Affinage

LIFR

Leukemia inhibitory factor receptor · UniProt P42702

Audit flag: ungrounded claim
Length
1097 aa
Mass
123.7 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    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

    PMID:8390097

    Open questions at the time
    • Stoichiometry and structural geometry of the LIFR:gp130 complex not resolved
    • Identity of associated JAKs not defined here
  2. 2000 High

    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

    PMID:11042511

    Open questions at the time
    • Did not address contributions of other cytoplasmic motifs
    • Performed in artificial homodimerization system, not native ligand-driven complex
  3. 2002 Medium

    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

    PMID:11943154 PMID:16051226

    Open questions at the time
    • Single-lab in vitro/overexpression data
    • Atomic-level interface mapping not performed
  4. 2004 High

    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

    PMID:14740318

    Open questions at the time
    • Tissue-specific developmental requirements not fully resolved
    • Mechanism linking signaling loss to skeletal/dysautonomic phenotypes incomplete
  5. 2005 High

    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

    PMID:16254248

    Open questions at the time
    • Kinetics of disassembly not characterized
    • Did not address CNTFRα-containing tripartite assembly dynamics
  6. 2007 Medium

    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

    PMID:17873291

    Open questions at the time
    • E3 ligases and trafficking adaptors not identified
    • Single-lab pharmacological evidence without genetic confirmation
  7. 2013 High

    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

    PMID:23487312

    Open questions at the time
    • Direct vs indirect nature of E-cadherin–receptor association not fully resolved
    • Generality beyond mESCs untested
  8. 2016 High

    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

    PMID:26249360 PMID:27642788

    Open questions at the time
    • Upstream cytokine driving the dormancy signal in vivo not defined
    • How dormancy is reawakened upon LIFR loss mechanistically incomplete
  9. 2017 High

    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

    PMID:28122243 PMID:28334964

    Open questions at the time
    • Quantitative interplay between acetylation and phosphorylation under physiological signaling not mapped
    • Full spectrum of LIFR-dependent organogenesis defects incomplete
  10. 2019 High

    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

    PMID:30692635 PMID:30851421 PMID:31142661

    Open questions at the time
    • ILEI binding interface on LIFR not structurally defined
    • Whether S1044 phosphorylation occurs in normal physiology untested
  11. 2021 High

    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

    PMID:33748712 PMID:34921145

    Open questions at the time
    • How LIFR loss engages SHP1 mechanistically not fully defined
    • Relationship between metabolic and tumor-suppressive functions unresolved
  12. 2021 Medium

    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

    PMID:29959592 PMID:30012200 PMID:34247191 PMID:34934614

    Open questions at the time
    • Relative contribution of each regulatory layer in vivo unclear
    • Single-lab data for individual miRNA interactions
  13. 2024 High

