{"gene":"LIFR","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1993,"finding":"LIFR (LIFRβ) heterodimerizes with gp130 to form the functional LIF receptor complex; both CNTF and LIF trigger ligand-induced association of these initially separate receptor components, resulting in tyrosine phosphorylation of receptor subunits. CNTF signals through a tripartite complex of CNTFRα + LIFRβ + gp130, converting the bipartite LIF receptor into a tripartite CNTF receptor by addition of CNTFRα.","method":"Co-immunoprecipitation, receptor reconstitution, tyrosine phosphorylation assays in transfected cells","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of receptor complex with biochemical validation of heterodimerization and tyrosine phosphorylation, widely replicated","pmids":["8390097"],"is_preprint":false},{"year":2000,"finding":"The cytoplasmic domain of LIFR is sufficient to generate signals for growth arrest and macrophage differentiation of mouse myeloid leukemic cells when induced to homodimerize independently of gp130. Two membrane-distal tyrosines on the YXXQ motif of LIFR are critical for STAT3 activation and for growth arrest and macrophage differentiation.","method":"Forced homodimerization of LIFR cytoplasmic domain constructs, site-directed mutagenesis of YXXQ tyrosines, differentiation assays in WEHI-3B D+ cells","journal":"Leukemia & lymphoma","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific residues combined with functional differentiation/growth arrest readouts in reconstituted system","pmids":["11042511"],"is_preprint":false},{"year":2002,"finding":"The membrane-distal cytokine-binding domain (CBD1) of LIFR directly 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.","method":"In vitro binding assay with purified domains, functional blocking assay in Ntera/D1 cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro reconstitution with purified domains, single lab, single study","pmids":["11943154"],"is_preprint":false},{"year":2004,"finding":"Null mutations in LIFR cause Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome. These mutations alter LIFR mRNA stability, resulting in absence of LIFR protein and impairment of JAK/STAT3 signaling in patient cells.","method":"Genetic mapping, mutation identification by sequencing, functional studies of LIFR mRNA stability and JAK/STAT3 phosphorylation in patient-derived cells","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutations identified in 19 families, functional validation of mRNA instability and signaling loss in patient cells, replicated across multiple independent families","pmids":["14740318"],"is_preprint":false},{"year":2005,"finding":"LIFR N-terminal cytokine-binding domain is required specifically for CNTF binding and signaling; deletion of this domain abolishes CNTF signaling but not LIF or oncostatin M signaling, revealing molecular differences between the CNTF active receptor complex and those of LIF and OSM.","method":"Overexpression of LIFR deletion mutant in cells, CNTF/LIF/OSM signaling assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain deletion mutagenesis with functional signaling readout, single lab, single study","pmids":["16051226"],"is_preprint":false},{"year":2005,"finding":"gp130 exists as a transient preformed homodimer on the plasma membrane stabilized by IL-6, whereas heterodimerization of gp130 with LIFR is mainly triggered by LIF ligand binding, as shown by FRET and BiFC in living cells.","method":"FRET (YFP/CFP-tagged receptors), bimolecular fluorescence complementation (BiFC) in live cells","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — two orthogonal live-cell imaging methods (FRET and BiFC) used in single study with stimulation controls","pmids":["16254248"],"is_preprint":false},{"year":2007,"finding":"LIFR protein stability is regulated by opposing activities of lysosomes (degradation) and proteasomes (stabilization via NF-κB/IκB degradation). TNF promotes LIFR lysosomal degradation and endocytosis, reducing LIFR-mediated STAT3 activation, whereas proteasome inhibition reduces basal LIFR expression.","method":"Lysosomal and proteasomal inhibitor treatments, NF-κB inhibition, Western blot for LIFR and pSTAT3 in RBE4 cells","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological inhibition of degradation pathways with functional STAT3 readout, single lab","pmids":["17873291"],"is_preprint":false},{"year":2009,"finding":"LIFR and its activating cytokines LIF, cardiotrophin-1, and cardiotrophin-like cytokine are upregulated by retinal preconditioning stress and mediate STAT3 activation; blocking LIFR with an antagonist (LIF05) during preconditioning attenuates STAT3 activation and reduces photoreceptor protection.","method":"Quantitative PCR, LIFR antagonist treatment, STAT3 phosphorylation assay, photoreceptor survival assay in rat retina","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — antagonist blockade with STAT3 and cell-survival functional readouts, single lab","pmids":["19344761"],"is_preprint":false},{"year":2010,"finding":"Neuropoietin activates STAT3 in adipocytes independently of LIFR phosphorylation and degradation, despite signaling through gp130; NP stimulation causes phosphorylation of gp130 but not LIFR.","method":"Western blot for phospho-LIFR and phospho-gp130 in adipocytes after NP stimulation, LIFR degradation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct biochemical measurement of receptor phosphorylation, single lab, single method","pmids":["20353755"],"is_preprint":false},{"year":2013,"finding":"E-cadherin is required for proper activation of the LIFR/Gp130 signaling pathway in mouse embryonic stem cells; E-cadherin associates with the LIFR-Gp130 receptor complex (likely via its extracellular domain), and loss of E-cadherin-mediated adhesion leads to downregulation of LIFR, Gp130, and pSTAT3, which can be rescued by constitutively active STAT3.","method":"Genetic knockout (β-catenin-null mESCs), E-cadherin–α-catenin fusion rescue, co-immunoprecipitation of E-cadherin with LIFR/Gp130, Western blot for pSTAT3","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (rescue with constitutively active STAT3), co-IP of E-cadherin with receptor complex, multiple orthogonal validations in single study","pmids":["23487312"],"is_preprint":false},{"year":2014,"finding":"A single amino acid substitution R28E in CNTF (CV-1) abrogates IL-6R binding while retaining CNTFR binding and signaling through CNTFR·gp130·LIFR, demonstrating that CNTF uses distinct receptor interfaces for IL-6R vs. CNTFRα interactions within the LIFR-containing complex.","method":"Immunoprecipitation of receptor binding, STAT3 phosphorylation assays, cytokine-dependent cellular proliferation assays","journal":"Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mutagenesis with functional signaling readouts, single lab","pmids":["24802752"],"is_preprint":false},{"year":2015,"finding":"LIFR functions as a metastasis suppressor in hepatocellular carcinoma by negatively regulating PI3K/AKT signaling; LIFR knockdown activates PI3K/AKT through enhanced phosphorylation of JAK1, which promotes MMP13 expression and HCC metastasis.","method":"LIFR knockdown and overexpression, Western blot for pJAK1, pAKT, MMP13, in vitro migration/invasion assays, in vivo xenograft metastasis models","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with mechanistic pathway analysis and in vivo validation, single lab","pmids":["26249360"],"is_preprint":false},{"year":2016,"finding":"LIFR promotes a dormancy phenotype in breast cancer cells disseminated to bone through LIFR:STAT3:SOCS3 signaling; loss of LIFR or STAT3 enables otherwise dormant breast cancer cells to downregulate dormancy/quiescence genes and colonize bone.","method":"LIFR and STAT3 knockdown/knockout, gene expression profiling, in vivo bone colonization assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (LIFR and STAT3) with specific in vivo bone colonization phenotype and molecular pathway definition, published in high-quality journal","pmids":["27642788"],"is_preprint":false},{"year":2017,"finding":"LIFR cytoplasmic domain contains a self-renewal domain (juxtamembrane 3K motif acetylated by p300) and a differentiation domain (C-terminal SPXX repeats phosphorylated by MAPK). LIFR acetylation promotes LIFR homodimerization and STAT3 hyper/hypo-activation depending on presence of gp130, driving mESC self-renewal; MAPK phosphorylation of SPXX repeats restricts STAT3 activation and promotes differentiation.","method":"Domain