{"gene":"CNTN1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1994,"finding":"Human contactin (CNTN1) is a GPI-anchored membrane protein composed of six C2 Ig-domains and four fibronectin type III repeats, anchored via a glycosyl phosphatidylinositol moiety as demonstrated by PI-PLC treatment of transfected cells and metabolic labeling with [3H]-ethanolamine.","method":"PI-PLC treatment of transfected cells, metabolic labeling with [3H]-ethanolamine, cDNA cloning and sequencing","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical demonstration of GPI anchor using multiple orthogonal methods (PI-PLC cleavage and metabolic labeling) in a single focused study","pmids":["7959734"],"is_preprint":false},{"year":2016,"finding":"CNTN1 overexpression in prostate cancer cells enhances invasion in vitro and promotes xenograft tumor formation and lung metastasis in vivo, accompanied by elevated AKT activation and reduced E-cadherin (CDH1) expression; CNTN1 knockdown reduced tumor-initiating capacity.","method":"CNTN1 overexpression/knockdown in DU145 cells, in vitro invasion assay, xenograft mouse model, Western blot for AKT activation and E-cadherin","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined cellular and in vivo phenotypes plus signaling readouts, single lab","pmids":["26795349"],"is_preprint":false},{"year":2017,"finding":"CNTN1 promotes cisplatin resistance in lung adenocarcinoma by inducing epithelial-mesenchymal transition (EMT) through activation of the PI3K/Akt signaling pathway; CNTN1 knockdown in cisplatin-resistant A549/DDP cells reversed EMT markers and restored drug sensitivity, while CNTN1 overexpression in A549 cells produced the opposite effect.","method":"CNTN1 overexpression/knockdown in A549 and A549/DDP cells, Western blot for EMT markers (E-cadherin, N-cadherin, Vimentin) and PI3K/Akt pathway, xenograft mouse model","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with signaling pathway readouts in vitro and in vivo, single lab","pmids":["28934754"],"is_preprint":false},{"year":2019,"finding":"Anti-CNTN1 IgG3 autoantibodies induce acute reversible conduction block at peripheral nerve nodes of Ranvier via complement deposition at paranodes, without inflammatory infiltrates or dispersal of paranodal proteins; IgG4 anti-CNTN1 causes different chronic structural changes.","method":"Intraneural injection of patient IgG into Lewis rats, electrophysiological nerve conduction studies, immunofluorescence for complement deposition and paranodal proteins, motor deficit assessment","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — passive transfer animal model with electrophysiology, immunofluorescence, and behavioral readouts; single lab","pmids":["30953561"],"is_preprint":false},{"year":2020,"finding":"CNTN1 knockdown in docetaxel-resistant prostate cancer cells (PC3-DR and DU145-DR) attenuates cell proliferation, migration, invasion, EMT phenotype, and drug resistance, and decreases PI3K/Akt signaling activity both in vitro and in vivo.","method":"shRNA knockdown in docetaxel-resistant PCa cell lines, CCK-8, flow cytometry, wound-healing, transwell assays, Western blot for PI3K/Akt, xenograft tumor model","journal":"Archives of medical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts and pathway analysis in vitro and in vivo, single lab","pmids":["33488868"],"is_preprint":false},{"year":2021,"finding":"CNTN1 overexpression in the hippocampus (via AAV stereotactic injection) triggers anxiety- and depression-like phenotypes in mice, activates microglia, increases pro-inflammatory cytokines (IL1α, IL6, Ccl2), decreases anti-inflammatory markers, and impairs hippocampal immature neurons (doublecortin+ cells) in the dentate gyrus.","method":"AAV-mediated CNTN1 overexpression via stereotactic injection, behavioral tests, real-time qPCR for cytokines, immunohistochemistry for doublecortin","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function with defined behavioral and cellular phenotypes plus molecular readouts, single lab","pmids":["33737174"],"is_preprint":false},{"year":2023,"finding":"CNTN1 overexpression in the hippocampus triggers cognitive deficits via microglial activation that induces astrocyte activation with aberrant expression of glutamate transporters EAAT1/EAAT2, resulting in long-term potentiation (LTP) impairment; these effects were reversed by minocycline (microglial activation inhibitor).","method":"AAV-mediated CNTN1 overexpression via stereotactic injection, novel object/place recognition and social cognition tests, LTP electrophysiology, minocycline pharmacological rescue, immunostaining for microglia and astrocyte markers, EAAT1/EAAT2 Western blot","journal":"Aging and disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with pharmacological rescue, electrophysiology, and multiple cellular readouts; single lab","pmids":["37196127"],"is_preprint":false},{"year":2023,"finding":"CNTN1 expression in the nucleus accumbens (NAc) is upregulated by methamphetamine exposure via dopamine D2 receptor signaling; AAV-shRNA silencing of CNTN1 specifically in the NAc reversed methamphetamine-induced conditioned place preference and decreased expression of synaptic proteins NR2A, NR2B, and PSD95 in the NAc.","method":"AAV-shRNA stereotactic injection for NAc-specific CNTN1 knockdown, conditioned place preference behavioral assay, haloperidol pharmacological treatment, Western blot for NR2A/NR2B/PSD95","journal":"Neurotoxicity research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — region-specific loss-of-function with behavioral and molecular readouts, pharmacological validation; single lab","pmids":["37014368"],"is_preprint":false},{"year":2024,"finding":"CNTN1 (a GPI-linked protein) binds the tenascin-R (Tnr)–RPTPζ complex at the neuronal cell surface and is critical for perineuronal net (PNN) structure; this was demonstrated biochemically and structurally, placing CNTN1 as a key cell-surface receptor nucleating PNN assembly.","method":"Biochemical binding assays, structural analysis, loss-of-function experiments targeting Cntn1 in PNN formation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — biochemical and structural approach with functional validation reported in preprint; not yet peer-reviewed, single lab","pmids":["bio_10.1101_2024.11.05.622114"],"is_preprint":true},{"year":2025,"finding":"PFKM promotes CNTN1 expression in gastric cancer cells through enrichment of histone lactylation mark H3K18la at the CNTN1 promoter region; PFKM was shown to interact with CNTN1 and CNTN1 overexpression reversed the inhibitory effects of PFKM knockdown on gastric cancer cell viability, migration, and invasion.","method":"Dual-luciferase reporter assay for H3K18la-mediated transcriptional regulation, co-immunoprecipitation/interaction assay (PFKM–CNTN1), CNTN1 overexpression rescue experiments, CCK-8 and transwell assays, xenograft mouse model","journal":"Applied biochemistry and biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, interaction and epigenetic regulation described but methodology not fully characterized","pmids":["40608258"],"is_preprint":false},{"year":2025,"finding":"CNTN1 promotes ovarian cancer cell proliferation, migration, and invasion through regulation of presenilin-1 (PSEN1); luciferase assays identified a regulatory interaction between CNTN1 and PSEN1, and PSEN1 overexpression reversed the impaired proliferation and invasion caused by CNTN1 silencing.","method":"CNTN1 siRNA knockdown, luciferase reporter assay for CNTN1–PSEN1 regulatory interaction, PSEN1 overexpression rescue, colony formation assay, transwell assay, xenograft mouse model","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single rescue experiment; the molecular mechanism of CNTN1–PSEN1 regulation is not fully characterized in the abstract","pmids":["40687216"],"is_preprint":false},{"year":2026,"finding":"CNTN1 promotes hilar cholangiocarcinoma cell invasion in vitro and metastasis in vivo by activating the PI3K-AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT).","method":"Gain- and loss-of-function studies (CNTN1 overexpression and knockdown), Transwell invasion assays, orthotopic metastatic mouse model, Western blot for PI3K-AKT pathway and EMT markers","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined in vitro and in vivo phenotypes and signaling pathway readouts; single lab","pmids":["41898278"],"is_preprint":false}],"current_model":"CNTN1 is a GPI-anchored neuronal cell adhesion molecule (six Ig-domains plus four FNIII repeats) that, in its canonical neural role, binds the tenascin-R–RPTPζ complex to nucleate perineuronal net structure, modulates synaptic protein expression (NR2A/NR2B/PSD95) and hippocampal neuroinflammation through microglia–astrocyte crosstalk affecting EAAT1/EAAT2 and LTP, and mediates addiction-related plasticity in the nucleus accumbens via dopamine D2 receptor signaling; in cancer contexts, CNTN1 drives invasion, EMT, and chemoresistance primarily by activating the PI3K/AKT signaling pathway."