{"gene":"PLXNC1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1998,"finding":"PLXNC1 (VESPR) was identified as a novel cellular receptor for the poxvirus-encoded semaphorin A39R. A39R.Fc fusion protein was used to affinity purify PLXNC1 from a human B cell line; tandem mass spectrometry of receptor peptides confirmed its identity as a new plexin family member containing a semaphorin-like domain. Binding of A39R to PLXNC1-expressing monocytes up-regulated ICAM-1 and induced cytokine production.","method":"Affinity purification with A39R.Fc fusion protein, tandem mass spectrometry, cDNA cloning, functional monocyte stimulation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical receptor isolation, peptide MS identification, functional ligand-receptor binding validated in cell-based assay; foundational identification paper","pmids":["9586637"],"is_preprint":false},{"year":2017,"finding":"Sema7A/PlxnC1 signaling is responsible for the segregation of nigrostriatal and mesolimbic dopaminergic pathways. The transcription factors Lmx1a and Lmx1b transcriptionally repress Plxnc1 expression in substantia nigra dopamine neurons, while Otx2 enhances Plxnc1 expression in ventral tegmental area neurons; this differential expression directs topographic dopaminergic circuit formation.","method":"Transcription factor knockout/overexpression, axon tracing, genetic epistasis, in vivo knockout and rescue experiments in mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with knockout and rescue, multiple transcription factor manipulations, pathway placement confirmed by axon tracing in vivo","pmids":["29038581"],"is_preprint":false},{"year":2021,"finding":"Sema7A/PlxnC1 signaling in the olfactory system promotes post-synaptic events and dendrite selection in mitral/tufted cells, resulting in glomerular enlargement and increased sensitivity to experienced odors. PlxnC1 is expressed in mitral/tufted cells during the neonatal critical period, and knockout experiments confirmed this pathway is required for olfactory imprinting.","method":"Knockout mice, rescue experiments, live imaging of dendrite localization, odor behavioral assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout and rescue with defined cellular (dendrite selection, glomerular morphology) and behavioral phenotypes; multiple orthogonal readouts","pmids":["33780330"],"is_preprint":false},{"year":2020,"finding":"PLXNC1 promotes gastric cancer cell proliferation and migration through transcriptional activation of IL6ST (gp130/interleukin-6 signal transducer). PLXNC1 knockdown abolished these effects, and overexpression of IL6ST rescued the malignant behavior of PLXNC1-deficient cells, placing PLXNC1 upstream of IL6ST in the IL-6/STAT3 signaling axis.","method":"shRNA knockdown, overexpression, rescue experiment with IL6ST, in vitro proliferation/migration assays, in vivo xenograft, GSEA","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via rescue experiment (single lab), multiple functional assays in vitro and in vivo, but no direct transcription binding assay confirming PLXNC1 as a transcription factor at the IL6ST promoter","pmids":["32117710"],"is_preprint":false},{"year":2023,"finding":"PLXNC1 physically binds to GRP78 (glucose-regulating protein 78) in IL-1β-treated chondrocytes, as confirmed by co-immunoprecipitation. PLXNC1 silencing decreased GRP78 expression and suppressed endoplasmic reticulum stress, inflammation, apoptosis, and extracellular matrix degradation; GRP78 overexpression abolished these protective effects, placing PLXNC1 upstream of GRP78-mediated ER stress.","method":"Co-immunoprecipitation (Co-IP), shRNA knockdown, western blotting, CCK-8 viability, TUNEL apoptosis, RT-qPCR","journal":"Journal of orthopaedic surgery and research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirmed binding, rescue experiment with GRP78 overexpression validates epistasis, single lab with two orthogonal methods","pmids":["37853395"],"is_preprint":false},{"year":2024,"finding":"PLXNC1 in gastric cancer cells promotes M2 macrophage polarization by transferring exosomal miR-92b-5p to macrophages, where miR-92b-5p inhibits SOCS7-STAT3 interactions and activates STAT3. PLXNC1 regulates exosomal miR-92b-5p levels through the MEK1/MSK1/CREB1 pathway. STAT3, in turn, transcriptionally regulates PLXNC1 expression (confirmed by ChIP-QPCR and dual-luciferase reporter assay), forming a feedback loop.","method":"Exosome isolation/characterization, small RNA-seq, flow cytometry, shRNA knockdown, ChIP-QPCR, dual-luciferase