mutagenesis, p300 co-immunoprecipitation/acetylation assay, MAPK phosphorylation assays, LIFR dimerization assays, STAT3 activation readouts in mESCs","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of specific residues with multiple orthogonal biochemical and functional readouts in a single rigorous study","pmids":["28122243"],"is_preprint":false},{"year":2017,"finding":"LIFR missense mutations cause decreased LIFR protein half-life and reduced cell membrane localization, resulting in reduced LIF-stimulated STAT3 phosphorylation, and Lifr knockout mice display urinary tract malformations including hydronephrosis, hydroureter, and ureteral abnormalities.","method":"Whole-exome sequencing, LIFR mutant half-life assays, cell membrane localization assays, STAT3 phosphorylation assays, Lifr knockout mouse phenotyping","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein stability, localization, signaling in patient variants + knockout mouse model), multiple patients and independent validation","pmids":["28334964"],"is_preprint":false},{"year":2018,"finding":"LIFR promotes tumor angiogenesis in colorectal cancer through ERK phosphorylation-driven upregulation of IL-8; IL-8 depletion reduces LIFR-induced angiogenic activity.","method":"LIFR knockdown/overexpression, IL-8 neutralization, ERK phosphorylation Western blot, in vitro/in vivo angiogenesis assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — mechanistic pathway dissection with IL-8 rescue experiment, single lab","pmids":["29751081"],"is_preprint":false},{"year":2018,"finding":"miR-589 directly targets the LIFR 3'-UTR to suppress LIFR expression, activating PI3K/AKT/c-Jun signaling; c-Jun in turn binds the miR-589 promoter to activate its transcription, forming a regulatory feedback loop promoting gastric cancer metastasis.","method":"Dual-luciferase reporter assay (miR-589 targeting LIFR 3'-UTR), ChIP for c-Jun at miR-589 promoter, Western blot, in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct luciferase validation of miRNA-target interaction + ChIP for transcription factor binding, single lab","pmids":["30012200"],"is_preprint":false},{"year":2018,"finding":"Nuclear PAK4 promotes bone metastasis of ERα-positive breast cancer by targeting LIFR; PAK4 binds ERα and co-translocates to the nucleus upon E2 stimulation, repressing LIFR expression as a bone metastasis suppressor.","method":"Co-immunoprecipitation of PAK4-ERα, nuclear fractionation, LIFR expression analysis upon PAK4 nuclear accumulation, in vitro invasion and in vivo metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and nuclear fractionation with functional in vivo validation, single lab","pmids":["30177834"],"is_preprint":false},{"year":2018,"finding":"miR-377-3p directly binds the 3'-UTR of LIFR to suppress LIFR expression and inhibit adipogenic differentiation of human bone marrow mesenchymal stem cells; LIFR expression increases during adipogenesis and its knockdown inhibits adipocyte differentiation.","method":"Luciferase reporter assay for miR-377-3p binding to LIFR 3'-UTR, LIFR knockdown with siRNA, adipogenic differentiation assays","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct luciferase validation of miRNA-target interaction with functional differentiation readout, single lab","pmids":["29959592"],"is_preprint":false},{"year":2019,"finding":"ILEI (FAM3C) signals through LIFR as its receptor to activate STAT3 and drive both EMT and breast cancer stem cell formation; reduction of either ILEI or LIFR reduces tumor growth, tumor-initiating cells, and metastasis in vivo.","method":"Co-immunoprecipitation of ILEI-LIFR interaction, LIFR knockdown rescue experiments, in vivo tumor and metastasis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — identification of ligand-receptor pair by co-IP, double knockdown epistasis, in vivo validation with multiple functional readouts","pmids":["30692635"],"is_preprint":false},{"year":2019,"finding":"EC359, a small-molecule inhibitor, directly interacts with LIFR to block LIF/LIFR interactions and attenuates downstream STAT3, mTOR, and AKT activation in TNBC; EC359 also blocks signaling by other LIFR ligands (CTF1, CNTF, OSM) that interact at the LIF/LIFR interface.","method":"Direct binding assay of EC359 to LIFR, LIF/LIFR interaction blocking assay, Western blot for downstream signaling, TNBC xenograft and PDX models","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct ligand-receptor interaction blocking demonstrated biochemically, multiple downstream pathway assays, in vivo xenograft validation","pmids":["31142661"],"is_preprint":false},{"year":2019,"finding":"LIFR phosphorylation at S1044 by ERK2 (but not ERK1) promotes AKT pathway activation, inducing expression of proliferation and metastatic genes in prostate cancer; pLIFR-S1044 and pAKT S473 show tight positive correlation in PCa tissue.","method":"Phospho-specific Western blot, ERK1/ERK2 siRNA knockdown, LIFR S1044 mutant constructs, AKT pathway readouts, IHC of patient tissue","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — phosphosite mutagenesis with kinase specificity determination and downstream pathway readout, single lab","pmids":["30851421"],"is_preprint":false},{"year":2021,"finding":"Loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes intracellular iron and confers resistance to ferroptosis inducers; this LIFR-NF-κB-LCN2 axis promotes liver tumorigenesis.","method":"Hepatocyte-specific Lifr knockout mice, mechanistic pathway dissection (SHP1, NF-κB, LCN2), LCN2-neutralizing antibody rescue experiments, PDX tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional knockout with mechanistic pathway dissection (SHP1→NF-κB→LCN2), antibody rescue in PDX models, multiple orthogonal methods","pmids":["34921145"],"is_preprint":false},{"year":2021,"finding":"HDAC inhibitors epigenetically induce LIFR expression by increasing histone acetylation in the proximal LIFR promoter, activating a pro-dormancy program in breast cancer cells; hypoxia increases H3K9me3 and decreases H3K9ac at the distal LIFR promoter to repress LIFR, and PTHrP binds the distal LIFR promoter to suppress its expression.","method":"ChIP for histone marks at LIFR promoter, HDACi treatment, PTHrP ChIP, LIFR expression and dormancy marker assays","journal":"Journal of bone oncology / Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with multiple histone marks, pharmacological rescue, two independent mechanisms of LIFR repression validated, single lab","pmids":["34247191","34934614"],"is_preprint":false},{"year":2021,"finding":"Adipocyte-specific LIFR knockout mice on high-fat diet show reduced adipose STAT3 activation, 50% expansion in adipose tissue, 20% body weight increase, and 75% reduction in hepatic triacylglycerides compared to controls; adipocyte-specific STAT3 knockout recapitulates these findings, demonstrating that LIFR signals through JAK/STAT3 in adipocytes to limit adipose expansion and contribute to ectopic liver fat accumulation.","method":"Adipoq-Cre;LIFR-KO and Adipoq-Cre;STAT3-KO mouse models, HFD feeding, STAT3 phosphorylation assays, LIF-induced lipolysis assays in differentiated adipocytes","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — two parallel conditional knockout models (LIFR and STAT3) with convergent phenotypes, direct STAT3 signaling validation in differentiated adipocytes","pmids":["33748712"],"is_preprint":false},{"year":2022,"finding":"ILEI promotes renal interstitial fibrosis EMT by binding and activating LIFR, with downstream phosphorylation of Akt and ERK; co-immunoprecipitation confirmed ILEI-LIFR complex formation in vitro.","method":"Co-immunoprecipitation of ILEI-LIFR, ILEI overexpression/knockdown, Western blot for pAkt and pERK, UUO mouse model, patient kidney tissue IHC","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirming ILEI-LIFR interaction with downstream signaling validation, in vivo UUO model, and patient tissue correlation","pmids":["35093095"],"is_preprint":false},{"year":2023,"finding":"OSMR deficiency activates OSM/LIFR/STAT3 signaling and aggravates cardiac hypertrophy; adenoviral knockdown of LIFR in myocardial tissue (Ad-shLIFR) ameliorates the hypertrophic phenotype and STAT3 activation caused by OSMR deletion, placing LIFR downstream of OSM/OSMR in cardiac signaling.","method":"OSMR knockout mice with aortic banding, Ad-shLIFR adenoviral knockdown, Western blot for STAT3 activation, macrophage adoptive transfer experiments","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (OSMR-KO + LIFR knockdown