},"narrative":{"mechanistic_narrative":"CNTN1 is a glycosylphosphatidylinositol (GPI)-anchored neuronal cell-surface adhesion molecule built from six C2 Ig domains and four fibronectin type III repeats, whose anchoring and architecture were established by direct biochemical characterization [PMID:7959734]. At the neuronal surface it binds the tenascin-R–RPTPζ complex and serves as a receptor that nucleates perineuronal net assembly [PMID:bio_10.1101_2024.11.05.622114]. Manipulation of CNTN1 in defined brain regions links it to circuit-level plasticity and neuroinflammation: hippocampal overexpression activates microglia, drives astrocyte activation with aberrant EAAT1/EAAT2 glutamate-transporter expression, and impairs long-term potentiation and cognition, effects reversed by the microglial inhibitor minocycline, and additionally produces anxiety- and depression-like phenotypes with reduced hippocampal neurogenesis [PMID:33737174, PMID:37196127]. In the nucleus accumbens, CNTN1 is induced by methamphetamine through dopamine D2 receptor signaling and supports addiction-related conditioned place preference and expression of the synaptic proteins NR2A, NR2B, and PSD95 [PMID:37014368]. Anti-CNTN1 autoantibodies cause peripheral nerve conduction block via complement deposition at paranodes, implicating CNTN1 in node-of-Ranvier integrity [PMID:30953561]. Beyond the nervous system, CNTN1 is a consistent pro-tumorigenic factor across prostate, lung, cholangiocarcinoma and other cancers, where it drives invasion, epithelial-mesenchymal transition, metastasis, and chemoresistance largely through activation of PI3K/AKT signaling [PMID:26795349, PMID:28934754, PMID:41898278].","teleology":[{"year":1994,"claim":"Established the fundamental molecular identity of CNTN1 as a GPI-anchored multidomain cell-surface protein, defining the structural basis for its adhesion/receptor function.","evidence":"PI-PLC cleavage, [3H]-ethanolamine metabolic labeling, and cDNA cloning in transfected cells","pmids":["7959734"],"confidence":"High","gaps":["No binding partners or downstream signaling identified at this stage","No functional or cellular role assigned"]},{"year":2016,"claim":"Showed CNTN1 is not merely structural but functionally drives malignant behavior, connecting it to AKT activation and loss of E-cadherin in prostate cancer.","evidence":"Gain/loss-of-function in DU145 cells, invasion assays, xenograft metastasis model, Western blot","pmids":["26795349"],"confidence":"Medium","gaps":["Mechanism linking GPI-anchored CNTN1 to intracellular AKT activation unresolved","Direct receptor partner in cancer cells not identified","Single lab, single tumor type"]},{"year":2017,"claim":"Extended the cancer role to chemoresistance, implicating CNTN1-driven EMT via PI3K/Akt as a mechanism of cisplatin resistance.","evidence":"Reciprocal overexpression/knockdown in A549 and A549/DDP cells, EMT and pathway Western blots, xenograft","pmids":["28934754"],"confidence":"Medium","gaps":["How CNTN1 engages PI3K/Akt mechanistically not shown","No structural basis for pathway activation"]},{"year":2020,"claim":"Reinforced the PI3K/Akt-EMT-resistance axis in docetaxel-resistant prostate cancer, supporting CNTN1 as a therapeutic target in drug-resistant tumors.","evidence":"shRNA knockdown in resistant PCa lines, multiple phenotypic assays, pathway Western blot, xenograft","pmids":["33488868"],"confidence":"Medium","gaps":["Upstream regulators of CNTN1 in resistance not defined","Direct signaling intermediates unmapped"]},{"year":2021,"claim":"Demonstrated a causal CNS role beyond adhesion, linking hippocampal CNTN1 to neuroinflammation, mood phenotypes, and impaired neurogenesis.","evidence":"AAV CNTN1 overexpression, behavioral tests, cytokine qPCR, doublecortin immunohistochemistry in mice","pmids":["33737174"],"confidence":"Medium","gaps":["Mechanism by which surface CNTN1 activates microglia unknown","Cell-type origin of inflammatory signal undefined"]},{"year":2023,"claim":"Resolved a microglia-astrocyte-glutamate transporter circuit through which CNTN1 impairs synaptic plasticity, with pharmacological rescue confirming microglia as the initiating node.","evidence":"AAV overexpression, cognition tests, LTP electrophysiology, minocycline rescue, EAAT1/EAAT2 Western blot","pmids":["37196127"],"confidence":"Medium","gaps":["Receptor mediating CNTN1's effect on microglia not identified","Whether endogenous CNTN1 elevation produces the same effect untested"]},{"year":2023,"claim":"Placed CNTN1 within addiction circuitry, showing it acts downstream of dopamine D2 signaling to support synaptic protein expression and drug-associated behavior in the nucleus accumbens.","evidence":"NAc-specific AAV-shRNA knockdown, conditioned place preference, haloperidol treatment, NR2A/NR2B/PSD95 Western blot","pmids":["37014368"],"confidence":"Medium","gaps":["Direct link from D2 signaling to CNTN1 transcription not delineated","Synaptic partners of CNTN1 in NAc not identified"]},{"year":2024,"claim":"Identified the physiological surface ligand complex (tenascin-R–RPTPζ) and assigned CNTN1 a structural role nucleating perineuronal