reporter assay, co-culture, xenograft mouse model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-QPCR and dual-luciferase confirm direct STAT3-PLXNC1 transcriptional regulation; exosome transfer mechanism supported by multiple assays in single lab","pmids":["39566403"],"is_preprint":false},{"year":2024,"finding":"PLXNC1 was identified as an ATM/ATR phosphorylation target in human neuroblastoma cells. Phosphoproteomics showed strong downregulation of ATM/ATR-phosphopeptides on PLXNC1 after ATM depletion, categorizing it among neurite extension factors; this suggests ATM kinase phosphorylates PLXNC1 as part of semaphorin-CRMP5-microtubule signaling relevant to neurite retraction.","method":"Global phosphoproteomics (phosphopeptide profiling), ATM depletion in human neuroblastoma cells","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single phosphoproteomics dataset, preprint, no direct mutagenesis or functional validation of the specific PLXNC1 phosphorylation event","pmids":["bio_10.1101_2024.06.26.600760"],"is_preprint":true},{"year":2025,"finding":"PLXNC1 and SEMA7A exhibit anti-correlated expression along the cortical sensorimotor-association axis and have repulsive functions in shaping cortico-cortical connectivity, as part of competing transcriptional programs (pericentral vs. central) that spatially pattern the neocortex.","method":"Multispecies transcriptomic analysis, in vivo connectivity experiments (details in preprint)","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint with limited mechanistic detail in abstract; anti-correlated expression and repulsive function described but experimental details sparse","pmids":["bio_10.1101_2025.06.26.660775"],"is_preprint":true},{"year":2026,"finding":"Sema7A binds PlxnC1 to promote neutrophil extracellular trap (NET) formation in acute lung injury. Molecular docking and in vitro experiments showed that baicalin (from Tanreqing injection) competitively inhibits Sema7A binding to PlxnC1, thereby suppressing NET formation.","method":"Molecular docking, in vitro competitive binding assay, in vivo ALI rat model, RNA sequencing, single-cell sequencing","journal":"Journal of ethnopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive inhibition of Sema7A/PlxnC1 binding validated by molecular docking and in vitro experiments with in vivo confirmation; single lab","pmids":["41713818"],"is_preprint":false}],"current_model":"PLXNC1 (VESPR/CD232) is a transmembrane plexin family receptor that binds semaphorin ligands (viral A39R semaphorin and mammalian Sema7A), transducing signals that regulate immune cell activation (monocyte cytokine production, M2 macrophage polarization, neutrophil extracellular trap formation), axon guidance and circuit formation in dopaminergic and olfactory systems (via Sema7A/PlxnC1 signaling controlling dendrite selection, glomerular patterning, and nigrostriatal/mesolimbic pathway segregation), and is subject to transcriptional regulation by Lmx1a/b (repression) and STAT3 (activation), while also functioning intracellularly to transcriptionally activate IL6ST and regulate GRP78-dependent ER stress downstream of pro-inflammatory stimuli."},"narrative":{"mechanistic_narrative":"PLXNC1 (VESPR/CD232) is a transmembrane plexin-family receptor characterized by a semaphorin-like domain that transduces semaphorin signals to govern immune cell activation and neural circuit formation [PMID:9586637]. It was originally isolated as the cellular receptor for the poxvirus-encoded semaphorin A39R, whose binding to PLXNC1-expressing monocytes up-regulates ICAM-1 and induces cytokine production [PMID:9586637]. In the nervous system, Sema7A/PLXNC1 signaling patterns connectivity: it directs topographic segregation of nigrostriatal versus mesolimbic dopaminergic pathways through differential transcriptional control of Plxnc1 (repression by Lmx1a/Lmx1b in substantia nigra neurons, enhancement by Otx2 in ventral tegmental area neurons) [PMID:29038581], and during a neonatal critical period it drives dendrite selection and glomerular enlargement in olfactory mitral/tufted cells to enable olfactory imprinting [PMID:33780330]. In disease and inflammatory contexts, Sema7A/PLXNC1 binding promotes neutrophil extracellular trap formation in acute lung injury [PMID:41713818], and PLXNC1 drives gastric cancer proliferation and migration by acting upstream of IL6ST in the IL-6/STAT3 axis [PMID:32117710] and by transferring exosomal miR-92b-5p to macrophages to promote M2 polarization, with STAT3 in turn directly activating