rescue) with functional cardiac phenotype readout","pmids":["37120549"],"is_preprint":false},{"year":2023,"finding":"A synthetic cytokimera GIL-11 (exchanging the gp130-binding site III of IL-11 with the LIFR-binding site III of LIF) efficiently recruits a non-natural receptor complex of gp130:IL-11R:LIFR, inducing signal transduction and cell proliferation; GIL-11 rescued IL-6R-deficient mice after partial hepatectomy, demonstrating functional gp130:IL-11R:LIFR signaling in liver regeneration.","method":"Cytokimera protein engineering, Ba/F3 cell proliferation assay, signaling assays in factor-dependent cells, IL-6R-knockout mouse partial hepatectomy survival model","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — engineered cytokimera with defined receptor complex reconstitution, cell signaling validation, and in vivo functional rescue in KO mice","pmids":["37061565"],"is_preprint":false},{"year":2024,"finding":"In response to liver damage, LIFR from hepatocytes promotes secretion of cholesterol and CXCL1 in a STAT3-dependent manner, mobilizing bone marrow neutrophils to the circulation and damaged liver; cholesterol then stimulates neutrophils via ERRα to secrete hepatocyte growth factor, accelerating hepatocyte proliferation and liver regeneration.","method":"Hepatocyte-specific Lifr knockout and overexpression mouse models, partial hepatectomy and toxic injury models, STAT3 pathway inhibition, cholesterol/CXCL1 measurement, ERRα receptor antagonism, HGF measurement","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout and overexpression with pharmacological pathway dissection, multiple in vivo models, bidirectional signaling axis defined","pmids":["39147934"],"is_preprint":false},{"year":2024,"finding":"SNORA28 acts as a molecular decoy recruiting BRD4, which increases H3K9 acetylation at the LIFR promoter region, stimulating LIFR transcription and activating the JAK1/STAT3 pathway to enhance CRC cell proliferation and radioresistance.","method":"ChIP for BRD4 and H3K9ac at LIFR promoter, SNORA28 overexpression/knockdown, Western blot for JAK1/STAT3, in vitro and in vivo proliferation/radiation survival assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP with functional pathway readout, single lab","pmids":["38424373"],"is_preprint":false},{"year":2024,"finding":"IFN-τ-induced IRF1 transactivates LIFR transcription by directly binding to the LIFR promoter, upregulating LIFR expression and enhancing bovine endometrial receptivity; LIFR knockdown blocks the pro-receptivity effects of IRF1.","method":"Dual-luciferase reporter assay (IRF1 binding to LIFR promoter), IRF1 overexpression/siRNA, LIFR knockdown epistasis, endometrial receptivity marker expression","journal":"Journal of reproductive immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct promoter binding validated by luciferase assay with epistasis knockdown, single lab, bovine system","pmids":["38432052"],"is_preprint":false},{"year":2025,"finding":"Uterine epithelium-specific Lifr knockout mice are completely infertile; gene expression analysis identified ERBB2 and c-Fos as hub regulators downstream of LIFR (and Gp130) in uterine epithelium before implantation, and pharmacological ERBB2 inhibition confirmed that LIFR-ERBB2-mediated signaling plays a crucial role in embryo implantation.","method":"Uterine epithelium-specific Lifr knockout mice, comprehensive endometrial gene expression analysis, ERBB2 inhibitor treatment, comparison with Gp130 eKO mice","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with transcriptomic analysis and pharmacological validation of downstream effector, single lab, recent publication","pmids":["40427591"],"is_preprint":false}],"current_model":"LIFR is a transmembrane receptor subunit that heterodimerizes with gp130 (and optionally CNTFRα) in response to IL-6 family cytokines (LIF, CNTF, CT-1, OSM, ILEI/FAM3C), triggering JAK/STAT3, PI3K/AKT, and MAPK signaling; its cytoplasmic YXXQ motif tyrosines are required for STAT3 activation, while juxtamembrane acetylation by p300 promotes self-renewal dimerization and C-terminal SPXX phosphorylation by MAPK promotes differentiation, with receptor stability regulated by opposing lysosomal degradation and proteasomal/NF-κB-dependent stabilization, and LIFR abundance controlled epigenetically by histone acetylation at its promoter and transcriptionally by IRF1, BRD4, and PTHrP."},"narrative":{"mechanistic_narrative":"LIFR (LIFRβ) is a transmembrane signaling receptor subunit that, upon binding IL-6 family cytokines, heterodimerizes with gp130 to form the functional LIF receptor and, with addition of CNTFRα, converts the bipartite complex into a tripartite CNTF receptor, triggering ligand-induced tyrosine phosphorylation and downstream JAK/STAT3 signaling [PMID:8390097, PMID:16254248]. The cytoplasmic domain alone is sufficient to drive signaling when dimerized, with two membrane-distal YXXQ tyrosines required for STAT3 activation and the resulting growth-arrest/differentiation output [PMID:11042511]. Receptor output is tuned by competing post-translational modifications of the cytoplasmic tail: juxtamembrane acetylation by p300 promotes LIFR homodimerization and self-renewal-associated STAT3 activity, while MAPK phosphorylation of C-terminal SPXX repeats restricts STAT3 and favors differentiation [PMID:28122243]. LIFR also serves as a receptor for additional ligands including ILEI/FAM3C, which activates STAT3, AKT, and ERK to drive EMT and stem-cell programs [PMID:30692635, PMID:35093095], and the receptor interface can be pharmacologically blocked by the small molecule EC359 to suppress LIF/LIFR-driven STAT3, mTOR, and AKT signaling [PMID:31142661]. Across tissues LIFR controls cell-fate and homeostatic programs: it sustains mouse embryonic stem cell self-renewal in concert with E-cadherin-stabilized receptor complexes [PMID:23487312, PMID:28122243], constrains adipose expansion via adipocyte STAT3 signaling [PMID:33748712], and orchestrates STAT3-dependent hepatocyte programs driving liver regeneration [PMID:39147934]. In cancer, LIFR acts as a context-dependent metastasis suppressor—restraining PI3K/AKT/JAK1 signaling and enforcing tumor-cell dormancy through a LIFR:STAT3:SOCS3 axis—whose loss derepresses an NF-κB→LCN2 ferroptosis-resistance program [PMID:26249360, PMID:27642788, PMID:34921145]. LIFR abundance is heavily regulated, transcriptionally by IRF1, BRD4/SNORA28, and PTHrP and post-transcriptionally by miRNAs targeting its 3'-UTR, and by opposing lysosomal degradation versus proteasome/NF-κB-dependent stabilization [PMID:17873291, PMID:30012200, PMID:34247191, PMID:34934614, PMID:38424373, PMID:38432052]. Null and missense mutations that destabilize LIFR mRNA or protein cause Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome and urinary tract malformations, establishing LIFR as essential for development [PMID:14740318, PMID:28334964].","teleology":[{"year":1993,"claim":"Established the core architecture of LIFR signaling by showing it is a non-signaling-alone subunit that must heterodimerize with gp130, and that adding CNTFRα reconfigures the complex for CNTF.","evidence":"Co-immunoprecipitation and receptor reconstitution with tyrosine phosphorylation assays in transfected cells","pmids":["8390097"],"confidence":"High","gaps":["Stoichiometry and structural geometry of the LIFR:gp130 complex not resolved","Identity of associated JAKs not defined here"]},{"year":2000,"claim":"Mapped the signaling output to the LIFR cytoplasmic domain and identified the membrane-distal YXXQ tyrosines as the determinants of STAT3 activation and differentiation.","evidence":"Forced homodimerization of LIFR cytoplasmic constructs with YXXQ mutagenesis and differentiation assays in myeloid leukemia cells","pmids":["11042511"],"confidence":"High","gaps":["Did not address contributions of other cytoplasmic motifs","Performed in artificial homodimerization system, not native ligand-driven complex"]},{"year":2002,"claim":"Defined the extracellular determinants of ligand selectivity, showing the membrane-distal CBD1 domain binds CNTFRα and that the N-terminal domain is specifically required for CNTF signaling.","evidence":"In vitro domain binding and blocking assays plus deletion mutagenesis with CNTF/LIF/OSM signaling readouts","pmids":["11943154","16051226"],"confidence":"Medium","gaps":["Single-lab in vitro/overexpression data","Atomic-level interface mapping not performed"]},{"year":2004,"claim":"Linked LIFR loss-of-function to human disease, showing null mutations destabilize