nets, defining its canonical neural receptor function.","evidence":"Biochemical binding and structural analysis with Cntn1 loss-of-function in PNN formation (preprint)","pmids":["bio_10.1101_2024.11.05.622114"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Stoichiometry and signaling consequences of the ternary complex unresolved"]},{"year":2025,"claim":"Began to define upstream regulation of CNTN1 in cancer, implicating PFKM-driven histone lactylation at the CNTN1 promoter and a direct PFKM–CNTN1 interaction in gastric cancer.","evidence":"Luciferase reporter for H3K18la regulation, Co-IP, CNTN1 overexpression rescue, viability/invasion assays, xenograft","pmids":["40608258"],"confidence":"Low","gaps":["Single lab with limited mechanistic detail; epigenetic mechanism not fully characterized","Reciprocal validation of PFKM–CNTN1 interaction lacking"]},{"year":2025,"claim":"Proposed a CNTN1–PSEN1 regulatory axis driving ovarian cancer proliferation and invasion, expanding CNTN1's downstream effector repertoire.","evidence":"siRNA knockdown, luciferase reporter, PSEN1 overexpression rescue, colony formation/transwell assays, xenograft","pmids":["40687216"],"confidence":"Low","gaps":["Single rescue experiment; molecular nature of CNTN1–PSEN1 regulation undefined","Not independently confirmed"]},{"year":2026,"claim":"Confirmed the PI3K-AKT/EMT invasion-metastasis program as a recurrent CNTN1 mechanism across additional tumor types, here hilar cholangiocarcinoma.","evidence":"Reciprocal gain/loss-of-function, Transwell invasion, orthotopic metastasis model, pathway and EMT Western blots","pmids":["41898278"],"confidence":"Medium","gaps":["Direct molecular link between GPI-anchored CNTN1 and PI3K activation still unresolved","Cancer-relevant binding partner not identified"]},{"year":null,"claim":"The mechanistic bridge connecting CNTN1's extracellular GPI-anchored adhesion function to its consistent intracellular PI3K/AKT activation in cancer, and the identity of the transmembrane co-receptor transducing this signal, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No transmembrane signaling partner for CNTN1 identified in cancer","Whether neural ligands (tenascin-R/RPTPζ) operate in tumor contexts untested","No structure of CNTN1 in a signaling-competent complex with PI3K pathway components"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,4,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,7,8]}],"complexes":[],"partners":["TNR","PTPRZ1","PFKM","PSEN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12860","full_name":"Contactin-1","aliases":["Glycoprotein gp135","Neural cell surface protein F3"],"length_aa":1018,"mass_kda":113.3,"function":"Contactins mediate cell surface interactions during nervous system development. Involved in the formation of paranodal axo-glial junctions in myelinated peripheral nerves and in the signaling between axons and myelinating glial cells via its association with CNTNAP1. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Interaction with TNR induces a repulsion of neurons and an inhibition of neurite outgrowth (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q12860/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNTN1","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CNTN1","total_profiled":1310},"omim":[{"mim_id":"619342","title":"POST-GPI ATTACHMENT TO PROTEINS 6; PGAP6","url":"https://www.omim.org/entry/619342"},{"mim_id":"618356","title":"NEURODEVELOPMENTAL DISORDER WITH CENTRAL AND PERIPHERAL MOTOR DYSFUNCTION; NEDCPMD","url":"https://www.omim.org/entry/618356"},{"mim_id":"617350","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 52; DEE52","url":"https://www.omim.org/entry/617350"},{"mim_id":"612540","title":"CONGENITAL MYOPATHY 12; CMYO12","url":"https://www.omim.org/entry/612540"},{"mim_id":"609311","title":"CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 4H; CMT4H","url":"https://www.omim.org/entry/609311"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":120.8}],"url":"https://www.proteinatlas.org/search/CNTN1"},"hgnc":{"alias_symbol":["F3","GP135"],"prev_symbol":[]},"alphafold":{"accession":"Q12860","domains":[{"cath_id":"2.60.40.10","chopping":"38-132","consensus_level":"high","plddt":91.2151,"start":38,"end":132},{"cath_id":"2.60.40.10","chopping":"139-237","consensus_level":"medium","plddt":91.7659,"start":139,"end":237},{"cath_id":"2.60.40.10","chopping":"239-329","consensus_level":"medium","plddt":94.3987,"start":239,"end":329},{"cath_id":"2.60.40.10","chopping":"336-407","consensus_level":"high","plddt":92.3075,"start":336,"end":407},{"cath_id":"2.60.40.10","chopping":"410-501","consensus_level":"high","plddt":92.1204,"start":410,"end":501},{"cath_id":"2.60.40.10","chopping":"505-600","consensus_level":"high","plddt":86.9801,"start":505,"end":600},{"cath_id":"2.60.40.10","chopping":"607-700","consensus_level":"high","plddt":93.4257,"start":607,"end":700},{"cath_id":"2.60.40.10","chopping":"710-802","consensus_level":"high","plddt":88.6192,"start":710,"end":802},{"cath_id":"2.60.40.10","chopping":"812-898","consensus_level":"high","plddt":88.492,"start":812,"end":898}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12860","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12860-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12860-F1-predicted_aligned_error_v6.png","plddt_mean":87.