PLXNC1 transcription to form a feedback loop [PMID:39566403]. PLXNC1 also physically binds GRP78 to drive ER stress, inflammation, and matrix degradation in IL-1β-treated chondrocytes [PMID:37853395].","teleology":[{"year":1998,"claim":"Established that PLXNC1 is a bona fide cell-surface receptor by isolating it as the binding partner for the viral semaphorin A39R and linking that engagement to immune activation.","evidence":"A39R.Fc affinity purification, tandem MS peptide identification, and monocyte stimulation assays in a human B cell line","pmids":["9586637"],"confidence":"High","gaps":["Did not identify the endogenous mammalian semaphorin ligand","Downstream intracellular signaling effectors of the receptor were not defined"]},{"year":2017,"claim":"Showed that Sema7A/PlxnC1 signaling patterns dopaminergic circuitry and that Plxnc1 expression is set by opposing transcription factors, explaining how the receptor achieves spatial specificity in vivo.","evidence":"Transcription factor knockout/overexpression, axon tracing, and genetic epistasis with rescue in mice","pmids":["29038581"],"confidence":"High","gaps":["Did not resolve the intracellular guidance signaling cascade downstream of PlxnC1","Direct transcription-factor binding at the Plxnc1 locus not shown"]},{"year":2021,"claim":"Demonstrated a developmental role for PlxnC1 in olfactory imprinting, establishing that Sema7A/PlxnC1 signaling drives postsynaptic dendrite selection during a critical window.","evidence":"Knockout and rescue mice, live imaging of dendrite localization, and odor behavioral assays","pmids":["33780330"],"confidence":"High","gaps":["Molecular link between receptor engagement and dendrite/glomerular remodeling not defined","Critical-period timing mechanism not mechanistically explained"]},{"year":2020,"claim":"Placed PLXNC1 upstream of IL6ST in the IL-6/STAT3 axis, implicating the receptor as a driver of gastric cancer proliferation and migration.","evidence":"shRNA knockdown, IL6ST overexpression rescue, in vitro proliferation/migration assays, xenograft, and GSEA","pmids":["32117710"],"confidence":"Medium","gaps":["No direct DNA-binding assay confirming PLXNC1 acts at the IL6ST promoter","Mechanism by which a plexin receptor regulates IL6ST transcription unresolved","Single-lab finding without independent replication"]},{"year":2023,"claim":"Identified a physical PLXNC1–GRP78 interaction that drives ER stress and inflammatory matrix degradation, extending PLXNC1 function into chondrocyte pathology.","evidence":"Co-IP, shRNA knockdown, GRP78 overexpression rescue, western blot, TUNEL, and RT-qPCR in IL-1β-treated chondrocytes","pmids":["37853395"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal validation or structural mapping of the interface","Whether interaction is direct versus complex-mediated not established","Single-lab finding"]},{"year":2024,"claim":"Defined a PLXNC1–exosomal miR-92b-5p–STAT3 circuit promoting M2 macrophage polarization and a STAT3-driven feedback loop that transcriptionally sustains PLXNC1 expression.","evidence":"Exosome isolation, small RNA-seq, flow cytometry, ChIP-qPCR, dual-luciferase reporter, co-culture, and xenograft","pmids":["39566403"],"confidence":"Medium","gaps":["Mechanism linking the receptor to MEK1/MSK1/CREB1-controlled exosomal miRNA loading not fully resolved","Single-lab finding without independent confirmation of the feedback loop"]},{"year":2024,"claim":"Flagged PLXNC1 as a candidate ATM/ATR phosphorylation substrate linked to neurite extension, hinting at kinase regulation of its neural signaling role.","evidence":"Global phosphoproteomics after ATM depletion in human neuroblastoma cells (preprint)","pmids":["bio_10.1101_2024.06.26.600760"],"confidence":"Low","gaps":["No direct mutagenesis or functional validation of the specific phosphorylation event","Preprint, single dataset","Functional consequence of phosphorylation for receptor activity unknown"]},{"year":2025,"claim":"Proposed that anti-correlated PLXNC1/SEMA7A expression along the cortical sensorimotor-association axis exerts repulsive control over cortico-cortical connectivity.","evidence":"Multispecies transcriptomic analysis and in vivo connectivity experiments (preprint)","pmids":["bio_10.1101_2025.06.26.660775"],"confidence":"Low","gaps":["Limited mechanistic detail in preprint abstract","Causal connectivity experiments not fully described","Cellular mechanism of repulsion not defined"]},{"year":2026,"claim":"Showed that Sema7A/PlxnC1 binding promotes neutrophil extracellular