LIFR mRNA, abolish protein, and impair JAK/STAT3 signaling, causing Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome.","evidence":"Genetic mapping and mutation sequencing in 19 families with mRNA stability and STAT3 phosphorylation studies in patient cells","pmids":["14740318"],"confidence":"High","gaps":["Tissue-specific developmental requirements not fully resolved","Mechanism linking signaling loss to skeletal/dysautonomic phenotypes incomplete"]},{"year":2005,"claim":"Distinguished the assembly dynamics of LIFR-containing complexes, showing LIFR:gp130 heterodimerization is ligand-triggered rather than preformed, unlike gp130 homodimers.","evidence":"FRET and BiFC live-cell imaging of tagged receptors with cytokine stimulation","pmids":["16254248"],"confidence":"High","gaps":["Kinetics of disassembly not characterized","Did not address CNTFRα-containing tripartite assembly dynamics"]},{"year":2007,"claim":"Revealed that LIFR signaling capacity is set by receptor abundance, controlled by opposing lysosomal degradation and proteasome/NF-κB-dependent stabilization.","evidence":"Pharmacological lysosome/proteasome and NF-κB inhibition with LIFR and pSTAT3 Western blot in RBE4 cells","pmids":["17873291"],"confidence":"Medium","gaps":["E3 ligases and trafficking adaptors not identified","Single-lab pharmacological evidence without genetic confirmation"]},{"year":2013,"claim":"Connected cell adhesion to LIFR signaling competence by showing E-cadherin associates with and is required for proper LIFR/gp130/STAT3 activation in stem cells.","evidence":"β-catenin-null mESCs, cadherin-catenin fusion rescue, co-IP, and STAT3 rescue experiments","pmids":["23487312"],"confidence":"High","gaps":["Direct vs indirect nature of E-cadherin–receptor association not fully resolved","Generality beyond mESCs untested"]},{"year":2016,"claim":"Defined a tumor-suppressive role for LIFR in enforcing disseminated cancer-cell dormancy via a LIFR:STAT3:SOCS3 program.","evidence":"LIFR/STAT3 knockdown and knockout with expression profiling and in vivo bone colonization assays","pmids":["27642788","26249360"],"confidence":"High","gaps":["Upstream cytokine driving the dormancy signal in vivo not defined","How dormancy is reawakened upon LIFR loss mechanistically incomplete"]},{"year":2017,"claim":"Resolved how LIFR cytoplasmic modifications bidirectionally control fate, with p300 acetylation driving self-renewal dimerization and MAPK SPXX phosphorylation driving differentiation, and tied missense mutations to receptor instability and developmental malformation.","evidence":"Domain mutagenesis, p300 acetylation and MAPK assays, dimerization/STAT3 readouts in mESCs, plus patient variant stability/localization studies and Lifr knockout mice","pmids":["28122243","28334964"],"confidence":"High","gaps":["Quantitative interplay between acetylation and phosphorylation under physiological signaling not mapped","Full spectrum of LIFR-dependent organogenesis defects incomplete"]},{"year":2019,"claim":"Expanded the LIFR ligand repertoire and identified druggable interfaces, establishing ILEI/FAM3C as a LIFR ligand driving EMT/stemness and EC359 as a direct LIFR-interface inhibitor blocking multiple ligands, while phospho-S1044 by ERK2 was shown to route LIFR into AKT signaling.","evidence":"Co-IP of ligand-receptor pairs, double-knockdown epistasis, in vivo tumor models, direct binding inhibition assays, and phosphosite mutagenesis with kinase-specificity tests","pmids":["30692635","31142661","30851421"],"confidence":"High","gaps":["ILEI binding interface on LIFR not structurally defined","Whether S1044 phosphorylation occurs in normal physiology untested"]},{"year":2021,"claim":"Mechanistically explained LIFR loss in liver cancer through a SHP1→NF-κB→LCN2 iron-sequestering axis conferring ferroptosis resistance, and demonstrated LIFR's homeostatic role limiting adipose expansion via adipocyte STAT3.","evidence":"Hepatocyte- and adipocyte-specific Lifr (and STAT3) knockout mice with pathway dissection and antibody/PDX rescue","pmids":["34921145","33748712"],"confidence":"High","gaps":["How LIFR loss engages SHP1 mechanistically not fully defined","Relationship between metabolic and tumor-suppressive functions unresolved"]},{"year":2021,"claim":"Defined the transcriptional and post-transcriptional control of LIFR abundance via histone acetylation, PTHrP, hypoxia, and 3'-UTR-targeting miRNAs.","evidence":"ChIP for histone marks/PTHrP, HDAC inhibitor treatment, and luciferase 3'-UTR reporter assays for miR-589/miR-377-3p","pmids":["34247191","34934614","30012200","29959592"],"confidence":"Medium","gaps":["Relative contribution of each regulatory layer in vivo unclear","Single-lab data for individual miRNA interactions"]},{"year":2024,"claim":"Established LIFR as a driver of regenerative and reproductive signaling programs, orchestrating hepatocyte STAT3-dependent cholesterol/CXCL1-mediated neutrophil recruitment for liver regeneration and LIFR-ERBB2 signaling required for embryo implantation, with transcriptional induction by IRF1 and BRD4/SNORA28.","evidence":"Hepatocyte- and uterine-specific Lifr knockout/overexpression mice, pharmacological pathway dissection, ERBB2 inhibition, and ChIP/luciferase promoter studies","pmids":["39147934","40427591","38432052","38424373"],"confidence":"High","gaps":["Cross-tissue conservation of these effector axes untested","How a single receptor selects distinct downstream effectors per tissue unresolved"]},{"year":null,"claim":"How LIFR's identical signaling machinery is wired to opposing outcomes—self-renewal versus differentiation, tumor suppression versus tumor promotion, across diverse tissues—remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling LIFR's tumor-suppressive and tumor-promoting roles","No high-resolution structure of native LIFR:gp130 or ligand-specific complexes","Determinants of tissue-specific effector selection (STAT3 vs AKT vs ERK) 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/35306361","citation_count":10,"is_preprint":false},{"pmid":"39382988","id":"PMC_39382988","title":"Design, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis.","date":"2024","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39382988","citation_count":10,"is_preprint":false},{"pmid":"37061565","id":"PMC_37061565","title":"Cytokimera GIL-11 rescued IL-6R deficient mice from partial hepatectomy-induced death by signaling via non-natural gp130:LIFR:IL-11R complexes.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37061565","citation_count":10,"is_preprint":false},{"pmid":"26285796","id":"PMC_26285796","title":"Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction?","date":"2015","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26285796","citation_count":10,"is_preprint":false},{"pmid":"18956948","id":"PMC_18956948","title":"Characterization, chromosomal assignment, and role of LIFR in early embryogenesis and stem cell establishment of rabbits.","date":"2008","source":"Cloning and stem cells","url":"https://pubmed.ncbi.nlm.nih.gov/18956948","citation_count":10,"is_preprint":false},{"pmid":"29038846","id":"PMC_29038846","title":"A possible implication of reduced levels of LIF, LIFR, and gp130 in vasculopathy related to systemic sclerosis.","date":"2017","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/29038846","citation_count":9,"is_preprint":false},{"pmid":"35034206","id":"PMC_35034206","title":"Circ_0003159 upregulates LIFR expression through competitively binding to miR-221-3p/miR-222-3p to block gastric cancer development.","date":"2022","source":"Journal of molecular 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FAM3C to maintain breast cancer stem cell self-renewal and invasiveness.","date":"2023","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37927213","citation_count":7,"is_preprint":false},{"pmid":"35778954","id":"PMC_35778954","title":"LncRNA LIFR-AS1 overexpression suppressed the progression of serous ovarian carcinoma.","date":"2022","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/35778954","citation_count":7,"is_preprint":false},{"pmid":"16051226","id":"PMC_16051226","title":"The N-terminal cytokine binding domain of LIFR is required for CNTF binding and signaling.