{"gene":"CNTFR","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2000,"finding":"CNTF binds first to CNTFRα, which then permits recruitment of gp130 and LIFRβ to form a tripartite receptor complex; heterodimerization of the β-subunits leads to tyrosine phosphorylation via constitutively associated JAKs, providing docking sites for SH2-containing signaling molecules (STAT proteins); activated STATs dimerize and translocate to the nucleus to bind specific DNA sequences and enhance transcription.","method":"Biochemical signaling studies and receptor complex assembly assays (reviewed with supporting experimental evidence)","journal":"Pharmaceutica acta Helvetiae","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor complex assembly, JAK/STAT pathway activation replicated across multiple labs and model systems","pmids":["10812968"],"is_preprint":false},{"year":2000,"finding":"CNTFRα lacks a conventional transmembrane domain and is anchored to the cell membrane via a glycosyl-phosphatidylinositol (GPI) linkage.","method":"Biochemical characterization of receptor topology (reviewed with supporting experimental basis)","journal":"Pharmaceutica acta Helvetiae","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GPI-anchoring established biochemically, reported consistently across reviewed literature","pmids":["10812968"],"is_preprint":false},{"year":2002,"finding":"The membrane-distal cytokine binding domain (CBD1) of LIFR interacts in vitro with soluble CNTFRα in the absence of CNTF ligand, and purified CBD1 partially blocks CNTF signaling (but not IL-6 or LIF signaling) in human Ntera/D1 cells, raising the possibility that LIFR and CNTFRα can form a ligand-free complex.","method":"In vitro protein–protein interaction assay with purified domains; functional signaling inhibition in cell line","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro binding plus cellular functional assay, single lab, single study","pmids":["11943154"],"is_preprint":false},{"year":2000,"finding":"Soluble CNTFRα alone, or in combination with CNTF, promotes macrophage chemotaxis in a concentration-dependent manner that is inhibited by a neutralizing anti-gp130 antibody; this chemotaxis is also inhibited by wortmannin, LY294002, or PD98059, implicating PI3K and MAPK signaling pathways. Stimulation with CNTFRα+CNTF causes tyrosine phosphorylation of an ~130 kD protein (presumed gp130) in macrophages.","method":"Microchemotaxis chamber assay, neutralizing antibody blocking, pharmacological inhibition (wortmannin, LY294002, PD98059), Western blot for tyrosine phosphorylation","journal":"Neuropeptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibitors and antibody blocking with functional readout, single lab","pmids":["11162290"],"is_preprint":false},{"year":2005,"finding":"CLC (cardiotrophin-like cytokine) is co-expressed at the single-cell level with clf and cntfr in developing mouse muscles during the developmental period corresponding to motor neuron loss in CNTFR-deficient mice, supporting CLC/sCNTFR heterodimer as a physiological ligand for the tripartite CNTF receptor complex.","method":"In situ hybridization co-expression analysis at single-cell resolution in mouse embryonic tissues","journal":"Cell communication and signaling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-expression data only; functional activation of receptor complex by CLC/sCNTFR not directly reconstituted in this study","pmids":["15683542"],"is_preprint":false},{"year":2019,"finding":"CNTFR acts as the receptor for CLCF1 in lung adenocarcinoma; a high-affinity engineered soluble eCNTFR-Fc decoy sequesters CLCF1 and inhibits tumor growth in xenograft and autochthonous KRAS/p53-mutant mouse models, with efficacy correlated with the presence of KRAS mutations retaining GTPase activity.","method":"Engineered soluble receptor (eCNTFR-Fc) functional neutralization assay, xenograft tumor models, genetically engineered mouse model","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal tumor models (xenograft + autochthonous GEM), validated with engineered decoy receptor and genetic correlation","pmids":["31700175"],"is_preprint":false},{"year":2024,"finding":"Blockade of the CLCF1-CNTFR axis by eCNTFR-Fc suppresses STAT3 signaling and TGF-β production in hepatocellular carcinoma, inhibiting tumor growth, stemness, and immunosuppressive tumor microenvironment formation; eCNTFR-Fc-armored GPC3 CAR-T cells showed enhanced cytotoxicity and functional persistence.","method":"Engineered eCNTFR-Fc in vitro and xenograft assays, western blot for STAT3 phosphorylation, cytokine measurement (TGF-β), CAR-T cell functional