    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

    PMID:38424373 PMID:38432052 PMID:39147934 PMID:40427591

    Open questions at the time
    • Cross-tissue conservation of these effector axes untested
    • How a single receptor selects distinct downstream effectors per tissue unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2
Partners
CDH1CNTFREP300FAM3CIL6STPAK4
Complex memberships
CNTFRα:LIFR:gp130 (CNTF receptor)LIFR:gp130 (LIF receptor)gp130:IL-11R:LIFR (engineered GIL-11 complex)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 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. Co-immunoprecipitation, receptor reconstitution, tyrosine phosphorylation assays in transfected cells Science High 8390097
2000 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. Forced homodimerization of LIFR cytoplasmic domain constructs, site-directed mutagenesis of YXXQ tyrosines, differentiation assays in WEHI-3B D+ cells Leukemia & lymphoma High 11042511
2002 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. In vitro binding assay with purified domains, functional blocking assay in Ntera/D1 cells FEBS letters Medium 11943154
2004 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. Genetic mapping, mutation identification by sequencing, functional studies of LIFR mRNA stability and JAK/STAT3 phosphorylation in patient-derived cells American journal of human genetics High 14740318
2005 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. Overexpression of LIFR deletion mutant in cells, CNTF/LIF/OSM signaling assays FEBS letters Medium 16051226
2005 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. FRET (YFP/CFP-tagged receptors), bimolecular fluorescence complementation (BiFC) in live cells Journal of cell science High 16254248
2007 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. Lysosomal and proteasomal inhibitor treatments, NF-κB inhibition, Western blot for LIFR and pSTAT3 in RBE4 cells Journal of molecular neuroscience Medium 17873291
2009 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. Quantitative PCR, LIFR antagonist treatment, STAT3 phosphorylation assay, photoreceptor survival assay in rat retina Neurobiology of disease Medium 19344761
2010 Neuropoietin activates STAT3 in adipocytes independently of LIFR phosphorylation and degradation, despite signaling through gp130; NP stimulation causes phosphorylation of gp130 but not LIFR. Western blot for phospho-LIFR and phospho-gp130 in adipocytes after NP stimulation, LIFR degradation assays Biochemical and biophysical research communications Medium 20353755
2013 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. Genetic knockout (β-catenin-null mESCs), E-cadherin–α-catenin fusion rescue, co-immunoprecipitation of E-cadherin with LIFR/Gp130, Western blot for pSTAT3 Development High 23487312
2014 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. Immunoprecipitation of receptor binding, STAT3 phosphorylation assays, cytokine-dependent cellular proliferation assays Journal of biological chemistry Medium 24802752
2015 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. LIFR knockdown and overexpression, Western blot for pJAK1, pAKT, MMP13, in vitro migration/invasion assays, in vivo xenograft metastasis models Carcinogenesis Medium 26249360
2016 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. LIFR and STAT3 knockdown/knockout, gene expression profiling, in vivo bone colonization assays Nature cell biology High 27642788
2017 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. Domain mutagenesis, p300 co-immunoprecipitation/acetylation assay, MAPK phosphorylation assays, LIFR dimerization assays, STAT3 activation readouts in mESCs Cell reports High 28122243
2017 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. Whole-exome sequencing, LIFR mutant half-life assays, cell membrane localization assays, STAT3 phosphorylation assays, Lifr knockout mouse phenotyping Human molecular genetics High 28334964
2018 LIFR promotes tumor angiogenesis in colorectal cancer through ERK phosphorylation-driven upregulation of IL-8; IL-8 depletion reduces LIFR-induced angiogenic activity. LIFR knockdown/overexpression, IL-8 neutralization, ERK phosphorylation Western blot, in vitro/in vivo angiogenesis assays Biochimica et biophysica acta. Molecular basis of disease Medium 29751081
2018 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. Dual-luciferase reporter assay (miR-589 targeting LIFR 3'-UTR), ChIP for c-Jun at miR-589 promoter, Western blot, in vivo xenograft Journal of experimental & clinical cancer research Medium 30012200
2018 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. Co-immunoprecipitation of PAK4-ERα, nuclear fractionation, LIFR expression analysis upon PAK4 nuclear accumulation, in vitro invasion and in vivo metastasis assays Oncogene Medium 30177834
2018 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. Luciferase reporter assay for miR-377-3p binding to LIFR 3'-UTR, LIFR knockdown with siRNA, adipogenic differentiation assays Molecular and cellular biochemistry Medium 29959592
2019 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. Co-immunoprecipitation of ILEI-LIFR interaction, LIFR knockdown rescue experiments, in vivo tumor and metastasis assays Oncogene High 30692635
2019 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. Direct binding assay of EC359 to LIFR, LIF/LIFR interaction blocking assay, Western blot for downstream signaling, TNBC xenograft and PDX models Molecular cancer therapeutics High 31142661
2019 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. Phospho-specific Western blot, ERK1/ERK2 siRNA knockdown, LIFR S1044 mutant constructs, AKT pathway readouts, IHC of patient tissue Cancer letters Medium 30851421
2021 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. Hepatocyte-specific Lifr knockout mice, mechanistic pathway dissection (SHP1, NF-κB, LCN2), LCN2-neutralizing antibody rescue experiments, PDX tumor models Nature communications High 34921145
2021 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. ChIP for histone marks at LIFR promoter, HDACi treatment, PTHrP ChIP, LIFR expression and dormancy marker assays Journal of bone oncology / Oncogene Medium 34247191 34934614
2021 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. Adipoq-Cre;LIFR-KO and Adipoq-Cre;STAT3-KO mouse models, HFD feeding, STAT3 phosphorylation assays, LIF-induced lipolysis assays in differentiated adipocytes iScience High 33748712
2022 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. Co-immunoprecipitation of ILEI-LIFR, ILEI overexpression/knockdown, Western blot for pAkt and pERK, UUO mouse model, patient kidney tissue IHC Journal of translational medicine Medium 35093095
2023 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. OSMR knockout mice with aortic banding, Ad-shLIFR adenoviral knockdown, Western blot for STAT3 activation, macrophage adoptive transfer experiments Journal of translational medicine Medium 37120549
2023 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. Cytokimera protein engineering, Ba/F3 cell proliferation assay, signaling assays in factor-dependent cells, IL-6R-knockout mouse partial hepatectomy survival model Communications biology High 37061565
2024 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. 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 Nature metabolism High 39147934
2024 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. 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 Advanced science Medium 38424373
2024 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. Dual-luciferase reporter assay (IRF1 binding to LIFR promoter), IRF1 overexpression/siRNA, LIFR knockdown epistasis, endometrial receptivity marker expression Journal of reproductive immunology Medium 38432052
2025 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. Uterine epithelium-specific Lifr knockout mice, comprehensive endometrial gene expression analysis, ERBB2 inhibitor treatment, comparison with Gp130 eKO mice Biomolecules Medium 40427591

