibody intervention, single lab, replicates gastric cancer mechanism in a second cancer type","pmids":["38717547"],"is_preprint":false},{"year":2026,"finding":"NPTXR co-localizes with NPTX2 in its role at peripheral sensory neurons: in the MC903-induced atopic dermatitis model, NPTXR is localized to pruriceptive CGRP+ and IB4+ sensory neuron subsets, and intra-trigeminal-ganglion injection of Nptxr siRNA significantly attenuated scratching behavior. NPTXR acts as a cognate receptor for NPTX2, and NPTX2 synergizes with IL-31 to potentiate p-ERK signaling in primary sensory neurons.","method":"siRNA knockdown in trigeminal ganglion (in vivo), immunohistochemistry for NPTXR localization, behavioral assay (scratch test), western blot for p-ERK","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with specific behavioral phenotype, immunohistochemical localization, and signaling readout; single lab with multiple orthogonal approaches","pmids":["41564473"],"is_preprint":false},{"year":2024,"finding":"In a rat model of chronic variable stress-induced anhedonia, NPTXR (Nptxr) protein was downregulated in the prefrontal cortex, associating its expression with glutamatergic synapse integrity. (R)-ketamine treatment reversed anhedonic behavior and was associated with proteomic changes, though NPTXR downregulation was identified as a correlate of the anhedonic state rather than a direct (R)-ketamine target.","method":"High-throughput proteomics of prefrontal cortex, chronic variable stress rat model, sucrose preference behavioral test","journal":"Pharmacology, biochemistry, and behavior","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomics correlation in a single study, no direct manipulation of NPTXR; associative not mechanistic","pmids":["39488299"],"is_preprint":false},{"year":2006,"finding":"Nptxr mRNA expression is upregulated (~1.6–6.0-fold) in rat left ventricular myocardium at 7 days post-myocardial infarction (congestive heart failure model), identified by cDNA filter array and validated by a ranked ratio analysis method. The upregulation was absent at 1-day post-MI, suggesting it is not an acute infarct response.","method":"cDNA filter array, ranked ratio analysis, in vivo rat MI model (LAD ligation)","journal":"Acta physiologica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single array-based expression measurement validated by ratio method, no functional follow-up on NPTXR protein itself","pmids":["16497176"],"is_preprint":false}],"current_model":"NPTXR is a transmembrane pentraxin-domain synaptic organizing protein that, together with NPTX2, clusters GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin interneurons to control circuit maturation and inhibitory/excitatory balance; its conserved pentraxin domain (structurally characterized by NMR) mediates interactions with synaptic partners including participation in a C1QL3–NPTXR–ADGRB3 trans-synaptic adhesion complex, and in peripheral sensory neurons NPTXR acts as a cognate receptor for NPTX2 to potentiate p-ERK-dependent pruritic signaling; additionally, NPTXR drives malignant behaviors in gastric and esophageal cancer cells via PI3K-AKT-mTOR, FAK-JNK, and YAP pathways, and its loss from CSF serves as a broadly replicated marker of synaptic dysfunction across multiple neurodegenerative diseases."},"narrative":{"mechanistic_narrative":"NPTXR is a pentraxin-domain synaptic organizing protein that, in cooperation with NPTX2, clusters GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin fast-spiking interneurons to drive circuit maturation and excitatory/inhibitory balance; loss of NPTXR (with NPTX2) reduces synaptic GluA4 and AMPAR currents, prolongs the developmental critical period, weakens feedforward inhibition, and produces epileptiform activity [PMID:25754824]. Its synapse-organizing activity is mediated through trans-synaptic adhesion: NPTXR participates in a C1QL3-bridged complex with the postsynaptic adhesion GPCR ADGRB3/BAI3, co-expressed with C1QL3 in the same excitatory neurons consistent with presynaptic secretion and postsynaptic engagement [PMID:33337553], and these ligand interactions are anchored by the conserved C-terminal pentraxin domain whose structure has been characterized by NMR [PMID:41495486]. Beyond the CNS, NPTXR functions as a cognate receptor for