assays","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo readouts in single lab study, mechanistic pathway (STAT3/TGF-β) identified","pmids":["42102942"],"is_preprint":false},{"year":2016,"finding":"miR-675-5p binds to the 3'-UTR of CNTFR mRNA (at the rs41274853 polymorphic region), as demonstrated by luciferase reporter assay, irrespective of which allele is present at the polymorphism.","method":"Luciferase reporter assay","journal":"International journal of sports medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single reporter assay, single lab, no direct effect on CNTFR protein levels measured","pmids":["26837930"],"is_preprint":false},{"year":2026,"finding":"miR-21-5p directly targets the CNTFR 3'-UTR, suppressing CNTFR expression and thereby promoting proliferation, invasion, and migration of esophageal squamous cell carcinoma cells; miR-21-5p mimics reduce CNTFR protein levels while miR-21-5p inhibitors increase CNTFR expression.","method":"Luciferase reporter assay, RT-qPCR, western blot, CCK-8, EdU, transwell, and flow cytometry assays","journal":"BMC gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR binding confirmed by reporter assay plus multiple functional readouts, single lab","pmids":["41673571"],"is_preprint":false},{"year":1993,"finding":"The human CNTFR gene was mapped to chromosome 9p13 by PCR on human/CHO somatic cell hybrid panels and radiation hybrid panels.","method":"PCR-based somatic cell hybrid mapping and radiation hybrid mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct PCR mapping on panel of hybrid cell lines, chromosomal localization clearly established","pmids":["8244400"],"is_preprint":false},{"year":2025,"finding":"CNTFR is detected at the plasma membrane of chondrogenic progenitor cells and shows time-dependent downregulation during chondrogenic differentiation; targeted knockdown of CNTFR differentially regulates COL1A1 (fibrocartilage marker) expression, indicating a role in cell-matrix signaling and survival pathways during chondrogenesis.","method":"Glycocapture-based cell surface proteomics, western blotting, immunocytochemistry, siRNA knockdown, qRT-PCR, matrix histochemistry","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, novel context; knockdown phenotype (COL1A1 regulation) shown but mechanism not fully elaborated","pmids":[],"is_preprint":true}],"current_model":"CNTFRα is a GPI-anchored, nervous-system- and muscle-enriched receptor subunit that acts as the ligand-binding specificity component for CNTF and related cytokines (including CLCF1/CLC); it first captures ligand and then recruits gp130 and LIFRβ into a tripartite signaling complex that activates constitutively associated JAKs, leading to tyrosine phosphorylation of receptor cytoplasmic domains, STAT3 (and other STAT) recruitment and dimerization, nuclear translocation, and transcriptional activation, with PI3K and MAPK also engaged downstream; soluble CNTFRα can additionally act in trans to confer CNTF responsiveness on cells expressing only gp130/LIFRβ, and the CLCF1-CNTFR axis drives STAT3 and TGF-β-dependent oncogenic and immunosuppressive signaling in tumors."},"narrative":{"mechanistic_narrative":"CNTFRα is a GPI-anchored receptor subunit that serves as the ligand-binding specificity component of a tripartite cytokine receptor complex: it first captures CNTF and then nucleates recruitment of gp130 and LIFRβ, whose heterodimerization activates constitutively associated JAKs to drive tyrosine phosphorylation, STAT recruitment and dimerization, and nuclear transcriptional activation [PMID:10812968]. Beyond the canonical JAK/STAT output, soluble CNTFRα together with CNTF engages gp130-dependent PI3K and MAPK signaling to promote macrophage chemotaxis [PMID:11162290], and CNTFRα can pre-associate with the LIFR membrane-distal cytokine binding domain in a ligand-free manner [PMID:11943154]. CNTFRα also functions as the receptor for CLCF1/CLC, with CLC co-expressed alongside cntfr in developing muscle at the time of motor neuron survival [PMID:15683542]; in cancer, the CLCF1–CNTFR axis drives STAT3 activation and TGF-β production, and an engineered soluble decoy (eCNTFR-Fc) sequesters CLCF1 to suppress tumor growth, stemness, and an immunosuppressive microenvironment in lung adenocarcinoma and hepatocellular carcinoma [PMID:31700175, PMID:42102942]. CNTFR expression is post-transcriptionally controlled through its 3'-UTR by miR-21-5p, loss of which derepresses CNTFR and constrains esophageal squamous carcinoma cell proliferation and invasion [PMID:41673571].","teleology":[{"year":1993,"claim":"Establishing the chromosomal locus of human CNTFR provided the genomic anchor for studying the receptor