{"gene":"CNTN3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":1994,"finding":"BIG-1 (CNTN3) was cloned as a novel brain-derived immunoglobulin superfamily molecule with six Ig-like domains, four fibronectin type III repeats, and a glycosylphosphatidylinositol (GPI)-anchoring domain. Recombinant BIG-1 protein promoted neurite outgrowth when used as a substrate for neurons in vitro, establishing it as an axon-associated cell adhesion molecule (AxCAM).","method":"PCR-based molecular cloning, recombinant protein production, in vitro neurite outgrowth assay","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro functional assay with recombinant protein, single lab, two orthogonal methods (cloning + neurite outgrowth assay)","pmids":["8060619"],"is_preprint":false},{"year":1994,"finding":"PANG (CNTN3) encodes a neuronal glycoprotein of ~113 kDa with six immunoglobulin C2-like and four type III fibronectin-like domains, bearing structural resemblance to axonal glycoproteins TAG-1 and F11. PANG is normally expressed in the brain but is ectopically transcribed in murine plasmacytomas due to activation by intracisternal A-type particle (IAP) long terminal repeat insertion.","method":"cDNA library cloning, full-length cDNA isolation, RT-PCR, domain analysis, Northern blot, IAP-LTR fusion transcript identification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (cDNA cloning, Northern blot, RT-PCR), single lab","pmids":["8108413"],"is_preprint":false},{"year":1995,"finding":"BIG-1 (CNTN3) mRNA expression is restricted to specific neuronal subtypes in rat brain, including granule cells of the dentate gyrus in adult hippocampus, with overlapping but distinct expression profiles compared to related TAG-1/F3 subgroup members (BIG-2, TAG-1, F3), suggesting distinct roles in the formation and maintenance of specific neuronal networks.","method":"In situ hybridization with riboprobes specific for BIG-1, BIG-2, TAG-1, and F3 in adult and developing rat brain sections","journal":"Journal of neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in situ hybridization with cell-type-specific resolution, single lab, single method","pmids":["8586965"],"is_preprint":false},{"year":1996,"finding":"The PANG (CNTN3) gene was mapped to mouse chromosome 6 (between Wnt7a and Pcp1) by somatic cell hybrid analysis, and human PANG was mapped to chromosome 3p26 by Southern blot analysis of human-rodent somatic cell hybrids.","method":"Somatic cell hybrid analysis, Southern blot","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic mapping by somatic cell hybrid analysis and Southern blot, single lab","pmids":["8661054"],"is_preprint":false},{"year":2019,"finding":"The second Fibronectin domain (Fn(2)) of CNTN3 mediates binding to the Amyloid Precursor Protein (APP), while the copper binding domain (CuBD) of APP mediates binding to CNTN3. Alanine substitution mutagenesis identified that the most critical amino acids for APP-CNTN3 binding reside on one face of CNTN3-Fn(2) and one face of APP-CuBD, defining the direct contact interface between these two proteins.","method":"Binding assays using APP-alkaline phosphatase (AP) fusion proteins and CNTN-Fc fusion proteins, alanine substitution mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay with mutagenesis defining precise interface residues, multiple orthogonal approaches (fusion protein binding + systematic alanine scanning)","pmids":["31318883"],"is_preprint":false},{"year":2026,"finding":"CNTN3 expression is elevated in colorectal cancer (CRC) tissues and cell lines. CNTN3 promotes CRC cell proliferation, inhibits apoptosis, and enhances epithelial-to-mesenchymal transition (EMT), migration, and invasion in vitro. The transcription factor PRRX2 binds to the CNTN3 promoter and transcriptionally activates CNTN3; PRRX2 knockdown reduces CNTN3 expression and reverses EMT marker alterations and metastatic phenotypes. In vivo xenograft experiments verified these findings.","method":"qPCR, Western blotting, immunohistochemistry, cell proliferation/apoptosis/migration/invasion assays, chromatin immunoprecipitation, dual-luciferase reporter assay, knockdown/rescue experiments, xenograft tumor model","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including ChIP and luciferase assay for transcriptional regulation, functional cellular assays and in vivo xenograft, single lab","pmids":["41882765"],"is_preprint":false}],"current_model":"CNTN3 (BIG-1/PANG) is a GPI-anchored immunoglobulin superfamily cell adhesion molecule expressed in specific neuronal subpopulations that promotes neurite outgrowth in vitro; its second fibronectin type III domain directly binds the copper-binding domain of APP (defined by mutagenesis), and in colorectal cancer it acts as a transcriptional target of PRRX2 to promote EMT, proliferation, and metastasis."