trap formation in acute lung injury and that this engagement is pharmacologically druggable.","evidence":"Molecular docking, in vitro competitive binding (baicalin), ALI rat model, RNA-seq, and single-cell sequencing","pmids":["41713818"],"confidence":"Medium","gaps":["Downstream signaling from PlxnC1 to NET machinery not mapped","Docking-based competitive inhibition not confirmed by direct structural data","Single-lab finding"]},{"year":null,"claim":"The intracellular signal-transduction mechanism by which PLXNC1 converts semaphorin binding into cytoskeletal, transcriptional, and immune outputs remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined cytoplasmic effector or signaling cascade for the receptor","No structural model of ligand-receptor engagement","Mechanism connecting a surface receptor to reported transcriptional activities (IL6ST) unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,5]}],"complexes":[],"partners":["SEMA7A","A39R","GRP78","IL6ST","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60486","full_name":"Plexin-C1","aliases":["Virus-encoded semaphorin protein receptor"],"length_aa":1568,"mass_kda":175.7,"function":"Receptor for SEMA7A, for smallpox semaphorin A39R, vaccinia virus semaphorin A39R and for herpesvirus Sema protein. Binding of semaphorins triggers cellular responses leading to the rearrangement of the cytoskeleton and to secretion of IL6 and IL8 (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/O60486/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLXNC1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLXNC1","total_profiled":1310},"omim":[{"mim_id":"604259","title":"PLEXIN C1; PLXNC1","url":"https://www.omim.org/entry/604259"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLXNC1"},"hgnc":{"alias_symbol":["VESPR","CD232"],"prev_symbol":[]},"alphafold":{"accession":"O60486","domains":[{"cath_id":"3.30.1680.10","chopping":"456-498","consensus_level":"medium","plddt":80.3047,"start":456,"end":498},{"cath_id":"2.60.40,2.60.40","chopping":"516-617","consensus_level":"high","plddt":78.2573,"start":516,"end":617},{"cath_id":"2.60.40.10","chopping":"664-752","consensus_level":"high","plddt":88.4643,"start":664,"end":752},{"cath_id":"2.60.40.10","chopping":"756-842","consensus_level":"high","plddt":83.2764,"start":756,"end":842},{"cath_id":"2.60.40,2.60.40","chopping":"847-937","consensus_level":"high","plddt":83.7196,"start":847,"end":937},{"cath_id":"3.10.20.90","chopping":"1195-1322","consensus_level":"medium","plddt":81.1705,"start":1195,"end":1322}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60486","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60486-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60486-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLXNC1","jax_strain_url":"https://www.jax.org/strain/search?query=PLXNC1"},"sequence":{"accession":"O60486","fasta_url":"https://rest.uniprot.org/uniprotkb/O60486.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60486/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60486"}},"corpus_meta":[{"pmid":"9586637","id":"PMC_9586637","title":"A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR.","date":"1998","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/9586637","citation_count":203,"is_preprint":false},{"pmid":"29038581","id":"PMC_29038581","title":"Transcriptional repression of Plxnc1 by Lmx1a and Lmx1b directs topographic dopaminergic circuit formation.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29038581","citation_count":27,"is_preprint":false},{"pmid":"39566403","id":"PMC_39566403","title":"EGCG targeting STAT3 transcriptionally represses PLXNC1 to inhibit M2 polarization mediated by gastric cancer cell-derived exosomal miR-92b-5p.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39566403","citation_count":26,"is_preprint":false},{"pmid":"33780330","id":"PMC_33780330","title":"The olfactory critical period is determined by activity-dependent Sema7A/PlxnC1 signaling within glomeruli.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33780330","citation_count":26,"is_preprint":false},{"pmid":"31317324","id":"PMC_31317324","title":"MiR-4500 Regulates PLXNC1 and Inhibits Papillary Thyroid Cancer Progression.","date":"2019","source":"Hormones & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31317324","citation_count":23,"is_preprint":false},{"pmid":"29514220","id":"PMC_29514220","title":"Long non-coding RNA CASC2 inhibits tumorigenesis via the miR-181a/PLXNC1 axis in melanoma.","date":"2018","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/29514220","citation_count":17,"is_preprint":false},{"pmid":"32117710","id":"PMC_32117710","title":"PLXNC1 Enhances Carcinogenesis Through Transcriptional Activation of IL6ST in Gastric Cancer.