gene.","evidence":"PCR-based somatic cell and radiation hybrid mapping localizing CNTFR to 9p13","pmids":["8244400"],"confidence":"Medium","gaps":["Locus mapping alone gives no functional or regulatory information"]},{"year":2000,"claim":"Defining the receptor assembly resolved how CNTFRα converts ligand binding into intracellular signaling: it captures CNTF first, then recruits gp130 and LIFRβ to activate JAK/STAT transcriptional output.","evidence":"Biochemical receptor complex assembly and JAK/STAT pathway signaling studies","pmids":["10812968"],"confidence":"High","gaps":["Stoichiometry and structural arrangement of the tripartite complex not resolved here","Does not address ligands beyond CNTF"]},{"year":2000,"claim":"Demonstrating GPI anchoring explained how a transmembrane-domain-less receptor subunit can present ligand and shed as a soluble form.","evidence":"Biochemical characterization of receptor membrane topology","pmids":["10812968"],"confidence":"Medium","gaps":["Mechanism and regulation of shedding to generate soluble CNTFRα not defined"]},{"year":2000,"claim":"Identifying that soluble CNTFRα with CNTF drives macrophage chemotaxis showed signaling extends beyond JAK/STAT to gp130-dependent PI3K and MAPK pathways and to non-neural cell behaviors.","evidence":"Microchemotaxis assays with anti-gp130 neutralization, pharmacological PI3K/MAPK inhibition, and anti-phosphotyrosine Western blot in macrophages","pmids":["11162290"],"confidence":"Medium","gaps":["~130 kD phosphoprotein only presumed to be gp130","Direct downstream effectors of PI3K/MAPK in this context not mapped"]},{"year":2002,"claim":"Showing that the LIFR CBD1 domain binds soluble CNTFRα without ligand raised the possibility of a pre-formed ligand-free receptor subcomplex.","evidence":"In vitro purified-domain interaction assay plus CBD1 blockade of CNTF (but not IL-6/LIF) signaling in Ntera/D1 cells","pmids":["11943154"],"confidence":"Medium","gaps":["Single lab, single study","Physiological relevance of a ligand-free CNTFRα–LIFR complex not established in vivo"]},{"year":2005,"claim":"Co-expression of CLC with cntfr and clf in developing muscle supported CLC/sCNTFR as a physiological ligand for the receptor complex during motor neuron survival.","evidence":"Single-cell in situ hybridization co-expression analysis in mouse embryonic tissues","pmids":["15683542"],"confidence":"Low","gaps":["Co-expression only; functional receptor activation by CLC/sCNTFR not reconstituted in this study","Causal link to motor neuron loss not directly tested here"]},{"year":2019,"claim":"Identifying CNTFR as the receptor for CLCF1 in lung adenocarcinoma converted CNTFR into an oncology target addressable by ligand sequestration.","evidence":"Engineered eCNTFR-Fc decoy neutralization in xenograft and autochthonous KRAS/p53-mutant mouse tumor models","pmids":["31700175"],"confidence":"High","gaps":["Downstream signaling consequences of CLCF1 blockade not detailed in this study","Basis for KRAS-mutation-dependent efficacy not mechanistically resolved"]},{"year":2024,"claim":"Linking the CLCF1-CNTFR axis to STAT3 and TGF-β output defined the signaling consequences of axis blockade and extended therapeutic relevance to hepatocellular carcinoma and CAR-T engineering.","evidence":"eCNTFR-Fc in vitro/xenograft assays, STAT3 phosphorylation Western blot, TGF-β measurement, and armored GPC3 CAR-T functional assays","pmids":["42102942"],"confidence":"Medium","gaps":["Single lab study","Direct versus indirect contribution of CNTFR to the immunosuppressive microenvironment not fully dissected"]},{"year":2026,"claim":"Demonstrating direct miR-21-5p targeting of the CNTFR 3'-UTR established a post-transcriptional control point linking CNTFR loss to a pro-tumor phenotype in esophageal squamous carcinoma.","evidence":"Luciferase reporter assay with miR-21-5p mimics/inhibitors plus RT-qPCR, Western blot, and proliferation/invasion/migration assays","pmids":["41673571"],"confidence":"Medium","gaps":["Single lab","Whether CNTFR loss acts through the canonical receptor complex in this context not addressed"]},{"year":null,"claim":"How the same CNTFR axis is partitioned between neurotrophic/developmental survival signaling and tumor-promoting versus tumor-suppressive roles across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the tripartite complex in the timeline","Mechanism of soluble CNTFRα generation and trans-signaling not defined","Context-dependence of CNTFR as tumor driver versus suppressor unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6]}],"complexes":["tripartite CNTF receptor complex (CNTFRα–gp130–LIFRβ)"],"partners":["CNTF","GP130","LIFR","CLCF1","CLC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P26992","full_name":"Ciliary neurotrophic factor receptor subunit alpha","aliases":[],"length_aa":372,"mass_kda":40.6,"function":"Binds to CNTF. The alpha subunit provides the receptor specificity. Receptor for heterodimeric neurotropic cytokine composed of CLCF1/CLC and CRLF1/CLF-1 (PubMed:26858303). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL6ST/GP130 and IL27RA/WSX1 (PubMed:19386761)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P26992/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNTFR","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CNTFR","total_profiled":1310},"omim":[{"mim_id":"614409","title":"SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE; SPG46","url":"https://www.omim.org/entry/614409"},{"mim_id":"607672","title":"CARDIOTROPHIN-LIKE CYTOKINE FACTOR 1; CLCF1","url":"https://www.omim.org/entry/607672"},{"mim_id":"605816","title":"EPSTEIN-BARR VIRUS-INDUCED GENE 3; EBI3","url":"https://www.omim.org/entry/605816"},{"mim_id":"604237","title":"CYTOKINE RECEPTOR-LIKE FACTOR 1; CRLF1","url":"https://www.omim.org/entry/604237"},{"mim_id":"603255","title":"NUCLEAR TRANSCRIPTION FACTOR, X BOX-BINDING, 1; NFX1","url":"https://www.omim.org/entry/603255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":106.8},{"tissue":"skeletal muscle","ntpm":120.6}],"url":"https://www.proteinatlas.org/search/CNTFR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P26992","domains":[{"cath_id":"2.60.40.10","chopping":"33-107","consensus_level":"high","plddt":94.292,"start":33,"end":107},{"cath_id":"2.60.40.10","chopping":"114-201","consensus_level":"high","plddt":95.9036,"start":114,"end":201},{"cath_id":"2.60.40.10","chopping":"209-300","consensus_level":"high","plddt":96.7459,"start":209,"end":300}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P26992","model_url":"https://alphafold.ebi.ac.uk/files/AF-P26992-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P26992-F1-predicted_aligned_error_v6.png","plddt_mean":82.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNTFR","jax_strain_url":"https://www.jax.org/strain/search?query=CNTFR"},"sequence":{"accession":"P26992","fasta_url":"https://rest.uniprot.org/uniprotkb/P26992.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P26992/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P26992"}},"corpus_meta":[{"pmid":"10812968","id":"PMC_10812968","title":"The ciliary neurotrophic factor and its receptor, CNTFR alpha.","date":"2000","source":"Pharmaceutica acta Helvetiae","url":"https://pubmed.ncbi.nlm.nih.gov/10812968","citation_count":158,"is_preprint":false},{"pmid":"9630704","id":"PMC_9630704","title":"Differential temporal expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR alpha, LIFR beta, IL-6R alpha and gp130) in injured peripheral nerves.","date":"1998","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9630704","citation_count":86,"is_preprint":false},{"pmid":"31700175","id":"PMC_31700175","title":"Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma.","date":"2019","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31700175","citation_count":63,"is_preprint":false},{"pmid":"9645962","id":"PMC_9645962","title":"Differential regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor alpha (CNTFR alpha) expression following focal cerebral ischemia.","date":"1998","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9645962","citation_count":41,"is_preprint":false},{"pmid":"11358282","id":"PMC_11358282","title":"Expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFR alpha, LIFR beta, IL-6R alpha, and gp130) in human peripheral neuropathies.","date":"2001","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/11358282","citation_count":18,"is_preprint":false},{"pmid":"15755520","id":"PMC_15755520","title":"Expression of ciliary neurotrophic factor (CNTF), CNTF receptor alpha (CNTFR-alpha) following experimental intracerebral hemorrhage in rats.","date":"2005","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/15755520","citation_count":17,"is_preprint":false},{"pmid":"11162290","id":"PMC_11162290","title":"CNTFR alpha alone or in combination with CNTF promotes macrophage chemotaxis in 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proteins); activated STATs dimerize and translocate to the nucleus to bind specific DNA sequences and enhance transcription.