},"narrative":{"mechanistic_narrative":"CNTN3 (BIG-1/PANG) is a GPI-anchored immunoglobulin superfamily cell adhesion molecule built from six Ig-like domains and four fibronectin type III repeats that functions as an axon-associated adhesion molecule promoting neurite outgrowth [PMID:8060619]. Its expression is restricted to specific neuronal subpopulations, including dentate gyrus granule cells, where it overlaps with but is distinct from related TAG-1/F3-subgroup members, consistent with roles in the formation of particular neuronal networks [PMID:8108413, PMID:8586965]. Mechanistically, the second fibronectin type III domain of CNTN3 directly binds the copper-binding domain of APP, with alanine-scanning mutagenesis defining the contact residues on one face of each protein [PMID:31318883]. Beyond its neuronal adhesion role, CNTN3 is a transcriptional target of PRRX2 in colorectal cancer, where its elevated expression drives proliferation, suppresses apoptosis, and promotes epithelial-to-mesenchymal transition, migration, and invasion [PMID:41882765].","teleology":[{"year":1994,"claim":"Establishing CNTN3 as a molecular entity answered whether the brain expresses a distinct GPI-anchored Ig-superfamily adhesion molecule capable of supporting axon growth.","evidence":"PCR-based cloning and recombinant protein neurite outgrowth assay (BIG-1); independent cDNA cloning and domain analysis (PANG)","pmids":["8060619","8108413"],"confidence":"Medium","gaps":["No identified binding partner or receptor for the neurite-promoting activity at the time","GPI anchoring inferred from domain structure, not directly demonstrated functionally","Mechanism of outgrowth promotion (homophilic vs heterophilic) unresolved"]},{"year":1995,"claim":"Mapping CNTN3 mRNA to defined neuronal subtypes addressed where this adhesion molecule could act, distinguishing it from related contactins.","evidence":"In situ hybridization of BIG-1, BIG-2, TAG-1, and F3 probes in developing and adult rat brain","pmids":["8586965"],"confidence":"Medium","gaps":["Expression pattern does not establish functional necessity in those neurons","No loss-of-function phenotype assessed"]},{"year":1996,"claim":"Chromosomal mapping placed CNTN3 in defined mouse and human loci, providing a genetic anchor for the gene.","evidence":"Somatic cell hybrid analysis and Southern blot mapping to mouse chr 6 and human 3p26","pmids":["8661054"],"confidence":"Medium","gaps":["No disease association established at the mapped locus","Purely positional, no functional consequence"]},{"year":2019,"claim":"Identifying APP as a direct binding partner answered which molecular interaction underlies CNTN3 function, defining a precise protein-protein interface.","evidence":"APP-AP and CNTN-Fc fusion protein binding assays with systematic alanine substitution mutagenesis","pmids":["31318883"],"confidence":"High","gaps":["Functional consequence of the CNTN3-APP interaction in vivo not established","No structural model of the complex","Whether the interaction modulates neurite outgrowth or APP processing untested"]},{"year":2026,"claim":"Linking CNTN3 to PRRX2-driven transcription in colorectal cancer answered whether this neuronal adhesion molecule has a pathological role outside the nervous system.","evidence":"qPCR, Western blot, IHC, ChIP, dual-luciferase reporter, knockdown/rescue functional assays, and xenograft tumor model in CRC","pmids":["41882765"],"confidence":"Medium","gaps":["Downstream effectors of CNTN3 in EMT not identified","Whether the APP interaction contributes to the cancer phenotype unknown","Single-lab finding without independent