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science (New York, N.Y.) 624 8390097
2021 A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nature communications 267 34921145
2016 Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nature cell biology 207 27642788
2004 Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome. American journal of human genetics 151 14740318
2017 Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4. Oncogene 99 29269867
2021 Targeting LIF/LIFR signaling in cancer. Genes & diseases 97 35685476
1998 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. Brain research 86 9630704
1995 Oligodendroblasts distinguished from O-2A glial progenitors by surface phenotype (O4+GalC-) and response to cytokines using signal transducer LIFR beta. Developmental biology 74 7875381
2019 TGFβ promotes breast cancer stem cell self-renewal through an ILEI/LIFR signaling axis. Oncogene 71 30692635
2019 EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer. Molecular cancer therapeutics 67 31142661
2005 Dimerization of the cytokine receptors gp130 and LIFR analysed in single cells. Journal of cell science 67 16254248
2021 Macrophages-derived exosomal lncRNA LIFR-AS1 promotes osteosarcoma cell progression via miR-29a/NFIA axis. Cancer cell international 62 33794884
2018 Functional role of a long non-coding RNA LIFR-AS1/miR-29a/TNFAIP3 axis in colorectal cancer resistance to pohotodynamic therapy. Biochimica et biophysica acta. Molecular basis of disease 61 29807108
2015 LIFR functions as a metastasis suppressor in hepatocellular carcinoma by negatively regulating phosphoinositide 3-kinase/AKT pathway. Carcinogenesis 61 26249360
2009 Preconditioning-induced protection from oxidative injury is mediated by leukemia inhibitory factor receptor (LIFR) and its ligands in the retina. Neurobiology of disease 60 19344761
2018 miR-589 promotes gastric cancer aggressiveness by a LIFR-PI3K/AKT-c-Jun regulatory feedback loop. Journal of experimental & clinical cancer research : CR 56 30012200
2013 E-cadherin is required for the proper activation of the Lifr/Gp130 signaling pathway in mouse embryonic stem cells. Development (Cambridge, England) 54 23487312
2009 Leukemia inhibitory factor receptor (LIFR) is detected as a novel suppressor gene of hepatocellular carcinoma using double-combination array. Cancer letters 54 19733004
1996 Expression of leukaemia inhibitory factor receptor subunits LIFR beta and gp130 in human oocytes and preimplantation embryos. Molecular human reproduction 49 9238703
2005 Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuates ischemic brain injury in rats. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 45 15716858
2020 lncRNA LIFR-AS1 suppresses invasion and metastasis of non-small cell lung cancer via the miR-942-5p/ZNF471 axis. Cancer cell international 43 32489316
2021 LncRNA LIFR-AS1 promotes proliferation and invasion of gastric cancer cell via miR-29a-3p/COL1A2 axis. Cancer cell international 42 33407453
2018 LIFR promotes tumor angiogenesis by up-regulating IL-8 levels in colorectal cancer. Biochimica et biophysica acta. Molecular basis of disease 41 29751081
2020 Novel Long Non-coding RNA lncAMPC Promotes Metastasis and Immunosuppression in Prostate Cancer by Stimulating LIF/LIFR Expression. Molecular therapy : the journal of the American Society of Gene Therapy 40 32592689
2020 Leukemia inhibitory factor promotes gastric cancer cell proliferation, migration, and invasion via the LIFR-Hippo-YAP pathway. Annals of the New York Academy of Sciences 40 32827446
2021 HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer. Oncogene 39 34247191
2018 A mandatory role of nuclear PAK4-LIFR axis in breast-to-bone metastasis of ERα-positive breast cancer cells. Oncogene 37 30177834
2020 EGFR-upregulated LIFR promotes SUCLG2-dependent castration resistance and neuroendocrine differentiation of prostate cancer. Oncogene 35 32963351