\",\n      \"method\": \"Biochemical signaling studies and receptor complex assembly assays (reviewed with supporting experimental evidence)\",\n      \"journal\": \"Pharmaceutica acta Helvetiae\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor complex assembly, JAK/STAT pathway activation replicated across multiple labs and model systems\",\n      \"pmids\": [\"10812968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CNTFRα lacks a conventional transmembrane domain and is anchored to the cell membrane via a glycosyl-phosphatidylinositol (GPI) linkage.\",\n      \"method\": \"Biochemical characterization of receptor topology (reviewed with supporting experimental basis)\",\n      \"journal\": \"Pharmaceutica acta Helvetiae\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GPI-anchoring established biochemically, reported consistently across reviewed literature\",\n      \"pmids\": [\"10812968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The membrane-distal cytokine binding domain (CBD1) of LIFR interacts in vitro with soluble CNTFRα in the absence of CNTF ligand, and purified CBD1 partially blocks CNTF signaling (but not IL-6 or LIF signaling) in human Ntera/D1 cells, raising the possibility that LIFR and CNTFRα can form a ligand-free complex.\",\n      \"method\": \"In vitro protein–protein interaction assay with purified domains; functional signaling inhibition in cell line\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro binding plus cellular functional assay, single lab, single study\",\n      \"pmids\": [\"11943154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Soluble CNTFRα alone, or in combination with CNTF, promotes macrophage chemotaxis in a concentration-dependent manner that is inhibited by a neutralizing anti-gp130 antibody; this chemotaxis is also inhibited by wortmannin, LY294002, or PD98059, implicating PI3K and MAPK signaling pathways. Stimulation with CNTFRα+CNTF causes tyrosine phosphorylation of an ~130 kD protein (presumed gp130) in macrophages.\",\n      \"method\": \"Microchemotaxis chamber assay, neutralizing antibody blocking, pharmacological inhibition (wortmannin, LY294002, PD98059), Western blot for tyrosine phosphorylation\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibitors and antibody blocking with functional readout, single lab\",\n      \"pmids\": [\"11162290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CLC (cardiotrophin-like cytokine) is co-expressed at the single-cell level with clf and cntfr in developing mouse muscles during the developmental period corresponding to motor neuron loss in CNTFR-deficient mice, supporting CLC/sCNTFR heterodimer as a physiological ligand for the tripartite CNTF receptor complex.\",\n      \"method\": \"In situ hybridization co-expression analysis at single-cell resolution in mouse embryonic tissues\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-expression data only; functional activation of receptor complex by CLC/sCNTFR not directly reconstituted in this study\",\n      \"pmids\": [\"15683542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CNTFR acts as the receptor for CLCF1 in lung adenocarcinoma; a high-affinity engineered soluble eCNTFR-Fc decoy sequesters CLCF1 and inhibits tumor growth in xenograft and autochthonous KRAS/p53-mutant mouse models, with efficacy correlated with the presence of KRAS mutations retaining GTPase activity.\",\n      \"method\": \"Engineered soluble receptor (eCNTFR-Fc) functional neutralization assay, xenograft tumor models, genetically engineered mouse model\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal tumor models (xenograft + autochthonous GEM), validated with engineered decoy receptor and genetic correlation\",\n      \"pmids\": [\"31700175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Blockade of the CLCF1-CNTFR axis by eCNTFR-Fc suppresses STAT3 signaling and TGF-β production in hepatocellular carcinoma, inhibiting tumor growth, stemness, and immunosuppressive tumor microenvironment formation; eCNTFR-Fc-armored GPC3 CAR-T cells showed enhanced cytotoxicity and functional persistence.\",\n      \"method\": \"Engineered eCNTFR-Fc in vitro and xenograft assays, western blot for STAT3 phosphorylation, cytokine measurement (TGF-β), CAR-T cell functional assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo readouts in single lab study, mechanistic pathway (STAT3/TGF-β) identified\",\n      \"pmids\": [\"42102942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-675-5p binds to the 3'-UTR of CNTFR mRNA (at the rs41274853 polymorphic region), as demonstrated by luciferase reporter assay, irrespective of which allele is present at the polymorphism.