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16051226","citation_count":7,"is_preprint":false},{"pmid":"26279654","id":"PMC_26279654","title":"Intragenic Deletion in the LIFR Gene in a Long-Term Survivor with Stüve-Wiedemann Syndrome.","date":"2015","source":"Molecular 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intracrine actions divergently influence breast cancer growth through p27 and LIFR.","date":"2024","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/38409028","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50615,"output_tokens":7759,"usd":0.134115,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17306,"output_tokens":5022,"usd":0.10604,"stage2_stop_reason":"end_turn"},"total_usd":0.240155,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"LIFR (LIFRβ) heterodimerizes with gp130 to form the functional LIF receptor complex; both CNTF and LIF trigger ligand-induced association of these initially separate receptor components, resulting in tyrosine phosphorylation of receptor subunits. CNTF signals through a tripartite complex of CNTFRα + LIFRβ + gp130, converting the bipartite LIF receptor into a tripartite CNTF receptor by addition of CNTFRα.\",\n      \"method\": \"Co-immunoprecipitation, receptor reconstitution, tyrosine phosphorylation assays in transfected cells\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of receptor complex with biochemical validation of heterodimerization and tyrosine phosphorylation, widely replicated\",\n      \"pmids\": [\"8390097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The cytoplasmic domain of LIFR is sufficient to generate signals for growth arrest and macrophage differentiation of mouse myeloid leukemic cells when induced to homodimerize independently of gp130. Two membrane-distal tyrosines on the YXXQ motif of LIFR are critical for STAT3 activation and for growth arrest and macrophage differentiation.\",\n      \"method\": \"Forced homodimerization of LIFR cytoplasmic domain constructs, site-directed mutagenesis of YXXQ tyrosines, differentiation assays in WEHI-3B D+ cells\",\n      \"journal\": \"Leukemia & lymphoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific residues combined with functional differentiation/growth arrest readouts in reconstituted system\",\n      \"pmids\": [\"11042511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The membrane-distal cytokine-binding domain (CBD1) of LIFR directly 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.\",\n      \"method\": \"In vitro binding assay with purified domains, functional blocking assay in Ntera/D1 cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro reconstitution with purified domains, single lab, single study\",\n      \"pmids\": [\"11943154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Null mutations in LIFR cause Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome. These mutations alter LIFR mRNA stability, resulting in absence of LIFR protein and impairment of JAK/STAT3 signaling in patient cells.\",\n      \"method\": \"Genetic mapping, mutation identification by sequencing, functional studies of LIFR mRNA stability and JAK/STAT3 phosphorylation in patient-derived cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutations identified in 19 families, functional validation of mRNA instability and signaling loss in patient cells, replicated across multiple independent families\",\n      \"pmids\": [\"14740318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"LIFR N-terminal cytokine-binding domain is required specifically for CNTF binding and signaling; deletion of this domain abolishes CNTF signaling but not LIF or oncostatin M signaling, revealing molecular differences between the CNTF active receptor complex and those of LIF and OSM.\",\n      \"method\": \"Overexpression of LIFR deletion mutant in cells, CNTF/LIF/OSM signaling assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain deletion mutagenesis with functional signaling readout, single lab, single study\",\n      \"pmids\": [\"16051226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"gp130 exists as a transient preformed homodimer on the plasma membrane stabilized by IL-6, whereas heterodimerization of gp130 with LIFR is mainly triggered by LIF ligand binding, as shown by FRET and BiFC in living cells.\",\n      \"method\": \"FRET (YFP/CFP-tagged receptors), bimolecular fluorescence complementation (BiFC) in live cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — two orthogonal live-cell imaging methods (FRET and BiFC) used in single study with stimulation controls\",\n      \"pmids\": [\"16254248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LIFR protein stability is regulated by opposing activities of lysosomes (degradation) and proteasomes (stabilization via NF-κB/IκB degradation). TNF promotes LIFR lysosomal degradation and endocytosis, reducing LIFR-mediated STAT3 activation, whereas proteasome inhibition reduces basal LIFR expression.\",\n      \"method\": \"Lysosomal and proteasomal inhibitor treatments, NF-κB inhibition, Western blot for LIFR and pSTAT3 in RBE4 cells\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological inhibition of degradation pathways with functional STAT3 readout, single lab\",\n      \"pmids\": [\"17873291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LIFR and its activating cytokines LIF, cardiotrophin-1, and cardiotrophin-like cytokine are upregulated by retinal preconditioning stress and mediate STAT3 activation; blocking LIFR with an antagonist (LIF05) during preconditioning attenuates STAT3 activation and reduces photoreceptor protection.\",\n      \"method\": \"Quantitative PCR, LIFR antagonist treatment, STAT3 phosphorylation assay, photoreceptor survival assay in rat retina\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — antagonist blockade with STAT3 and cell-survival functional readouts, single lab\",\n      \"pmids\": [\"19344761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Neuropoietin activates STAT3 in adipocytes independently of LIFR phosphorylation and degradation, despite signaling through gp130; NP stimulation causes phosphorylation of gp130 but not LIFR.\",\n      \"method\": \"Western blot for phospho-LIFR and phospho-gp130 in adipocytes after NP stimulation, LIFR degradation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct biochemical measurement of receptor phosphorylation, single lab, single method\",\n      \"pmids\": [\"20353755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E-cadherin is required for proper activation of the LIFR/Gp130 signaling pathway in mouse embryonic stem cells; E-cadherin associates with the LIFR-Gp130 receptor complex (likely via its extracellular domain), and loss of E-cadherin-mediated adhesion leads to downregulation of LIFR, Gp130, and pSTAT3, which can be rescued by constitutively active STAT3.\",\n      \"method\": \"Genetic knockout (β-catenin-null mESCs), E-cadherin–α-catenin fusion rescue, co-immunoprecipitation of E-cadherin with LIFR/Gp130, Western blot for pSTAT3\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (rescue with constitutively active STAT3), co-IP of E-cadherin with receptor complex, multiple orthogonal validations in single study\",\n      \"pmids\": [\"23487312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A single amino acid substitution R28E in CNTF (CV-1) abrogates IL-6R binding while retaining CNTFR binding and signaling through CNTFR·gp130·LIFR, demonstrating that CNTF uses distinct receptor interfaces for IL-6R vs. CNTFRα interactions within the LIFR-containing complex.\",\n      \"method\": \"Immunoprecipitation of receptor binding, STAT3 phosphorylation assays, cytokine-dependent cellular proliferation assays\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mutagenesis with functional signaling readouts, single lab\",\n      \"pmids\": [\"24802752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LIFR functions as a metastasis suppressor in hepatocellular carcinoma by negatively regulating PI3K/AKT signaling; LIFR knockdown activates PI3K/AKT through enhanced phosphorylation of JAK1, which promotes MMP13 expression and HCC metastasis.\",\n      \"method\": \"LIFR knockdown and overexpression, Western blot for pJAK1, pAKT, MMP13, in vitro migration/invasion assays, in vivo xenograft metastasis models\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with mechanistic pathway analysis and in vivo validation, single lab\",\n      \"pmids\": [\"26249360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LIFR promotes a dormancy phenotype in breast cancer cells disseminated to bone through LIFR:STAT3:SOCS3 signaling; loss of LIFR or STAT3 enables otherwise dormant breast cancer cells to downregulate dormancy/quiescence genes and colonize bone.