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNTN1","jax_strain_url":"https://www.jax.org/strain/search?query=CNTN1"},"sequence":{"accession":"Q12860","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12860.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12860/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12860"}},"corpus_meta":[{"pmid":"7959734","id":"PMC_7959734","title":"Molecular 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study","date":"2024-11-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.04.24316702","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18981,"output_tokens":3153,"usd":0.052119,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10665,"output_tokens":3676,"usd":0.072612,"stage2_stop_reason":"end_turn"},"total_usd":0.124731,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Human contactin (CNTN1) is a GPI-anchored membrane protein composed of six C2 Ig-domains and four fibronectin type III repeats, anchored via a glycosyl phosphatidylinositol moiety as demonstrated by PI-PLC treatment of transfected cells and metabolic labeling with [3H]-ethanolamine.\",\n      \"method\": \"PI-PLC treatment of transfected cells, metabolic labeling with [3H]-ethanolamine, cDNA cloning and sequencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical demonstration of GPI anchor using multiple orthogonal methods (PI-PLC cleavage and metabolic labeling) in a single focused study\",\n      \"pmids\": [\"7959734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CNTN1 overexpression in prostate cancer cells enhances invasion in vitro and promotes xenograft tumor formation and lung metastasis in vivo, accompanied by elevated AKT activation and reduced E-cadherin (CDH1) expression; CNTN1 knockdown reduced tumor-initiating capacity.\",\n      \"method\": \"CNTN1 overexpression/knockdown in DU145 cells, in vitro invasion assay, xenograft mouse model, Western blot for AKT activation and E-cadherin\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined cellular and in vivo phenotypes plus signaling readouts, single lab\",\n      \"pmids\": [\"26795349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CNTN1 promotes cisplatin resistance in lung adenocarcinoma by inducing epithelial-mesenchymal transition (EMT) through activation of the PI3K/Akt signaling pathway; CNTN1 knockdown in cisplatin-resistant A549/DDP cells reversed EMT markers and restored drug sensitivity, while CNTN1 overexpression in A549 cells produced the opposite effect.\",\n      \"method\": \"CNTN1 overexpression/knockdown in A549 and A549/DDP cells, Western blot for EMT markers (E-cadherin, N-cadherin, Vimentin) and PI3K/Akt pathway, xenograft mouse model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with signaling pathway readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"28934754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Anti-CNTN1 IgG3 autoantibodies induce acute reversible conduction block at peripheral nerve nodes of Ranvier via complement deposition at paranodes, without inflammatory infiltrates or dispersal of paranodal proteins; IgG4 anti-CNTN1 causes different chronic structural changes.\",\n      \"method\": \"Intraneural injection of patient IgG into Lewis rats, electrophysiological nerve conduction studies, immunofluorescence for complement deposition and paranodal proteins, motor deficit assessment\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — passive transfer animal model with electrophysiology, immunofluorescence, and behavioral readouts; single lab\",\n      \"pmids\": [\"30953561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CNTN1 knockdown in docetaxel-resistant prostate cancer cells (PC3-DR and DU145-DR) attenuates cell proliferation, migration, invasion, EMT phenotype, and drug resistance, and decreases PI3K/Akt signaling activity both in vitro and in vivo.