confirmation"]},{"year":null,"claim":"The biochemical mechanism linking CNTN3 adhesion/APP binding to its neuronal network role and its oncogenic EMT function remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No signaling pathway downstream of CNTN3 defined","No in vivo neuronal loss-of-function phenotype","Functional integration of APP binding with cell adhesion and cancer roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["APP","PRRX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P232","full_name":"Contactin-3","aliases":["Brain-derived immunoglobulin superfamily protein 1","BIG-1","Plasmacytoma-associated neuronal glycoprotein"],"length_aa":1028,"mass_kda":112.9,"function":"Contactins mediate cell surface interactions during nervous system development. Has some neurite outgrowth-promoting activity (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9P232/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNTN3","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/CNTN3","total_profiled":1310},"omim":[{"mim_id":"609739","title":"IMMUNOGLOBULIN-LIKE DOMAIN-CONTAINING RECEPTOR 1; ILDR1","url":"https://www.omim.org/entry/609739"},{"mim_id":"609646","title":"DEAFNESS, AUTOSOMAL RECESSIVE 42; DFNB42","url":"https://www.omim.org/entry/609646"},{"mim_id":"607220","title":"CONTACTIN 6; CNTN6","url":"https://www.omim.org/entry/607220"},{"mim_id":"607219","title":"CONTACTIN 5; CNTN5","url":"https://www.omim.org/entry/607219"},{"mim_id":"601325","title":"CONTACTIN 3; CNTN3","url":"https://www.omim.org/entry/601325"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CNTN3"},"hgnc":{"alias_symbol":["BIG-1"],"prev_symbol":["PANG"]},"alphafold":{"accession":"Q9P232","domains":[{"cath_id":"2.60.40.10","chopping":"25-120","consensus_level":"high","plddt":89.5465,"start":25,"end":120},{"cath_id":"2.60.40.10","chopping":"127-224","consensus_level":"medium","plddt":91.8302,"start":127,"end":224},{"cath_id":"2.60.40.10","chopping":"324-405","consensus_level":"medium","plddt":90.8165,"start":324,"end":405},{"cath_id":"2.60.40.10","chopping":"407-488","consensus_level":"high","plddt":87.4116,"start":407,"end":488},{"cath_id":"2.60.40.10","chopping":"502-596","consensus_level":"high","plddt":85.4866,"start":502,"end":596},{"cath_id":"2.60.40.10","chopping":"608-616_626-696","consensus_level":"high","plddt":93.2859,"start":608,"end":696},{"cath_id":"2.60.40.10","chopping":"706-798","consensus_level":"medium","plddt":89.6438,"start":706,"end":798},{"cath_id":"2.60.40.10","chopping":"808-898","consensus_level":"medium","plddt":86.8974,"start":808,"end":898},{"cath_id":"2.60.40.10","chopping":"909-992","consensus_level":"medium","plddt":82.8918,"start":909,"end":992}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P232","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P232-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P232-F1-predicted_aligned_error_v6.png","plddt_mean":86.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNTN3","jax_strain_url":"https://www.jax.org/strain/search?query=CNTN3"},"sequence":{"accession":"Q9P232","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P232.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P232/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P232"}},"corpus_meta":[{"pmid":"17200148","id":"PMC_17200148","title":"Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.","date":"2007","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17200148","citation_count":711,"is_preprint":false},{"pmid":"22018631","id":"PMC_22018631","title":"Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.","date":"2011","source":"The Lancet. 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Yellow Pang-da) Grain.","date":"2021","source":"Pakistan journal of biological sciences : PJBS","url":"https://pubmed.ncbi.nlm.nih.gov/34486302","citation_count":5,"is_preprint":false},{"pmid":"31318883","id":"PMC_31318883","title":"Defining the binding interface of Amyloid Precursor Protein (APP) and Contactin3 (CNTN3) by site-directed mutagenesis.