\",\n      \"method\": \"LIFR and STAT3 knockdown/knockout, gene expression profiling, in vivo bone colonization assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (LIFR and STAT3) with specific in vivo bone colonization phenotype and molecular pathway definition, published in high-quality journal\",\n      \"pmids\": [\"27642788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LIFR cytoplasmic domain contains a self-renewal domain (juxtamembrane 3K motif acetylated by p300) and a differentiation domain (C-terminal SPXX repeats phosphorylated by MAPK). LIFR acetylation promotes LIFR homodimerization and STAT3 hyper/hypo-activation depending on presence of gp130, driving mESC self-renewal; MAPK phosphorylation of SPXX repeats restricts STAT3 activation and promotes differentiation.\",\n      \"method\": \"Domain mutagenesis, p300 co-immunoprecipitation/acetylation assay, MAPK phosphorylation assays, LIFR dimerization assays, STAT3 activation readouts in mESCs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of specific residues with multiple orthogonal biochemical and functional readouts in a single rigorous study\",\n      \"pmids\": [\"28122243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LIFR missense mutations cause decreased LIFR protein half-life and reduced cell membrane localization, resulting in reduced LIF-stimulated STAT3 phosphorylation, and Lifr knockout mice display urinary tract malformations including hydronephrosis, hydroureter, and ureteral abnormalities.\",\n      \"method\": \"Whole-exome sequencing, LIFR mutant half-life assays, cell membrane localization assays, STAT3 phosphorylation assays, Lifr knockout mouse phenotyping\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein stability, localization, signaling in patient variants + knockout mouse model), multiple patients and independent validation\",\n      \"pmids\": [\"28334964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LIFR promotes tumor angiogenesis in colorectal cancer through ERK phosphorylation-driven upregulation of IL-8; IL-8 depletion reduces LIFR-induced angiogenic activity.\",\n      \"method\": \"LIFR knockdown/overexpression, IL-8 neutralization, ERK phosphorylation Western blot, in vitro/in vivo angiogenesis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — mechanistic pathway dissection with IL-8 rescue experiment, single lab\",\n      \"pmids\": [\"29751081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-589 directly targets the LIFR 3'-UTR to suppress LIFR expression, activating PI3K/AKT/c-Jun signaling; c-Jun in turn binds the miR-589 promoter to activate its transcription, forming a regulatory feedback loop promoting gastric cancer metastasis.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-589 targeting LIFR 3'-UTR), ChIP for c-Jun at miR-589 promoter, Western blot, in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct luciferase validation of miRNA-target interaction + ChIP for transcription factor binding, single lab\",\n      \"pmids\": [\"30012200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nuclear PAK4 promotes bone metastasis of ERα-positive breast cancer by targeting LIFR; PAK4 binds ERα and co-translocates to the nucleus upon E2 stimulation, repressing LIFR expression as a bone metastasis suppressor.\",\n      \"method\": \"Co-immunoprecipitation of PAK4-ERα, nuclear fractionation, LIFR expression analysis upon PAK4 nuclear accumulation, in vitro invasion and in vivo metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and nuclear fractionation with functional in vivo validation, single lab\",\n      \"pmids\": [\"30177834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-377-3p directly binds the 3'-UTR of LIFR to suppress LIFR expression and inhibit adipogenic differentiation of human bone marrow mesenchymal stem cells; LIFR expression increases during adipogenesis and its knockdown inhibits adipocyte differentiation.\",\n      \"method\": \"Luciferase reporter assay for miR-377-3p binding to LIFR 3'-UTR, LIFR knockdown with siRNA, adipogenic differentiation assays\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct luciferase validation of miRNA-target interaction with functional differentiation readout, single lab\",\n      \"pmids\": [\"29959592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ILEI (FAM3C) signals through LIFR as its receptor to activate STAT3 and drive both EMT and breast cancer stem cell formation; reduction of either ILEI or LIFR reduces tumor growth, tumor-initiating cells, and metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation of ILEI-LIFR interaction, LIFR knockdown rescue experiments, in vivo tumor and metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identification of ligand-receptor pair by co-IP, double knockdown epistasis, in vivo validation with multiple functional readouts\",\n      \"pmids\": [\"30692635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EC359, a small-molecule inhibitor, directly interacts with LIFR to block LIF/LIFR interactions and attenuates downstream STAT3, mTOR, and AKT activation in TNBC; EC359 also blocks signaling by other LIFR ligands (CTF1, CNTF, OSM) that interact at the LIF/LIFR interface.\",\n      \"method\": \"Direct binding assay of EC359 to LIFR, LIF/LIFR interaction blocking assay, Western blot for downstream signaling, TNBC xenograft and PDX models\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct ligand-receptor interaction blocking demonstrated biochemically, multiple downstream pathway assays, in vivo xenograft validation\",\n      \"pmids\": [\"31142661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LIFR phosphorylation at S1044 by ERK2 (but not ERK1) promotes AKT pathway activation, inducing expression of proliferation and metastatic genes in prostate cancer; pLIFR-S1044 and pAKT S473 show tight positive correlation in PCa tissue.\",\n      \"method\": \"Phospho-specific Western blot, ERK1/ERK2 siRNA knockdown, LIFR S1044 mutant constructs, AKT pathway readouts, IHC of patient tissue\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — phosphosite mutagenesis with kinase specificity determination and downstream pathway readout, single lab\",\n      \"pmids\": [\"30851421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes intracellular iron and confers resistance to ferroptosis inducers; this LIFR-NF-κB-LCN2 axis promotes liver tumorigenesis.\",\n      \"method\": \"Hepatocyte-specific Lifr knockout mice, mechanistic pathway dissection (SHP1, NF-κB, LCN2), LCN2-neutralizing antibody rescue experiments, PDX tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional knockout with mechanistic pathway dissection (SHP1→NF-κB→LCN2), antibody rescue in PDX models, multiple orthogonal methods\",\n      \"pmids\": [\"34921145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC inhibitors epigenetically induce LIFR expression by increasing histone acetylation in the proximal LIFR promoter, activating a pro-dormancy program in breast cancer cells; hypoxia increases H3K9me3 and decreases H3K9ac at the distal LIFR promoter to repress LIFR, and PTHrP binds the distal LIFR promoter to suppress its expression.\",\n      \"method\": \"ChIP for histone marks at LIFR promoter, HDACi treatment, PTHrP ChIP, LIFR expression and dormancy marker assays\",\n      \"journal\": \"Journal of bone oncology / Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with multiple histone marks, pharmacological rescue, two independent mechanisms of LIFR repression validated, single lab\",\n      \"pmids\": [\"34247191\", \"34934614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Adipocyte-specific LIFR knockout mice on high-fat diet show reduced adipose STAT3 activation, 50% expansion in adipose tissue, 20% body weight increase, and 75% reduction in hepatic triacylglycerides compared to controls; adipocyte-specific STAT3 knockout recapitulates these findings, demonstrating that LIFR signals through JAK/STAT3 in adipocytes to limit adipose expansion and contribute to ectopic liver fat accumulation.\",\n      \"method\": \"Adipoq-Cre;LIFR-KO and Adipoq-Cre;STAT3-KO mouse models, HFD feeding, STAT3 phosphorylation assays, LIF-induced lipolysis assays in differentiated adipocytes\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two parallel conditional knockout models (LIFR and STAT3) with convergent phenotypes, direct STAT3 signaling validation in differentiated adipocytes\",\n      \"pmids\": [\"33748712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ILEI promotes renal interstitial fibrosis EMT by binding and activating LIFR, with downstream phosphorylation of Akt and ERK; co-immunoprecipitation confirmed ILEI-LIFR complex formation in vitro.