NPTX2 in pruriceptive CGRP+/IB4+ peripheral sensory neurons, where it potentiates p-ERK-dependent itch signaling and supports scratching behavior [PMID:41564473]. NPTXR also drives malignant phenotypes in gastric and esophageal carcinoma cells, where its silencing suppresses proliferation, invasion, adhesion, and stemness and promotes apoptosis via PI3K-AKT-mTOR, FAK-JNK, and YAP signaling, and anti-NPTXR antibody limits tumor growth and metastasis [PMID:32847597, PMID:38717547].","teleology":[{"year":2015,"claim":"Established the core synaptic function of NPTXR: whether it organizes AMPA receptors at specific synapses was unknown, and the double knockout showed it is required, with NPTX2, for GluA4 clustering and proper circuit maturation.","evidence":"NPTX2-/-/NPTXR-/- double knockout mice with electrophysiology, immunofluorescence, and GluA4 quantification","pmids":["25754824"],"confidence":"High","gaps":["Redundancy with NPTX2 prevents attribution of an NPTXR-specific contribution","Molecular interface that recruits GluA4 not defined","No structural basis for the synaptic interaction established here"]},{"year":2021,"claim":"Addressed how NPTXR is positioned at the synapse by identifying a trans-synaptic adhesion complex in which C1QL3 bridges NPTXR to the postsynaptic adhesion GPCR ADGRB3.","evidence":"In vivo interactome co-immunoprecipitation/pulldown plus single-cell RNA-seq co-expression analysis","pmids":["33337553"],"confidence":"Medium","gaps":["Functional consequence of the complex inferred, not tested by mutagenesis or reconstitution","Single lab without reciprocal validation","Stoichiometry and direct binding interfaces undefined"]},{"year":2026,"claim":"Began structural dissection of the ligand-binding module by producing the conserved C-terminal pentraxin domain and obtaining backbone NMR assignments, providing a foundation for mapping NPTXR-ligand interactions.","evidence":"NMR backbone resonance assignment of uniformly 15N,13C-labeled NPTXR pentraxin domain","pmids":["41495486"],"confidence":"Medium","gaps":["Assignments only; no full structure or ligand-bound complex","No functional mutagenesis validation of the domain","Does not yet map interaction surfaces with NPTX2, C1QL3, or ADGRB3"]},{"year":2020,"claim":"Extended NPTXR function beyond neurons by showing it promotes malignant behavior in gastric cancer through oncogenic signaling and is a therapeutic target.","evidence":"siRNA knockdown, in vitro functional assays, mouse xenograft, and anti-NPTXR monoclonal antibody treatment with signaling pathway analysis","pmids":["32847597"],"confidence":"Medium","gaps":["Mechanistic link between NPTXR and PI3K-AKT-mTOR/FAK-JNK/YAP activation not resolved at the receptor level","Single lab and single cancer context","Ligand driving oncogenic signaling not identified"]},{"year":2024,"claim":"Tested generality of the oncogenic role by replicating NPTXR-dependent proliferation, survival, and adhesion phenotypes and antibody sensitivity in a second tumor type, esophageal squamous cell carcinoma.","evidence":"siRNA knockdown with proliferation, apoptosis, adhesion assays and anti-NPTXR monoclonal antibody treatment in vitro","pmids":["38717547"],"confidence":"Medium","gaps":["No in vivo validation in ESCC","Downstream signaling not profiled as in gastric cancer","Mechanism of antibody action undefined"]},{"year":2026,"claim":"Identified a peripheral function: NPTXR acts as a cognate receptor for NPTX2 in pruriceptive sensory neurons to drive p-ERK-dependent itch signaling and scratching behavior.","evidence":"Intra-trigeminal-ganglion Nptxr siRNA, immunohistochemistry, scratch behavioral assay, and p-ERK western blot in an atopic dermatitis model","pmids":["41564473"],"confidence":"Medium","gaps":["Direct NPTX2-NPTXR binding not demonstrated biochemically here","Coupling between NPTXR and ERK activation not defined","Single lab and single disease model"]},{"year":2024,"claim":"Associated NPTXR levels with glutamatergic synapse integrity by showing prefrontal cortex downregulation in a stress-induced anhedonia model.","evidence":"High-throughput proteomics of prefrontal cortex in a chronic variable stress rat model with sucrose preference testing","pmids":["39488299"],"confidence":"Low","gaps":["Associative proteomics only with no direct manipulation