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32117710","citation_count":17,"is_preprint":false},{"pmid":"34277610","id":"PMC_34277610","title":"PLXNC1: A Novel Potential Immune-Related Target for Stomach Adenocarcinoma.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34277610","citation_count":15,"is_preprint":false},{"pmid":"37853395","id":"PMC_37853395","title":"PLXNC1 interference alleviates the inflammatory injury, apoptosis and extracellular matrix degradation of IL-1β-exposed chondrocytes via suppressing GRP78 expression.","date":"2023","source":"Journal of orthopaedic surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/37853395","citation_count":8,"is_preprint":false},{"pmid":"22933835","id":"PMC_22933835","title":"PLXNC1 and RDH13 associated with bilateral convergent strabismus with exophthalmus in German Brown cattle.","date":"2012","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/22933835","citation_count":4,"is_preprint":false},{"pmid":"42004227","id":"PMC_42004227","title":"Identification of PLXNC1 as a novel biomarker for consensus molecular subtype 4 in colorectal cancer.","date":"2025","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/42004227","citation_count":0,"is_preprint":false},{"pmid":"41713818","id":"PMC_41713818","title":"Tanreqing injection regulates Sema7a/Plxnc1 signaling pathway mediated neutrophil extracellular trap formation to alleviate lipopolysaccharide-induced acute lung injury.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41713818","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.26.660775","title":"Competing Programs Shape Cortical Sensorimotor-Association Axis Development","date":"2025-06-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.26.660775","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.19.24316720","title":"Genome-wide investigation of rare germline copy-number variants in retinoblastoma","date":"2024-11-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.19.24316720","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.26.600760","title":"The ataxia-telangiectasia disease protein ATM controls vesicular protein secretion via CHGA and microtubule dynamics via CRMP5","date":"2024-06-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.26.600760","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11210,"output_tokens":2626,"usd":0.03651,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9800,"output_tokens":3390,"usd":0.066875,"stage2_stop_reason":"end_turn"},"total_usd":0.103385,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"PLXNC1 (VESPR) was identified as a novel cellular receptor for the poxvirus-encoded semaphorin A39R. A39R.Fc fusion protein was used to affinity purify PLXNC1 from a human B cell line; tandem mass spectrometry of receptor peptides confirmed its identity as a new plexin family member containing a semaphorin-like domain. Binding of A39R to PLXNC1-expressing monocytes up-regulated ICAM-1 and induced cytokine production.\",\n      \"method\": \"Affinity purification with A39R.Fc fusion protein, tandem mass spectrometry, cDNA cloning, functional monocyte stimulation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical receptor isolation, peptide MS identification, functional ligand-receptor binding validated in cell-based assay; foundational identification paper\",\n      \"pmids\": [\"9586637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sema7A/PlxnC1 signaling is responsible for the segregation of nigrostriatal and mesolimbic dopaminergic pathways. The transcription factors Lmx1a and Lmx1b transcriptionally repress Plxnc1 expression in substantia nigra dopamine neurons, while Otx2 enhances Plxnc1 expression in ventral tegmental area neurons; this differential expression directs topographic dopaminergic circuit formation.\",\n      \"method\": \"Transcription factor knockout/overexpression, axon tracing, genetic epistasis, in vivo knockout and rescue experiments in mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with knockout and rescue, multiple transcription factor manipulations, pathway placement confirmed by axon tracing in vivo\",\n      \"pmids\": [\"29038581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Sema7A/PlxnC1 signaling in the olfactory system promotes post-synaptic events and dendrite selection in mitral/tufted cells, resulting in glomerular enlargement and increased sensitivity to experienced odors. PlxnC1 is expressed in mitral/tufted cells during the neonatal critical period, and knockout experiments confirmed this pathway is required for olfactory imprinting.