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31318883","citation_count":4,"is_preprint":false},{"pmid":"19096768","id":"PMC_19096768","title":"Understanding the BIG results: Insights from the BIG 1-98 trial analyses.","date":"2008","source":"Advances in therapy","url":"https://pubmed.ncbi.nlm.nih.gov/19096768","citation_count":4,"is_preprint":false},{"pmid":"40055382","id":"PMC_40055382","title":"Machine learning-based spatial characterization of tumor-immune microenvironment in the EORTC 10994/BIG 1-00 early breast cancer trial.","date":"2025","source":"NPJ breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40055382","citation_count":4,"is_preprint":false},{"pmid":"8661054","id":"PMC_8661054","title":"Plasmacytoma-associated neuronal glycoprotein, Pang, maps to mouse chromosome 6 and human chromosome 3.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8661054","citation_count":4,"is_preprint":false},{"pmid":"31800174","id":"PMC_31800174","title":"PLLA/POSS Nanofibers Loaded with Multitargeted pANG Composite Nanoparticles for Promotion of Vascularization in Shear Flow.","date":"2019","source":"Macromolecular bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/31800174","citation_count":3,"is_preprint":false},{"pmid":"19785285","id":"PMC_19785285","title":"Identification and characterization of a psychrophilic yeast strain newly isolated from the fermentative starter (Loog-pang) of a traditional drink in Thailand.","date":"2009","source":"Biocontrol science","url":"https://pubmed.ncbi.nlm.nih.gov/19785285","citation_count":3,"is_preprint":false},{"pmid":"40824521","id":"PMC_40824521","title":"Probiotic potential and phytase-producing capacity of yeast isolated from Thai traditional fermentation starter (Look-pang).","date":"2025","source":"Folia microbiologica","url":"https://pubmed.ncbi.nlm.nih.gov/40824521","citation_count":2,"is_preprint":false},{"pmid":"32337480","id":"PMC_32337480","title":"Independent Validation of EarlyR Gene Signature in BIG 1-98: A Randomized, Double-Blind, Phase III Trial Comparing Letrozole and Tamoxifen as Adjuvant Endocrine Therapy for Postmenopausal Women With Hormone Receptor-Positive, Early Breast Cancer.","date":"2019","source":"JNCI cancer spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/32337480","citation_count":1,"is_preprint":false},{"pmid":"41882765","id":"PMC_41882765","title":"PRRX2-CNTN3 axis promotes epithelial-to-mesenchymal transition and metastasis in colorectal cancer.","date":"2026","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/41882765","citation_count":0,"is_preprint":false},{"pmid":"41419752","id":"PMC_41419752","title":"Chromosome-level genome assembly of Trichogramma ostriniae Pang & Chen (Hymenoptera: Trichogrammatidae).","date":"2025","source":"Scientific data","url":"https://pubmed.ncbi.nlm.nih.gov/41419752","citation_count":0,"is_preprint":false},{"pmid":"42206462","id":"PMC_42206462","title":"Development of a Functional Loog-Pang Starter Using Selected Yeast and Fungal Strains for Black Glutinous Rice Sato Fermentation.","date":"2026","source":"TheScientificWorldJournal","url":"https://pubmed.ncbi.nlm.nih.gov/42206462","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33319,"output_tokens":1678,"usd":0.062563,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8478,"output_tokens":1940,"usd":0.045445,"stage2_stop_reason":"end_turn"},"total_usd":0.108008,"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\": \"BIG-1 (CNTN3) was cloned as a novel brain-derived immunoglobulin superfamily molecule with six Ig-like domains, four fibronectin type III repeats, and a glycosylphosphatidylinositol (GPI)-anchoring domain. Recombinant BIG-1 protein promoted neurite outgrowth when used as a substrate for neurons in vitro, establishing it as an axon-associated cell adhesion molecule (AxCAM).\",\n      \"method\": \"PCR-based molecular cloning, recombinant protein production, in vitro neurite outgrowth assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro functional assay with recombinant protein, single lab, two orthogonal methods (cloning + neurite outgrowth assay)\",\n      \"pmids\": [\"8060619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"PANG (CNTN3) encodes a neuronal glycoprotein of ~113 kDa with six immunoglobulin C2-like and four type III fibronectin-like domains, bearing structural resemblance to axonal glycoproteins TAG-1 and F11. PANG is normally expressed in the brain but is ectopically transcribed in murine plasmacytomas due to activation by intracisternal A-type particle (IAP) long terminal repeat insertion.