of NPTXR","Causality versus correlate of anhedonic state unresolved","Not a direct (R)-ketamine target"]},{"year":2006,"claim":"Earliest expression observation linking NPTXR to non-neural tissue, showing delayed Nptxr mRNA upregulation in post-infarct myocardium.","evidence":"cDNA filter array with ranked ratio analysis in a rat myocardial infarction model","pmids":["16497176"],"confidence":"Low","gaps":["Single array-based measurement with no protein-level or functional follow-up","No mechanistic role in cardiac tissue established","Significance of the delayed kinetics unexplained"]},{"year":null,"claim":"How the pentraxin domain physically engages NPTX2, C1QL3/ADGRB3, and oncogenic signaling partners to transduce both synaptic organization and tumor-promoting signals remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No ligand-bound structure linking the pentraxin domain to its partners","No defined receptor-to-effector mechanism for ERK or PI3K-AKT-mTOR activation","NPTXR-specific contribution distinct from NPTX2 not isolated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4]}],"complexes":["C1QL3-NPTXR-ADGRB3 trans-synaptic adhesion complex"],"partners":["NPTX2","NPTX1","C1QL3","ADGRB3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95502","full_name":"Neuronal pentraxin receptor","aliases":[],"length_aa":500,"mass_kda":52.8,"function":"May be involved in mediating uptake of synaptic material during synapse remodeling or in mediating the synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/O95502/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPTXR","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPTXR","total_profiled":1310},"omim":[{"mim_id":"609474","title":"NEURONAL PENTRAXIN RECEPTOR; NPTXR","url":"https://www.omim.org/entry/609474"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":179.3}],"url":"https://www.proteinatlas.org/search/NPTXR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O95502","domains":[{"cath_id":"2.60.120.200","chopping":"295-495","consensus_level":"high","plddt":95.5171,"start":295,"end":495},{"cath_id":"1.20.5","chopping":"255-283","consensus_level":"medium","plddt":86.1772,"start":255,"end":283}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95502","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95502-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95502-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPTXR","jax_strain_url":"https://www.jax.org/strain/search?query=NPTXR"},"sequence":{"accession":"O95502","fasta_url":"https://rest.uniprot.org/uniprotkb/O95502.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95502/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95502"}},"corpus_meta":[{"pmid":"25754824","id":"PMC_25754824","title":"Pentraxins 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In NPTX2(-/-)/NPTXR(-/-) double knockout mice, GluA4 is dramatically reduced at PVFSI synapses, AMPAR-mediated currents are diminished, and the circuit exhibits delayed maturation, prolonged critical period, reduced feedforward inhibition, and epileptiform discharges.\",\n      \"method\": \"Double knockout mouse model (NPTX2-/-/NPTXR-/-), electrophysiology, immunofluorescence, GluA4 quantification\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean double-KO with multiple orthogonal readouts (receptor quantification, electrophysiology, circuit-level phenotype); replicated across developmental timepoints in same study\",\n      \"pmids\": [\"25754824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1QL3 mediates formation of a novel trans-synaptic adhesion complex involving NPTXR (and NPTX1) with the postsynaptic adhesion GPCR ADGRB3/BAI3. The complex was identified by in vivo interactome study (co-immunoprecipitation/pulldown), and single-cell RNA-seq confirmed co-expression of C1ql3, Nptx1, and Nptxr in the same excitatory neurons, consistent with presynaptic secretion and postsynaptic ADGRB3 binding.