\",\n      \"method\": \"Knockout mice, rescue experiments, live imaging of dendrite localization, odor behavioral assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout and rescue with defined cellular (dendrite selection, glomerular morphology) and behavioral phenotypes; multiple orthogonal readouts\",\n      \"pmids\": [\"33780330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLXNC1 promotes gastric cancer cell proliferation and migration through transcriptional activation of IL6ST (gp130/interleukin-6 signal transducer). PLXNC1 knockdown abolished these effects, and overexpression of IL6ST rescued the malignant behavior of PLXNC1-deficient cells, placing PLXNC1 upstream of IL6ST in the IL-6/STAT3 signaling axis.\",\n      \"method\": \"shRNA knockdown, overexpression, rescue experiment with IL6ST, in vitro proliferation/migration assays, in vivo xenograft, GSEA\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via rescue experiment (single lab), multiple functional assays in vitro and in vivo, but no direct transcription binding assay confirming PLXNC1 as a transcription factor at the IL6ST promoter\",\n      \"pmids\": [\"32117710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLXNC1 physically binds to GRP78 (glucose-regulating protein 78) in IL-1β-treated chondrocytes, as confirmed by co-immunoprecipitation. PLXNC1 silencing decreased GRP78 expression and suppressed endoplasmic reticulum stress, inflammation, apoptosis, and extracellular matrix degradation; GRP78 overexpression abolished these protective effects, placing PLXNC1 upstream of GRP78-mediated ER stress.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), shRNA knockdown, western blotting, CCK-8 viability, TUNEL apoptosis, RT-qPCR\",\n      \"journal\": \"Journal of orthopaedic surgery and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirmed binding, rescue experiment with GRP78 overexpression validates epistasis, single lab with two orthogonal methods\",\n      \"pmids\": [\"37853395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLXNC1 in gastric cancer cells promotes M2 macrophage polarization by transferring exosomal miR-92b-5p to macrophages, where miR-92b-5p inhibits SOCS7-STAT3 interactions and activates STAT3. PLXNC1 regulates exosomal miR-92b-5p levels through the MEK1/MSK1/CREB1 pathway. STAT3, in turn, transcriptionally regulates PLXNC1 expression (confirmed by ChIP-QPCR and dual-luciferase reporter assay), forming a feedback loop.\",\n      \"method\": \"Exosome isolation/characterization, small RNA-seq, flow cytometry, shRNA knockdown, ChIP-QPCR, dual-luciferase reporter assay, co-culture, xenograft mouse model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-QPCR and dual-luciferase confirm direct STAT3-PLXNC1 transcriptional regulation; exosome transfer mechanism supported by multiple assays in single lab\",\n      \"pmids\": [\"39566403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLXNC1 was identified as an ATM/ATR phosphorylation target in human neuroblastoma cells. Phosphoproteomics showed strong downregulation of ATM/ATR-phosphopeptides on PLXNC1 after ATM depletion, categorizing it among neurite extension factors; this suggests ATM kinase phosphorylates PLXNC1 as part of semaphorin-CRMP5-microtubule signaling relevant to neurite retraction.\",\n      \"method\": \"Global phosphoproteomics (phosphopeptide profiling), ATM depletion in human neuroblastoma cells\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single phosphoproteomics dataset, preprint, no direct mutagenesis or functional validation of the specific PLXNC1 phosphorylation event\",\n      \"pmids\": [\"bio_10.1101_2024.06.26.600760\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLXNC1 and SEMA7A exhibit anti-correlated expression along the cortical sensorimotor-association axis and have repulsive functions in shaping cortico-cortical connectivity, as part of competing transcriptional programs (pericentral vs. central) that spatially pattern the neocortex.