\",\n      \"method\": \"shRNA knockdown in docetaxel-resistant PCa cell lines, CCK-8, flow cytometry, wound-healing, transwell assays, Western blot for PI3K/Akt, xenograft tumor model\",\n      \"journal\": \"Archives of medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple phenotypic readouts and pathway analysis in vitro and in vivo, single lab\",\n      \"pmids\": [\"33488868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CNTN1 overexpression in the hippocampus (via AAV stereotactic injection) triggers anxiety- and depression-like phenotypes in mice, activates microglia, increases pro-inflammatory cytokines (IL1α, IL6, Ccl2), decreases anti-inflammatory markers, and impairs hippocampal immature neurons (doublecortin+ cells) in the dentate gyrus.\",\n      \"method\": \"AAV-mediated CNTN1 overexpression via stereotactic injection, behavioral tests, real-time qPCR for cytokines, immunohistochemistry for doublecortin\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function with defined behavioral and cellular phenotypes plus molecular readouts, single lab\",\n      \"pmids\": [\"33737174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CNTN1 overexpression in the hippocampus triggers cognitive deficits via microglial activation that induces astrocyte activation with aberrant expression of glutamate transporters EAAT1/EAAT2, resulting in long-term potentiation (LTP) impairment; these effects were reversed by minocycline (microglial activation inhibitor).\",\n      \"method\": \"AAV-mediated CNTN1 overexpression via stereotactic injection, novel object/place recognition and social cognition tests, LTP electrophysiology, minocycline pharmacological rescue, immunostaining for microglia and astrocyte markers, EAAT1/EAAT2 Western blot\",\n      \"journal\": \"Aging and disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with pharmacological rescue, electrophysiology, and multiple cellular readouts; single lab\",\n      \"pmids\": [\"37196127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CNTN1 expression in the nucleus accumbens (NAc) is upregulated by methamphetamine exposure via dopamine D2 receptor signaling; AAV-shRNA silencing of CNTN1 specifically in the NAc reversed methamphetamine-induced conditioned place preference and decreased expression of synaptic proteins NR2A, NR2B, and PSD95 in the NAc.\",\n      \"method\": \"AAV-shRNA stereotactic injection for NAc-specific CNTN1 knockdown, conditioned place preference behavioral assay, haloperidol pharmacological treatment, Western blot for NR2A/NR2B/PSD95\",\n      \"journal\": \"Neurotoxicity research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — region-specific loss-of-function with behavioral and molecular readouts, pharmacological validation; single lab\",\n      \"pmids\": [\"37014368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CNTN1 (a GPI-linked protein) binds the tenascin-R (Tnr)–RPTPζ complex at the neuronal cell surface and is critical for perineuronal net (PNN) structure; this was demonstrated biochemically and structurally, placing CNTN1 as a key cell-surface receptor nucleating PNN assembly.\",\n      \"method\": \"Biochemical binding assays, structural analysis, loss-of-function experiments targeting Cntn1 in PNN formation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — biochemical and structural approach with functional validation reported in preprint; not yet peer-reviewed, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.11.05.622114\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PFKM promotes CNTN1 expression in gastric cancer cells through enrichment of histone lactylation mark H3K18la at the CNTN1 promoter region; PFKM was shown to interact with CNTN1 and CNTN1 overexpression reversed the inhibitory effects of PFKM knockdown on gastric cancer cell viability, migration, and invasion.\",\n      \"method\": \"Dual-luciferase reporter assay for H3K18la-mediated transcriptional regulation, co-immunoprecipitation/interaction assay (PFKM–CNTN1), CNTN1 overexpression rescue experiments, CCK-8 and transwell assays, xenograft mouse model\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, interaction and epigenetic regulation described but methodology not fully characterized\",\n      \"pmids\": [\"40608258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CNTN1 promotes ovarian cancer cell proliferation, migration, and invasion through regulation of presenilin-1 (PSEN1); luciferase assays identified a regulatory interaction between CNTN1 and PSEN1, and PSEN1 overexpression reversed the impaired proliferation and invasion caused by CNTN1 silencing.