\",\n      \"method\": \"In vivo interactome study (co-immunoprecipitation/pulldown), single-cell RNA-seq co-expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP/pulldown in vivo plus co-expression corroboration, single lab, functional consequence of complex inferred but not directly tested by mutagenesis or reconstitution\",\n      \"pmids\": [\"33337553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The conserved C-terminal pentraxin (PTX) domain of NPTXR (NPTXRPTX) was produced as uniformly 15N,13C-labeled recombinant protein and near-complete backbone NMR resonance assignments were obtained, providing the first structural characterization of this domain and a foundation for studying NPTXR–ligand interactions that drive synapse organization.\",\n      \"method\": \"NMR spectroscopy (backbone resonance assignment of uniformly 15N,13C-labeled NPTXRPTX)\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural characterization (assignments only, no functional mutagenesis validation yet), single lab, first structural data on this domain\",\n      \"pmids\": [\"41495486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In gastric cancer cells, NPTXR regulates activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. siRNA-mediated NPTXR silencing promoted caspase-mediated apoptosis and attenuated proliferation, cell cycle progression, migration, invasion, adhesion, and stem cell-like properties in vitro, and inhibited tumorigenicity in mouse xenograft models. Anti-NPTXR monoclonal antibody inhibited peritoneal metastasis in mice.\",\n      \"method\": \"siRNA knockdown, in vitro functional assays (proliferation, apoptosis, migration, invasion, adhesion), mouse xenograft model, anti-NPTXR monoclonal antibody treatment, signaling pathway analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD with defined cellular phenotypes plus in vivo validation and antibody intervention, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"32847597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In esophageal squamous cell carcinoma (ESCC) cells, siRNA-mediated NPTXR knockdown reduced cell proliferation, increased apoptosis, and decreased cell adhesion. An anti-NPTXR monoclonal antibody significantly inhibited ESCC cell proliferation in vitro, consistent with findings in gastric cancer.\",\n      \"method\": \"siRNA knockdown, cell proliferation assay, apoptosis assay, adhesion assay, anti-NPTXR monoclonal antibody treatment in vitro\",\n      \"journal\": \"Annals of surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple defined cellular phenotypes plus antibody intervention, single lab, replicates gastric cancer mechanism in a second cancer type\",\n      \"pmids\": [\"38717547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NPTXR co-localizes with NPTX2 in its role at peripheral sensory neurons: in the MC903-induced atopic dermatitis model, NPTXR is localized to pruriceptive CGRP+ and IB4+ sensory neuron subsets, and intra-trigeminal-ganglion injection of Nptxr siRNA significantly attenuated scratching behavior. NPTXR acts as a cognate receptor for NPTX2, and NPTX2 synergizes with IL-31 to potentiate p-ERK signaling in primary sensory neurons.\",\n      \"method\": \"siRNA knockdown in trigeminal ganglion (in vivo), immunohistochemistry for NPTXR localization, behavioral assay (scratch test), western blot for p-ERK\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with specific behavioral phenotype, immunohistochemical localization, and signaling readout; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"41564473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a rat model of chronic variable stress-induced anhedonia, NPTXR (Nptxr) protein was downregulated in the prefrontal cortex, associating its expression with glutamatergic synapse integrity. (R)-ketamine treatment reversed anhedonic behavior and was associated with proteomic changes, though NPTXR downregulation was identified as a correlate of the anhedonic state rather than a direct (R)-ketamine target.\",\n      \"method\": \"High-throughput proteomics of prefrontal cortex, chronic variable stress rat model, sucrose preference behavioral test\",\n      \"journal\": \"Pharmacology, biochemistry, and behavior\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomics correlation in a single study, no direct manipulation of NPTXR; associative not mechanistic\",\n      \"pmids\": [\"39488299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nptxr mRNA expression is upregulated (~1.6–6.0-fold) in rat left ventricular myocardium at 7 days post-myocardial infarction (congestive heart failure model), identified by cDNA filter array and validated by a ranked ratio analysis method. The upregulation was absent at 1-day post-MI, suggesting it is not an acute infarct response.