\",\n      \"method\": \"Luciferase reporter assay\",\n      \"journal\": \"International journal of sports medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single reporter assay, single lab, no direct effect on CNTFR protein levels measured\",\n      \"pmids\": [\"26837930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"miR-21-5p directly targets the CNTFR 3'-UTR, suppressing CNTFR expression and thereby promoting proliferation, invasion, and migration of esophageal squamous cell carcinoma cells; miR-21-5p mimics reduce CNTFR protein levels while miR-21-5p inhibitors increase CNTFR expression.\",\n      \"method\": \"Luciferase reporter assay, RT-qPCR, western blot, CCK-8, EdU, transwell, and flow cytometry assays\",\n      \"journal\": \"BMC gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR binding confirmed by reporter assay plus multiple functional readouts, single lab\",\n      \"pmids\": [\"41673571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The human CNTFR gene was mapped to chromosome 9p13 by PCR on human/CHO somatic cell hybrid panels and radiation hybrid panels.\",\n      \"method\": \"PCR-based somatic cell hybrid mapping and radiation hybrid mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct PCR mapping on panel of hybrid cell lines, chromosomal localization clearly established\",\n      \"pmids\": [\"8244400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CNTFR is detected at the plasma membrane of chondrogenic progenitor cells and shows time-dependent downregulation during chondrogenic differentiation; targeted knockdown of CNTFR differentially regulates COL1A1 (fibrocartilage marker) expression, indicating a role in cell-matrix signaling and survival pathways during chondrogenesis.\",\n      \"method\": \"Glycocapture-based cell surface proteomics, western blotting, immunocytochemistry, siRNA knockdown, qRT-PCR, matrix histochemistry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, novel context; knockdown phenotype (COL1A1 regulation) shown but mechanism not fully elaborated\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CNTFRα is a GPI-anchored, nervous-system- and muscle-enriched receptor subunit that acts as the ligand-binding specificity component for CNTF and related cytokines (including CLCF1/CLC); it first captures ligand and then recruits gp130 and LIFRβ into a tripartite signaling complex that activates constitutively associated JAKs, leading to tyrosine phosphorylation of receptor cytoplasmic domains, STAT3 (and other STAT) recruitment and dimerization, nuclear translocation, and transcriptional activation, with PI3K and MAPK also engaged downstream; soluble CNTFRα can additionally act in trans to confer CNTF responsiveness on cells expressing only gp130/LIFRβ, and the CLCF1-CNTFR axis drives STAT3 and TGF-β-dependent oncogenic and immunosuppressive signaling in tumors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNTFRα is a GPI-anchored receptor subunit that serves as the ligand-binding specificity component of a tripartite cytokine receptor complex: it first captures CNTF and then nucleates recruitment of gp130 and LIFRβ, whose heterodimerization activates constitutively associated JAKs to drive tyrosine phosphorylation, STAT recruitment and dimerization, and nuclear transcriptional activation [#0, #1]. Beyond the canonical JAK/STAT output, soluble CNTFRα together with CNTF engages gp130-dependent PI3K and MAPK signaling to promote macrophage chemotaxis [#3], and CNTFRα can pre-associate with the LIFR membrane-distal cytokine binding domain in a ligand-free manner [#2]. CNTFRα also functions as the receptor for CLCF1/CLC, with CLC co-expressed alongside cntfr in developing muscle at the time of motor neuron survival [#4]; in cancer, the CLCF1–CNTFR axis drives STAT3 activation and TGF-β production, and an engineered soluble decoy (eCNTFR-Fc) sequesters CLCF1 to suppress tumor growth, stemness, and an immunosuppressive microenvironment in lung adenocarcinoma and hepatocellular carcinoma [#5, #6]. CNTFR expression is post-transcriptionally controlled through its 3'-UTR by miR-21-5p, loss of which derepresses CNTFR and constrains esophageal squamous carcinoma cell proliferation and invasion [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing the chromosomal locus of human CNTFR provided the genomic anchor for studying the receptor gene.\",\n      \"evidence\": \"PCR-based somatic cell and radiation hybrid mapping localizing CNTFR to 9p13\",\n      \"pmids\": [\"8244400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Locus mapping alone gives no functional or regulatory information\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the receptor assembly resolved how CNTFRα converts ligand binding into intracellular signaling: it captures CNTF first, then recruits gp130 and LIFRβ to activate JAK/STAT transcriptional output.