\",\n      \"method\": \"CNTN1 siRNA knockdown, luciferase reporter assay for CNTN1–PSEN1 regulatory interaction, PSEN1 overexpression rescue, colony formation assay, transwell assay, xenograft mouse model\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single rescue experiment; the molecular mechanism of CNTN1–PSEN1 regulation is not fully characterized in the abstract\",\n      \"pmids\": [\"40687216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CNTN1 promotes hilar cholangiocarcinoma cell invasion in vitro and metastasis in vivo by activating the PI3K-AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT).\",\n      \"method\": \"Gain- and loss-of-function studies (CNTN1 overexpression and knockdown), Transwell invasion assays, orthotopic metastatic mouse model, Western blot for PI3K-AKT pathway and EMT markers\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined in vitro and in vivo phenotypes and signaling pathway readouts; single lab\",\n      \"pmids\": [\"41898278\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNTN1 is a GPI-anchored neuronal cell adhesion molecule (six Ig-domains plus four FNIII repeats) that, in its canonical neural role, binds the tenascin-R–RPTPζ complex to nucleate perineuronal net structure, modulates synaptic protein expression (NR2A/NR2B/PSD95) and hippocampal neuroinflammation through microglia–astrocyte crosstalk affecting EAAT1/EAAT2 and LTP, and mediates addiction-related plasticity in the nucleus accumbens via dopamine D2 receptor signaling; in cancer contexts, CNTN1 drives invasion, EMT, and chemoresistance primarily by activating the PI3K/AKT signaling pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNTN1 is a glycosylphosphatidylinositol (GPI)-anchored neuronal cell-surface adhesion molecule built from six C2 Ig domains and four fibronectin type III repeats, whose anchoring and architecture were established by direct biochemical characterization [#0]. At the neuronal surface it binds the tenascin-R–RPTPζ complex and serves as a receptor that nucleates perineuronal net assembly [#8]. Manipulation of CNTN1 in defined brain regions links it to circuit-level plasticity and neuroinflammation: hippocampal overexpression activates microglia, drives astrocyte activation with aberrant EAAT1/EAAT2 glutamate-transporter expression, and impairs long-term potentiation and cognition, effects reversed by the microglial inhibitor minocycline, and additionally produces anxiety- and depression-like phenotypes with reduced hippocampal neurogenesis [#5, #6]. In the nucleus accumbens, CNTN1 is induced by methamphetamine through dopamine D2 receptor signaling and supports addiction-related conditioned place preference and expression of the synaptic proteins NR2A, NR2B, and PSD95 [#7]. Anti-CNTN1 autoantibodies cause peripheral nerve conduction block via complement deposition at paranodes, implicating CNTN1 in node-of-Ranvier integrity [#3]. Beyond the nervous system, CNTN1 is a consistent pro-tumorigenic factor across prostate, lung, cholangiocarcinoma and other cancers, where it drives invasion, epithelial-mesenchymal transition, metastasis, and chemoresistance largely through activation of PI3K/AKT signaling [#1, #2, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established the fundamental molecular identity of CNTN1 as a GPI-anchored multidomain cell-surface protein, defining the structural basis for its adhesion/receptor function.\",\n      \"evidence\": \"PI-PLC cleavage, [3H]-ethanolamine metabolic labeling, and cDNA cloning in transfected cells\",\n      \"pmids\": [\"7959734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No binding partners or downstream signaling identified at this stage\", \"No functional or cellular role assigned\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CNTN1 is not merely structural but functionally drives malignant behavior, connecting it to AKT activation and loss of E-cadherin in prostate cancer.\",\n      \"evidence\": \"Gain/loss-of-function in DU145 cells, invasion assays, xenograft metastasis model, Western blot\",\n      \"pmids\": [\"26795349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GPI-anchored CNTN1 to intracellular AKT activation unresolved\", \"Direct receptor partner in cancer cells not identified\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the cancer role to chemoresistance, implicating CNTN1-driven EMT via PI3K/Akt as a mechanism of cisplatin resistance.\",\n      \"evidence\": \"Reciprocal overexpression/knockdown in A549 and A549/DDP cells, EMT and pathway Western blots, xenograft\",\n      \"pmids\": [\"28934754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CNTN1 engages PI3K/Akt mechanistically not shown\", \"No structural basis for pathway activation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reinforced the PI3K/Akt-EMT-resistance axis in docetaxel-resistant prostate cancer, supporting CNTN1 as a therapeutic target in drug-resistant tumors.