\",\n      \"method\": \"cDNA library cloning, full-length cDNA isolation, RT-PCR, domain analysis, Northern blot, IAP-LTR fusion transcript identification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (cDNA cloning, Northern blot, RT-PCR), single lab\",\n      \"pmids\": [\"8108413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"BIG-1 (CNTN3) mRNA expression is restricted to specific neuronal subtypes in rat brain, including granule cells of the dentate gyrus in adult hippocampus, with overlapping but distinct expression profiles compared to related TAG-1/F3 subgroup members (BIG-2, TAG-1, F3), suggesting distinct roles in the formation and maintenance of specific neuronal networks.\",\n      \"method\": \"In situ hybridization with riboprobes specific for BIG-1, BIG-2, TAG-1, and F3 in adult and developing rat brain sections\",\n      \"journal\": \"Journal of neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in situ hybridization with cell-type-specific resolution, single lab, single method\",\n      \"pmids\": [\"8586965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The PANG (CNTN3) gene was mapped to mouse chromosome 6 (between Wnt7a and Pcp1) by somatic cell hybrid analysis, and human PANG was mapped to chromosome 3p26 by Southern blot analysis of human-rodent somatic cell hybrids.\",\n      \"method\": \"Somatic cell hybrid analysis, Southern blot\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic mapping by somatic cell hybrid analysis and Southern blot, single lab\",\n      \"pmids\": [\"8661054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The second Fibronectin domain (Fn(2)) of CNTN3 mediates binding to the Amyloid Precursor Protein (APP), while the copper binding domain (CuBD) of APP mediates binding to CNTN3. Alanine substitution mutagenesis identified that the most critical amino acids for APP-CNTN3 binding reside on one face of CNTN3-Fn(2) and one face of APP-CuBD, defining the direct contact interface between these two proteins.\",\n      \"method\": \"Binding assays using APP-alkaline phosphatase (AP) fusion proteins and CNTN-Fc fusion proteins, alanine substitution mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay with mutagenesis defining precise interface residues, multiple orthogonal approaches (fusion protein binding + systematic alanine scanning)\",\n      \"pmids\": [\"31318883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CNTN3 expression is elevated in colorectal cancer (CRC) tissues and cell lines. CNTN3 promotes CRC cell proliferation, inhibits apoptosis, and enhances epithelial-to-mesenchymal transition (EMT), migration, and invasion in vitro. The transcription factor PRRX2 binds to the CNTN3 promoter and transcriptionally activates CNTN3; PRRX2 knockdown reduces CNTN3 expression and reverses EMT marker alterations and metastatic phenotypes. In vivo xenograft experiments verified these findings.\",\n      \"method\": \"qPCR, Western blotting, immunohistochemistry, cell proliferation/apoptosis/migration/invasion assays, chromatin immunoprecipitation, dual-luciferase reporter assay, knockdown/rescue experiments, xenograft tumor model\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including ChIP and luciferase assay for transcriptional regulation, functional cellular assays and in vivo xenograft, single lab\",\n      \"pmids\": [\"41882765\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNTN3 (BIG-1/PANG) is a GPI-anchored immunoglobulin superfamily cell adhesion molecule expressed in specific neuronal subpopulations that promotes neurite outgrowth in vitro; its second fibronectin type III domain directly binds the copper-binding domain of APP (defined by mutagenesis), and in colorectal cancer it acts as a transcriptional target of PRRX2 to promote EMT, proliferation, and metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNTN3 (BIG-1/PANG) is a GPI-anchored immunoglobulin superfamily cell adhesion molecule built from six Ig-like domains and four fibronectin type III repeats that functions as an axon-associated adhesion molecule promoting neurite