\",\n      \"evidence\": \"Biochemical receptor complex assembly and JAK/STAT pathway signaling studies\",\n      \"pmids\": [\"10812968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural arrangement of the tripartite complex not resolved here\", \"Does not address ligands beyond CNTF\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating GPI anchoring explained how a transmembrane-domain-less receptor subunit can present ligand and shed as a soluble form.\",\n      \"evidence\": \"Biochemical characterization of receptor membrane topology\",\n      \"pmids\": [\"10812968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism and regulation of shedding to generate soluble CNTFRα not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying that soluble CNTFRα with CNTF drives macrophage chemotaxis showed signaling extends beyond JAK/STAT to gp130-dependent PI3K and MAPK pathways and to non-neural cell behaviors.\",\n      \"evidence\": \"Microchemotaxis assays with anti-gp130 neutralization, pharmacological PI3K/MAPK inhibition, and anti-phosphotyrosine Western blot in macrophages\",\n      \"pmids\": [\"11162290\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"~130 kD phosphoprotein only presumed to be gp130\", \"Direct downstream effectors of PI3K/MAPK in this context not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that the LIFR CBD1 domain binds soluble CNTFRα without ligand raised the possibility of a pre-formed ligand-free receptor subcomplex.\",\n      \"evidence\": \"In vitro purified-domain interaction assay plus CBD1 blockade of CNTF (but not IL-6/LIF) signaling in Ntera/D1 cells\",\n      \"pmids\": [\"11943154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single study\", \"Physiological relevance of a ligand-free CNTFRα–LIFR complex not established in vivo\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Co-expression of CLC with cntfr and clf in developing muscle supported CLC/sCNTFR as a physiological ligand for the receptor complex during motor neuron survival.\",\n      \"evidence\": \"Single-cell in situ hybridization co-expression analysis in mouse embryonic tissues\",\n      \"pmids\": [\"15683542\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Co-expression only; functional receptor activation by CLC/sCNTFR not reconstituted in this study\", \"Causal link to motor neuron loss not directly tested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying CNTFR as the receptor for CLCF1 in lung adenocarcinoma converted CNTFR into an oncology target addressable by ligand sequestration.\",\n      \"evidence\": \"Engineered eCNTFR-Fc decoy neutralization in xenograft and autochthonous KRAS/p53-mutant mouse tumor models\",\n      \"pmids\": [\"31700175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling consequences of CLCF1 blockade not detailed in this study\", \"Basis for KRAS-mutation-dependent efficacy not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking the CLCF1-CNTFR axis to STAT3 and TGF-β output defined the signaling consequences of axis blockade and extended therapeutic relevance to hepatocellular carcinoma and CAR-T engineering.\",\n      \"evidence\": \"eCNTFR-Fc in vitro/xenograft assays, STAT3 phosphorylation Western blot, TGF-β measurement, and armored GPC3 CAR-T functional assays\",\n      \"pmids\": [\"42102942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Direct versus indirect contribution of CNTFR to the immunosuppressive microenvironment not fully dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrating direct miR-21-5p targeting of the CNTFR 3'-UTR established a post-transcriptional control point linking CNTFR loss to a pro-tumor phenotype in esophageal squamous carcinoma.\",\n      \"evidence\": \"Luciferase reporter assay with miR-21-5p mimics/inhibitors plus RT-qPCR, Western blot, and proliferation/invasion/migration assays\",\n      \"pmids\": [\"41673571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether CNTFR loss acts through the canonical receptor complex in this context not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same CNTFR axis is partitioned between neurotrophic/developmental survival signaling and tumor-promoting versus tumor-suppressive roles across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the tripartite complex in the timeline\", \"Mechanism of soluble CNTFRα generation and trans-signaling not defined\", \"Context-dependence of CNTFR as tumor driver versus suppressor unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"tripartite CNTF receptor complex (CNTFRα–gp130–LIFRβ)\"],\n    \"partners\": [\"CNTF\", \"gp130\", \"LIFR\", \"CLCF1\", \"CLC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}