\",\n      \"method\": \"Multispecies transcriptomic analysis, in vivo connectivity experiments (details in preprint)\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint with limited mechanistic detail in abstract; anti-correlated expression and repulsive function described but experimental details sparse\",\n      \"pmids\": [\"bio_10.1101_2025.06.26.660775\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Sema7A binds PlxnC1 to promote neutrophil extracellular trap (NET) formation in acute lung injury. Molecular docking and in vitro experiments showed that baicalin (from Tanreqing injection) competitively inhibits Sema7A binding to PlxnC1, thereby suppressing NET formation.\",\n      \"method\": \"Molecular docking, in vitro competitive binding assay, in vivo ALI rat model, RNA sequencing, single-cell sequencing\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive inhibition of Sema7A/PlxnC1 binding validated by molecular docking and in vitro experiments with in vivo confirmation; single lab\",\n      \"pmids\": [\"41713818\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLXNC1 (VESPR/CD232) is a transmembrane plexin family receptor that binds semaphorin ligands (viral A39R semaphorin and mammalian Sema7A), transducing signals that regulate immune cell activation (monocyte cytokine production, M2 macrophage polarization, neutrophil extracellular trap formation), axon guidance and circuit formation in dopaminergic and olfactory systems (via Sema7A/PlxnC1 signaling controlling dendrite selection, glomerular patterning, and nigrostriatal/mesolimbic pathway segregation), and is subject to transcriptional regulation by Lmx1a/b (repression) and STAT3 (activation), while also functioning intracellularly to transcriptionally activate IL6ST and regulate GRP78-dependent ER stress downstream of pro-inflammatory stimuli.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLXNC1 (VESPR/CD232) is a transmembrane plexin-family receptor characterized by a semaphorin-like domain that transduces semaphorin signals to govern immune cell activation and neural circuit formation [#0]. It was originally isolated as the cellular receptor for the poxvirus-encoded semaphorin A39R, whose binding to PLXNC1-expressing monocytes up-regulates ICAM-1 and induces cytokine production [#0]. In the nervous system, Sema7A/PLXNC1 signaling patterns connectivity: it directs topographic segregation of nigrostriatal versus mesolimbic dopaminergic pathways through differential transcriptional control of Plxnc1 (repression by Lmx1a/Lmx1b in substantia nigra neurons, enhancement by Otx2 in ventral tegmental area neurons) [#1], and during a neonatal critical period it drives dendrite selection and glomerular enlargement in olfactory mitral/tufted cells to enable olfactory imprinting [#2]. In disease and inflammatory contexts, Sema7A/PLXNC1 binding promotes neutrophil extracellular trap formation in acute lung injury [#8], and PLXNC1 drives gastric cancer proliferation and migration by acting upstream of IL6ST in the IL-6/STAT3 axis [#3] and by transferring exosomal miR-92b-5p to macrophages to promote M2 polarization, with STAT3 in turn directly activating PLXNC1 transcription to form a feedback loop [#5]. PLXNC1 also physically binds GRP78 to drive ER stress, inflammation, and matrix degradation in IL-1\\u03b2-treated chondrocytes [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that PLXNC1 is a bona fide cell-surface receptor by isolating it as the binding partner for the viral semaphorin A39R and linking that engagement to immune activation.\",\n      \"evidence\": \"A39R.Fc affinity purification, tandem MS peptide identification, and monocyte stimulation assays in a human B cell line\",\n      \"pmids\": [\"9586637\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not identify the endogenous mammalian semaphorin ligand\",\n        \"Downstream intracellular signaling effectors of the receptor were not defined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that Sema7A/PlxnC1 signaling patterns dopaminergic circuitry and that Plxnc1 expression is set by opposing transcription factors, explaining how the receptor achieves spatial specificity in vivo.\",\n      \"evidence\": \"Transcription factor knockout/overexpression, axon tracing, and genetic epistasis with rescue in mice\",\n      \"pmids\": [\"29038581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Did not resolve the intracellular guidance signaling cascade downstream of PlxnC1\",\n        \"Direct transcription-factor binding at the Plxnc1 locus not shown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a developmental role for PlxnC1 in olfactory imprinting, establishing that Sema7A/PlxnC1 signaling drives postsynaptic dendrite selection during a critical window.