\",\n      \"method\": \"Co-immunoprecipitation of ILEI-LIFR, ILEI overexpression/knockdown, Western blot for pAkt and pERK, UUO mouse model, patient kidney tissue IHC\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirming ILEI-LIFR interaction with downstream signaling validation, in vivo UUO model, and patient tissue correlation\",\n      \"pmids\": [\"35093095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OSMR deficiency activates OSM/LIFR/STAT3 signaling and aggravates cardiac hypertrophy; adenoviral knockdown of LIFR in myocardial tissue (Ad-shLIFR) ameliorates the hypertrophic phenotype and STAT3 activation caused by OSMR deletion, placing LIFR downstream of OSM/OSMR in cardiac signaling.\",\n      \"method\": \"OSMR knockout mice with aortic banding, Ad-shLIFR adenoviral knockdown, Western blot for STAT3 activation, macrophage adoptive transfer experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (OSMR-KO + LIFR knockdown rescue) with functional cardiac phenotype readout\",\n      \"pmids\": [\"37120549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A synthetic cytokimera GIL-11 (exchanging the gp130-binding site III of IL-11 with the LIFR-binding site III of LIF) efficiently recruits a non-natural receptor complex of gp130:IL-11R:LIFR, inducing signal transduction and cell proliferation; GIL-11 rescued IL-6R-deficient mice after partial hepatectomy, demonstrating functional gp130:IL-11R:LIFR signaling in liver regeneration.\",\n      \"method\": \"Cytokimera protein engineering, Ba/F3 cell proliferation assay, signaling assays in factor-dependent cells, IL-6R-knockout mouse partial hepatectomy survival model\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — engineered cytokimera with defined receptor complex reconstitution, cell signaling validation, and in vivo functional rescue in KO mice\",\n      \"pmids\": [\"37061565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In response to liver damage, LIFR from hepatocytes promotes secretion of cholesterol and CXCL1 in a STAT3-dependent manner, mobilizing bone marrow neutrophils to the circulation and damaged liver; cholesterol then stimulates neutrophils via ERRα to secrete hepatocyte growth factor, accelerating hepatocyte proliferation and liver regeneration.\",\n      \"method\": \"Hepatocyte-specific Lifr knockout and overexpression mouse models, partial hepatectomy and toxic injury models, STAT3 pathway inhibition, cholesterol/CXCL1 measurement, ERRα receptor antagonism, HGF measurement\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout and overexpression with pharmacological pathway dissection, multiple in vivo models, bidirectional signaling axis defined\",\n      \"pmids\": [\"39147934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNORA28 acts as a molecular decoy recruiting BRD4, which increases H3K9 acetylation at the LIFR promoter region, stimulating LIFR transcription and activating the JAK1/STAT3 pathway to enhance CRC cell proliferation and radioresistance.\",\n      \"method\": \"ChIP for BRD4 and H3K9ac at LIFR promoter, SNORA28 overexpression/knockdown, Western blot for JAK1/STAT3, in vitro and in vivo proliferation/radiation survival assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP with functional pathway readout, single lab\",\n      \"pmids\": [\"38424373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IFN-τ-induced IRF1 transactivates LIFR transcription by directly binding to the LIFR promoter, upregulating LIFR expression and enhancing bovine endometrial receptivity; LIFR knockdown blocks the pro-receptivity effects of IRF1.\",\n      \"method\": \"Dual-luciferase reporter assay (IRF1 binding to LIFR promoter), IRF1 overexpression/siRNA, LIFR knockdown epistasis, endometrial receptivity marker expression\",\n      \"journal\": \"Journal of reproductive immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct promoter binding validated by luciferase assay with epistasis knockdown, single lab, bovine system\",\n      \"pmids\": [\"38432052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Uterine epithelium-specific Lifr knockout mice are completely infertile; gene expression analysis identified ERBB2 and c-Fos as hub regulators downstream of LIFR (and Gp130) in uterine epithelium before implantation, and pharmacological ERBB2 inhibition confirmed that LIFR-ERBB2-mediated signaling plays a crucial role in embryo implantation.\",\n      \"method\": \"Uterine epithelium-specific Lifr knockout mice, comprehensive endometrial gene expression analysis, ERBB2 inhibitor treatment, comparison with Gp130 eKO mice\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with transcriptomic analysis and pharmacological validation of downstream effector, single lab, recent publication\",\n      \"pmids\": [\"40427591\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LIFR is a transmembrane receptor subunit that heterodimerizes with gp130 (and optionally CNTFRα) in response to IL-6 family cytokines (LIF, CNTF, CT-1, OSM, ILEI/FAM3C), triggering JAK/STAT3, PI3K/AKT, and MAPK signaling; its cytoplasmic YXXQ motif tyrosines are required for STAT3 activation, while juxtamembrane acetylation by p300 promotes self-renewal dimerization and C-terminal SPXX phosphorylation by MAPK promotes differentiation, with receptor stability regulated by opposing lysosomal degradation and proteasomal/NF-κB-dependent stabilization, and LIFR abundance controlled epigenetically by histone acetylation at its promoter and transcriptionally by IRF1, BRD4, and PTHrP.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LIFR (LIFRβ) is a transmembrane signaling receptor subunit that, upon binding IL-6 family cytokines, heterodimerizes with gp130 to form the functional LIF receptor and, with addition of CNTFRα, converts the bipartite complex into a tripartite CNTF receptor, triggering ligand-induced tyrosine phosphorylation and downstream JAK/STAT3 signaling [#0, #5]. The cytoplasmic domain alone is sufficient to drive signaling when dimerized, with two membrane-distal YXXQ tyrosines required for STAT3 activation and the resulting growth-arrest/differentiation output [#1]. Receptor output is tuned by competing post-translational modifications of the cytoplasmic tail: juxtamembrane acetylation by p300 promotes LIFR homodimerization and self-renewal-associated STAT3 activity, while MAPK phosphorylation of C-terminal SPXX repeats restricts STAT3 and favors differentiation [#13]. LIFR also serves as a receptor for additional ligands including ILEI/FAM3C, which activates STAT3, AKT, and ERK to drive EMT and stem-cell programs [#19, #25], and the receptor interface can be pharmacologically blocked by the small molecule EC359 to suppress LIF/LIFR-driven STAT3, mTOR, and AKT signaling [#20]. Across tissues LIFR controls cell-fate and homeostatic programs: it sustains mouse embryonic stem cell self-renewal in concert with E-cadherin-stabilized receptor complexes [#9, #13], constrains adipose expansion via adipocyte STAT3 signaling [#24], and orchestrates STAT3-dependent hepatocyte programs driving liver regeneration [#28]. In cancer, LIFR acts as a context-dependent metastasis suppressor—restraining PI3K/AKT/JAK1 signaling and enforcing tumor-cell dormancy through a LIFR:STAT3:SOCS3 axis—whose loss derepresses an NF-κB→LCN2 ferroptosis-resistance program [#11, #12, #22]. LIFR abundance is heavily regulated, transcriptionally by IRF1, BRD4/SNORA28, and PTHrP and post-transcriptionally by miRNAs targeting its 3'-UTR, and by opposing lysosomal degradation versus proteasome/NF-κB-dependent stabilization [#6, #16, #23, #29, #30]. Null and missense mutations that destabilize LIFR mRNA or protein cause Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome and urinary tract malformations, establishing LIFR as essential for development [#3, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the core architecture of LIFR signaling by showing it is a non-signaling-alone subunit that must heterodimerize with gp130, and that adding CNTFRα reconfigures the complex for CNTF.\",\n      \"evidence\": \"Co-immunoprecipitation and receptor reconstitution with tyrosine phosphorylation assays in transfected cells\",\n      \"pmids\": [\"8390097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural geometry of the LIFR:gp130 complex not resolved\", \"Identity of associated JAKs not defined here\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapped the signaling output to the LIFR cytoplasmic domain and identified the membrane-distal YXXQ tyrosines as the determinants of STAT3 activation and differentiation.