\",\n      \"method\": \"cDNA filter array, ranked ratio analysis, in vivo rat MI model (LAD ligation)\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single array-based expression measurement validated by ratio method, no functional follow-up on NPTXR protein itself\",\n      \"pmids\": [\"16497176\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPTXR is a transmembrane pentraxin-domain synaptic organizing protein that, together with NPTX2, clusters GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin interneurons to control circuit maturation and inhibitory/excitatory balance; its conserved pentraxin domain (structurally characterized by NMR) mediates interactions with synaptic partners including participation in a C1QL3–NPTXR–ADGRB3 trans-synaptic adhesion complex, and in peripheral sensory neurons NPTXR acts as a cognate receptor for NPTX2 to potentiate p-ERK-dependent pruritic signaling; additionally, NPTXR drives malignant behaviors in gastric and esophageal cancer cells via PI3K-AKT-mTOR, FAK-JNK, and YAP pathways, and its loss from CSF serves as a broadly replicated marker of synaptic dysfunction across multiple neurodegenerative diseases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPTXR is a pentraxin-domain synaptic organizing protein that, in cooperation with NPTX2, clusters GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin fast-spiking interneurons to drive circuit maturation and excitatory/inhibitory balance; loss of NPTXR (with NPTX2) reduces synaptic GluA4 and AMPAR currents, prolongs the developmental critical period, weakens feedforward inhibition, and produces epileptiform activity [#0]. Its synapse-organizing activity is mediated through trans-synaptic adhesion: NPTXR participates in a C1QL3-bridged complex with the postsynaptic adhesion GPCR ADGRB3/BAI3, co-expressed with C1QL3 in the same excitatory neurons consistent with presynaptic secretion and postsynaptic engagement [#1], and these ligand interactions are anchored by the conserved C-terminal pentraxin domain whose structure has been characterized by NMR [#2]. Beyond the CNS, NPTXR functions as a cognate receptor for NPTX2 in pruriceptive CGRP+/IB4+ peripheral sensory neurons, where it potentiates p-ERK-dependent itch signaling and supports scratching behavior [#5]. NPTXR also drives malignant phenotypes in gastric and esophageal carcinoma cells, where its silencing suppresses proliferation, invasion, adhesion, and stemness and promotes apoptosis via PI3K-AKT-mTOR, FAK-JNK, and YAP signaling, and anti-NPTXR antibody limits tumor growth and metastasis [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the core synaptic function of NPTXR: whether it organizes AMPA receptors at specific synapses was unknown, and the double knockout showed it is required, with NPTX2, for GluA4 clustering and proper circuit maturation.\",\n      \"evidence\": \"NPTX2-/-/NPTXR-/- double knockout mice with electrophysiology, immunofluorescence, and GluA4 quantification\",\n      \"pmids\": [\"25754824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Redundancy with NPTX2 prevents attribution of an NPTXR-specific contribution\",\n        \"Molecular interface that recruits GluA4 not defined\",\n        \"No structural basis for the synaptic interaction established here\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Addressed how NPTXR is positioned at the synapse by identifying a trans-synaptic adhesion complex in which C1QL3 bridges NPTXR to the postsynaptic adhesion GPCR ADGRB3.\",\n      \"evidence\": \"In vivo interactome co-immunoprecipitation/pulldown plus single-cell RNA-seq co-expression analysis\",\n      \"pmids\": [\"33337553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of the complex inferred, not tested by mutagenesis or reconstitution\",\n        \"Single lab without reciprocal validation\",\n        \"Stoichiometry and direct binding interfaces undefined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Began structural dissection of the ligand-binding module by producing the conserved C-terminal pentraxin domain and obtaining backbone NMR assignments, providing a foundation for mapping NPTXR-ligand interactions.