\",\n      \"evidence\": \"Knockout and rescue mice, live imaging of dendrite localization, and odor behavioral assays\",\n      \"pmids\": [\"33780330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular link between receptor engagement and dendrite/glomerular remodeling not defined\",\n        \"Critical-period timing mechanism not mechanistically explained\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed PLXNC1 upstream of IL6ST in the IL-6/STAT3 axis, implicating the receptor as a driver of gastric cancer proliferation and migration.\",\n      \"evidence\": \"shRNA knockdown, IL6ST overexpression rescue, in vitro proliferation/migration assays, xenograft, and GSEA\",\n      \"pmids\": [\"32117710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct DNA-binding assay confirming PLXNC1 acts at the IL6ST promoter\",\n        \"Mechanism by which a plexin receptor regulates IL6ST transcription unresolved\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a physical PLXNC1\\u2013GRP78 interaction that drives ER stress and inflammatory matrix degradation, extending PLXNC1 function into chondrocyte pathology.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, GRP78 overexpression rescue, western blot, TUNEL, and RT-qPCR in IL-1\\u03b2-treated chondrocytes\",\n      \"pmids\": [\"37853395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal validation or structural mapping of the interface\",\n        \"Whether interaction is direct versus complex-mediated not established\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a PLXNC1\\u2013exosomal miR-92b-5p\\u2013STAT3 circuit promoting M2 macrophage polarization and a STAT3-driven feedback loop that transcriptionally sustains PLXNC1 expression.\",\n      \"evidence\": \"Exosome isolation, small RNA-seq, flow cytometry, ChIP-qPCR, dual-luciferase reporter, co-culture, and xenograft\",\n      \"pmids\": [\"39566403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking the receptor to MEK1/MSK1/CREB1-controlled exosomal miRNA loading not fully resolved\",\n        \"Single-lab finding without independent confirmation of the feedback loop\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Flagged PLXNC1 as a candidate ATM/ATR phosphorylation substrate linked to neurite extension, hinting at kinase regulation of its neural signaling role.\",\n      \"evidence\": \"Global phosphoproteomics after ATM depletion in human neuroblastoma cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.06.26.600760\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct mutagenesis or functional validation of the specific phosphorylation event\",\n        \"Preprint, single dataset\",\n        \"Functional consequence of phosphorylation for receptor activity unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed that anti-correlated PLXNC1/SEMA7A expression along the cortical sensorimotor-association axis exerts repulsive control over cortico-cortical connectivity.\",\n      \"evidence\": \"Multispecies transcriptomic analysis and in vivo connectivity experiments (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.26.660775\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Limited mechanistic detail in preprint abstract\",\n        \"Causal connectivity experiments not fully described\",\n        \"Cellular mechanism of repulsion not defined\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed that Sema7A/PlxnC1 binding promotes neutrophil extracellular trap formation in acute lung injury and that this engagement is pharmacologically druggable.\",\n      \"evidence\": \"Molecular docking, in vitro competitive binding (baicalin), ALI rat model, RNA-seq, and single-cell sequencing\",\n      \"pmids\": [\"41713818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling from PlxnC1 to NET machinery not mapped\",\n        \"Docking-based competitive inhibition not confirmed by direct structural data\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signal-transduction mechanism by which PLXNC1 converts semaphorin binding into cytoskeletal, transcriptional, and immune outputs remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No defined cytoplasmic effector or signaling cascade for the receptor\",\n        \"No structural model of ligand-receptor engagement\",\n        \"Mechanism connecting a surface receptor to reported transcriptional activities (IL6ST) unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SEMA7A\",\n      \"A39R\",\n      \"GRP78\",\n      \"IL6ST\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}