outgrowth [#0]. Its expression is restricted to specific neuronal subpopulations, including dentate gyrus granule cells, where it overlaps with but is distinct from related TAG-1/F3-subgroup members, consistent with roles in the formation of particular neuronal networks [#1, #2]. Mechanistically, the second fibronectin type III domain of CNTN3 directly binds the copper-binding domain of APP, with alanine-scanning mutagenesis defining the contact residues on one face of each protein [#4]. Beyond its neuronal adhesion role, CNTN3 is a transcriptional target of PRRX2 in colorectal cancer, where its elevated expression drives proliferation, suppresses apoptosis, and promotes epithelial-to-mesenchymal transition, migration, and invasion [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing CNTN3 as a molecular entity answered whether the brain expresses a distinct GPI-anchored Ig-superfamily adhesion molecule capable of supporting axon growth.\",\n      \"evidence\": \"PCR-based cloning and recombinant protein neurite outgrowth assay (BIG-1); independent cDNA cloning and domain analysis (PANG)\",\n      \"pmids\": [\"8060619\", \"8108413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No identified binding partner or receptor for the neurite-promoting activity at the time\",\n        \"GPI anchoring inferred from domain structure, not directly demonstrated functionally\",\n        \"Mechanism of outgrowth promotion (homophilic vs heterophilic) unresolved\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping CNTN3 mRNA to defined neuronal subtypes addressed where this adhesion molecule could act, distinguishing it from related contactins.\",\n      \"evidence\": \"In situ hybridization of BIG-1, BIG-2, TAG-1, and F3 probes in developing and adult rat brain\",\n      \"pmids\": [\"8586965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Expression pattern does not establish functional necessity in those neurons\",\n        \"No loss-of-function phenotype assessed\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Chromosomal mapping placed CNTN3 in defined mouse and human loci, providing a genetic anchor for the gene.\",\n      \"evidence\": \"Somatic cell hybrid analysis and Southern blot mapping to mouse chr 6 and human 3p26\",\n      \"pmids\": [\"8661054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No disease association established at the mapped locus\",\n        \"Purely positional, no functional consequence\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying APP as a direct binding partner answered which molecular interaction underlies CNTN3 function, defining a precise protein-protein interface.\",\n      \"evidence\": \"APP-AP and CNTN-Fc fusion protein binding assays with systematic alanine substitution mutagenesis\",\n      \"pmids\": [\"31318883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of the CNTN3-APP interaction in vivo not established\",\n        \"No structural model of the complex\",\n        \"Whether the interaction modulates neurite outgrowth or APP processing untested\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linking CNTN3 to PRRX2-driven transcription in colorectal cancer answered whether this neuronal adhesion molecule has a pathological role outside the nervous system.\",\n      \"evidence\": \"qPCR, Western blot, IHC, ChIP, dual-luciferase reporter, knockdown/rescue functional assays, and xenograft tumor model in CRC\",\n      \"pmids\": [\"41882765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effectors of CNTN3 in EMT not identified\",\n        \"Whether the APP interaction contributes to the cancer phenotype unknown\",\n        \"Single-lab finding without independent confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism linking CNTN3 adhesion/APP binding to its neuronal network role and its oncogenic EMT function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No signaling pathway downstream of CNTN3 defined\",\n        \"No in vivo neuronal loss-of-function phenotype\",\n        \"Functional integration of APP binding with cell adhesion and cancer roles unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"APP\",\n      \"PRRX2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}