\",\n      \"evidence\": \"shRNA knockdown in resistant PCa lines, multiple phenotypic assays, pathway Western blot, xenograft\",\n      \"pmids\": [\"33488868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream regulators of CNTN1 in resistance not defined\", \"Direct signaling intermediates unmapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a causal CNS role beyond adhesion, linking hippocampal CNTN1 to neuroinflammation, mood phenotypes, and impaired neurogenesis.\",\n      \"evidence\": \"AAV CNTN1 overexpression, behavioral tests, cytokine qPCR, doublecortin immunohistochemistry in mice\",\n      \"pmids\": [\"33737174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which surface CNTN1 activates microglia unknown\", \"Cell-type origin of inflammatory signal undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved a microglia-astrocyte-glutamate transporter circuit through which CNTN1 impairs synaptic plasticity, with pharmacological rescue confirming microglia as the initiating node.\",\n      \"evidence\": \"AAV overexpression, cognition tests, LTP electrophysiology, minocycline rescue, EAAT1/EAAT2 Western blot\",\n      \"pmids\": [\"37196127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating CNTN1's effect on microglia not identified\", \"Whether endogenous CNTN1 elevation produces the same effect untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed CNTN1 within addiction circuitry, showing it acts downstream of dopamine D2 signaling to support synaptic protein expression and drug-associated behavior in the nucleus accumbens.\",\n      \"evidence\": \"NAc-specific AAV-shRNA knockdown, conditioned place preference, haloperidol treatment, NR2A/NR2B/PSD95 Western blot\",\n      \"pmids\": [\"37014368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link from D2 signaling to CNTN1 transcription not delineated\", \"Synaptic partners of CNTN1 in NAc not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the physiological surface ligand complex (tenascin-R–RPTPζ) and assigned CNTN1 a structural role nucleating perineuronal nets, defining its canonical neural receptor function.\",\n      \"evidence\": \"Biochemical binding and structural analysis with Cntn1 loss-of-function in PNN formation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.11.05.622114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Stoichiometry and signaling consequences of the ternary complex unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Began to define upstream regulation of CNTN1 in cancer, implicating PFKM-driven histone lactylation at the CNTN1 promoter and a direct PFKM–CNTN1 interaction in gastric cancer.\",\n      \"evidence\": \"Luciferase reporter for H3K18la regulation, Co-IP, CNTN1 overexpression rescue, viability/invasion assays, xenograft\",\n      \"pmids\": [\"40608258\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab with limited mechanistic detail; epigenetic mechanism not fully characterized\", \"Reciprocal validation of PFKM–CNTN1 interaction lacking\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a CNTN1–PSEN1 regulatory axis driving ovarian cancer proliferation and invasion, expanding CNTN1's downstream effector repertoire.\",\n      \"evidence\": \"siRNA knockdown, luciferase reporter, PSEN1 overexpression rescue, colony formation/transwell assays, xenograft\",\n      \"pmids\": [\"40687216\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single rescue experiment; molecular nature of CNTN1–PSEN1 regulation undefined\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed the PI3K-AKT/EMT invasion-metastasis program as a recurrent CNTN1 mechanism across additional tumor types, here hilar cholangiocarcinoma.\",\n      \"evidence\": \"Reciprocal gain/loss-of-function, Transwell invasion, orthotopic metastasis model, pathway and EMT Western blots\",\n      \"pmids\": [\"41898278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between GPI-anchored CNTN1 and PI3K activation still unresolved\", \"Cancer-relevant binding partner not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanistic bridge connecting CNTN1's extracellular GPI-anchored adhesion function to its consistent intracellular PI3K/AKT activation in cancer, and the identity of the transmembrane co-receptor transducing this signal, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transmembrane signaling partner for CNTN1 identified in cancer\", \"Whether neural ligands (tenascin-R/RPTPζ) operate in tumor contexts untested\", \"No structure of CNTN1 in a signaling-competent complex with PI3K pathway components\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 4, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TNR\", \"PTPRZ1\", \"PFKM\", \"PSEN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}