\",\n      \"evidence\": \"Forced homodimerization of LIFR cytoplasmic constructs with YXXQ mutagenesis and differentiation assays in myeloid leukemia cells\",\n      \"pmids\": [\"11042511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address contributions of other cytoplasmic motifs\", \"Performed in artificial homodimerization system, not native ligand-driven complex\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the extracellular determinants of ligand selectivity, showing the membrane-distal CBD1 domain binds CNTFRα and that the N-terminal domain is specifically required for CNTF signaling.\",\n      \"evidence\": \"In vitro domain binding and blocking assays plus deletion mutagenesis with CNTF/LIF/OSM signaling readouts\",\n      \"pmids\": [\"11943154\", \"16051226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vitro/overexpression data\", \"Atomic-level interface mapping not performed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked LIFR loss-of-function to human disease, showing null mutations destabilize LIFR mRNA, abolish protein, and impair JAK/STAT3 signaling, causing Stüve-Wiedemann/Schwartz-Jampel type 2 syndrome.\",\n      \"evidence\": \"Genetic mapping and mutation sequencing in 19 families with mRNA stability and STAT3 phosphorylation studies in patient cells\",\n      \"pmids\": [\"14740318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific developmental requirements not fully resolved\", \"Mechanism linking signaling loss to skeletal/dysautonomic phenotypes incomplete\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished the assembly dynamics of LIFR-containing complexes, showing LIFR:gp130 heterodimerization is ligand-triggered rather than preformed, unlike gp130 homodimers.\",\n      \"evidence\": \"FRET and BiFC live-cell imaging of tagged receptors with cytokine stimulation\",\n      \"pmids\": [\"16254248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of disassembly not characterized\", \"Did not address CNTFRα-containing tripartite assembly dynamics\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed that LIFR signaling capacity is set by receptor abundance, controlled by opposing lysosomal degradation and proteasome/NF-κB-dependent stabilization.\",\n      \"evidence\": \"Pharmacological lysosome/proteasome and NF-κB inhibition with LIFR and pSTAT3 Western blot in RBE4 cells\",\n      \"pmids\": [\"17873291\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligases and trafficking adaptors not identified\", \"Single-lab pharmacological evidence without genetic confirmation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected cell adhesion to LIFR signaling competence by showing E-cadherin associates with and is required for proper LIFR/gp130/STAT3 activation in stem cells.\",\n      \"evidence\": \"β-catenin-null mESCs, cadherin-catenin fusion rescue, co-IP, and STAT3 rescue experiments\",\n      \"pmids\": [\"23487312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect nature of E-cadherin–receptor association not fully resolved\", \"Generality beyond mESCs untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a tumor-suppressive role for LIFR in enforcing disseminated cancer-cell dormancy via a LIFR:STAT3:SOCS3 program.\",\n      \"evidence\": \"LIFR/STAT3 knockdown and knockout with expression profiling and in vivo bone colonization assays\",\n      \"pmids\": [\"27642788\", \"26249360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream cytokine driving the dormancy signal in vivo not defined\", \"How dormancy is reawakened upon LIFR loss mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved how LIFR cytoplasmic modifications bidirectionally control fate, with p300 acetylation driving self-renewal dimerization and MAPK SPXX phosphorylation driving differentiation, and tied missense mutations to receptor instability and developmental malformation.\",\n      \"evidence\": \"Domain mutagenesis, p300 acetylation and MAPK assays, dimerization/STAT3 readouts in mESCs, plus patient variant stability/localization studies and Lifr knockout mice\",\n      \"pmids\": [\"28122243\", \"28334964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative interplay between acetylation and phosphorylation under physiological signaling not mapped\", \"Full spectrum of LIFR-dependent organogenesis defects incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the LIFR ligand repertoire and identified druggable interfaces, establishing ILEI/FAM3C as a LIFR ligand driving EMT/stemness and EC359 as a direct LIFR-interface inhibitor blocking multiple ligands, while phospho-S1044 by ERK2 was shown to route LIFR into AKT signaling.\",\n      \"evidence\": \"Co-IP of ligand-receptor pairs, double-knockdown epistasis, in vivo tumor models, direct binding inhibition assays, and phosphosite mutagenesis with kinase-specificity tests\",\n      \"pmids\": [\"30692635\", \"31142661\", \"30851421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ILEI binding interface on LIFR not structurally defined\", \"Whether S1044 phosphorylation occurs in normal physiology untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistically explained LIFR loss in liver cancer through a SHP1→NF-κB→LCN2 iron-sequestering axis conferring ferroptosis resistance, and demonstrated LIFR's homeostatic role limiting adipose expansion via adipocyte STAT3.\",\n      \"evidence\": \"Hepatocyte- and adipocyte-specific Lifr (and STAT3) knockout mice with pathway dissection and antibody/PDX rescue\",\n      \"pmids\": [\"34921145\", \"33748712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LIFR loss engages SHP1 mechanistically not fully defined\", \"Relationship between metabolic and tumor-suppressive functions unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the transcriptional and post-transcriptional control of LIFR abundance via histone acetylation, PTHrP, hypoxia, and 3'-UTR-targeting miRNAs.\",\n      \"evidence\": \"ChIP for histone marks/PTHrP, HDAC inhibitor treatment, and luciferase 3'-UTR reporter assays for miR-589/miR-377-3p\",\n      \"pmids\": [\"34247191\", \"34934614\", \"30012200\", \"29959592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each regulatory layer in vivo unclear\", \"Single-lab data for individual miRNA interactions\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established LIFR as a driver of regenerative and reproductive signaling programs, orchestrating hepatocyte STAT3-dependent cholesterol/CXCL1-mediated neutrophil recruitment for liver regeneration and LIFR-ERBB2 signaling required for embryo implantation, with transcriptional induction by IRF1 and BRD4/SNORA28.\",\n      \"evidence\": \"Hepatocyte- and uterine-specific Lifr knockout/overexpression mice, pharmacological pathway dissection, ERBB2 inhibition, and ChIP/luciferase promoter studies\",\n      \"pmids\": [\"39147934\", \"40427591\", \"38432052\", \"38424373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-tissue conservation of these effector axes untested\", \"How a single receptor selects distinct downstream effectors per tissue unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LIFR's identical signaling machinery is wired to opposing outcomes—self-renewal versus differentiation, tumor suppression versus tumor promotion, across diverse tissues—remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling LIFR's tumor-suppressive and tumor-promoting roles\", \"No high-resolution structure of native LIFR:gp130 or ligand-specific complexes\", \"Determinants of tissue-specific effector selection (STAT3 vs AKT vs ERK) unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004888\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 14, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 13, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [24, 28]}\n    ],\n    \"complexes\": [\n      \"LIFR:gp130 (LIF receptor)\",\n      \"CNTFRα:LIFR:gp130 (CNTF receptor)\",\n      \"gp130:IL-11R:LIFR (engineered GIL-11 complex)\"\n    ],\n    \"partners\": [\n      \"IL6ST\",\n      \"CNTFR\",\n      \"CDH1\",\n      \"FAM3C\",\n      \"EP300\",\n      \"PAK4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"LIFR","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"sparse","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 38424373"},"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}