\",\n      \"evidence\": \"NMR backbone resonance assignment of uniformly 15N,13C-labeled NPTXR pentraxin domain\",\n      \"pmids\": [\"41495486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Assignments only; no full structure or ligand-bound complex\",\n        \"No functional mutagenesis validation of the domain\",\n        \"Does not yet map interaction surfaces with NPTX2, C1QL3, or ADGRB3\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended NPTXR function beyond neurons by showing it promotes malignant behavior in gastric cancer through oncogenic signaling and is a therapeutic target.\",\n      \"evidence\": \"siRNA knockdown, in vitro functional assays, mouse xenograft, and anti-NPTXR monoclonal antibody treatment with signaling pathway analysis\",\n      \"pmids\": [\"32847597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link between NPTXR and PI3K-AKT-mTOR/FAK-JNK/YAP activation not resolved at the receptor level\",\n        \"Single lab and single cancer context\",\n        \"Ligand driving oncogenic signaling not identified\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tested generality of the oncogenic role by replicating NPTXR-dependent proliferation, survival, and adhesion phenotypes and antibody sensitivity in a second tumor type, esophageal squamous cell carcinoma.\",\n      \"evidence\": \"siRNA knockdown with proliferation, apoptosis, adhesion assays and anti-NPTXR monoclonal antibody treatment in vitro\",\n      \"pmids\": [\"38717547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vivo validation in ESCC\",\n        \"Downstream signaling not profiled as in gastric cancer\",\n        \"Mechanism of antibody action undefined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a peripheral function: NPTXR acts as a cognate receptor for NPTX2 in pruriceptive sensory neurons to drive p-ERK-dependent itch signaling and scratching behavior.\",\n      \"evidence\": \"Intra-trigeminal-ganglion Nptxr siRNA, immunohistochemistry, scratch behavioral assay, and p-ERK western blot in an atopic dermatitis model\",\n      \"pmids\": [\"41564473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct NPTX2-NPTXR binding not demonstrated biochemically here\",\n        \"Coupling between NPTXR and ERK activation not defined\",\n        \"Single lab and single disease model\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Associated NPTXR levels with glutamatergic synapse integrity by showing prefrontal cortex downregulation in a stress-induced anhedonia model.\",\n      \"evidence\": \"High-throughput proteomics of prefrontal cortex in a chronic variable stress rat model with sucrose preference testing\",\n      \"pmids\": [\"39488299\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Associative proteomics only with no direct manipulation of NPTXR\",\n        \"Causality versus correlate of anhedonic state unresolved\",\n        \"Not a direct (R)-ketamine target\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Earliest expression observation linking NPTXR to non-neural tissue, showing delayed Nptxr mRNA upregulation in post-infarct myocardium.\",\n      \"evidence\": \"cDNA filter array with ranked ratio analysis in a rat myocardial infarction model\",\n      \"pmids\": [\"16497176\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single array-based measurement with no protein-level or functional follow-up\",\n        \"No mechanistic role in cardiac tissue established\",\n        \"Significance of the delayed kinetics unexplained\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the pentraxin domain physically engages NPTX2, C1QL3/ADGRB3, and oncogenic signaling partners to transduce both synaptic organization and tumor-promoting signals remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No ligand-bound structure linking the pentraxin domain to its partners\",\n        \"No defined receptor-to-effector mechanism for ERK or PI3K-AKT-mTOR activation\",\n        \"NPTXR-specific contribution distinct from NPTX2 not isolated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"C1QL3-NPTXR-ADGRB3 trans-synaptic adhesion complex\"\n    ],\n    \"partners\": [\n      \"NPTX2\",\n      \"NPTX1\",\n      \"C1QL3\",\n      \"ADGRB3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}