1993 The leukemia inhibitory factor receptor (LIFR) gene is located within a cluster of cytokine receptor loci on mouse chromosome 15 and human chromosome 5p12-p13. Genomics 35 8276403
2014 Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology. Orphanet journal of rare diseases 34 24618404
2019 LIFR-AS1 modulates Sufu to inhibit cell proliferation and migration by miR-197-3p in breast cancer. Bioscience reports 33 31127025
2021 LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer. Cell death discovery 31 34400617
2021 M6A-mediated up-regulation of LncRNA LIFR-AS1 enhances the progression of pancreatic cancer via miRNA-150-5p/ VEGFA/Akt signaling. Cell cycle (Georgetown, Tex.) 30 34658294
2017 Mutations in the leukemia inhibitory factor receptor (LIFR) gene and Lifr deficiency cause urinary tract malformations. Human molecular genetics 28 28334964
2022 The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights. Biochimica et biophysica acta. Reviews on cancer 27 35680099
2009 Loss of mandibular lymph node integrity is associated with an increase in sensitivity to HSV-1 infection in CD118-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 27 19265146
2019 Phosphorylation of LIFR promotes prostate cancer progression by activating the AKT pathway. Cancer letters 26 30851421
2021 Hsa_circ_0001073 targets miR-626/LIFR axis to inhibit lung cancer progression. Environmental toxicology 25 33475233
2024 LIFR regulates cholesterol-driven bidirectional hepatocyte-neutrophil cross-talk to promote liver regeneration. Nature metabolism 24 39147934
2021 Lidocaine Suppresses Gastric Cancer Development Through Circ_ANO5/miR-21-5p/LIFR Axis. Digestive diseases and sciences 24 34050852
2021 miR-221-3p regulates hepatocellular carcinoma cell proliferation, migration and invasion via targeting LIFR. Annals of hepatology 24 34699986
2014 The amino acid exchange R28E in ciliary neurotrophic factor (CNTF) abrogates interleukin-6 receptor-dependent but retains CNTF receptor-dependent signaling via glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR). The Journal of biological chemistry 24 24802752
2024 SNORA28 Promotes Proliferation and Radioresistance in Colorectal Cancer Cells through the STAT3 Pathway by Increasing H3K9 Acetylation in the LIFR Promoter. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 23 38924373
2019 Utilizing cell line-derived organoids to evaluate the efficacy of a novel LIFR-inhibitor, EC359 in targeting pancreatic tumor stroma. Genes & cancer 23 30899415
2024 Super-Enhancer Driven LIF/LIFR-STAT3-SOX2 Regulatory Feedback Loop Promotes Cancer Stemness in Head and Neck Squamous Cell Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 39206755
2021 Long non-coding RNA LIFR-AS1 suppressed the proliferation, angiogenesis, migration and invasion of papillary thyroid cancer cells via the miR-31-5p/SIDT2 axis. Cell cycle (Georgetown, Tex.) 22 34781815
2018 miR-377-3p regulates adipogenic differentiation of human bone marrow mesenchymal stem cells by regulating LIFR. Molecular and cellular biochemistry 22 29959592
2022 The ILEI/LIFR complex induces EMT via the Akt and ERK pathways in renal interstitial fibrosis. Journal of translational medicine 21 35093095
2020 Long noncoding RNA LIFR-AS1 suppresses proliferation, migration and invasion and promotes apoptosis through modulating miR-4262/NF-κB pathway in glioma. Neurological research 21 33070767
2018 Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis. Journal of ethnopharmacology 21 29428242
2007 Opposing effects of proteasomes and lysosomes on LIFR: modulation by TNF. Journal of molecular neuroscience : MN 21 17873291
2005 Single inner cell masses yield embryonic stem cell lines differing in lifr expression and their developmental potential. Biochemical and biophysical research communications 21 15883053
2000 Structural and functional studies on the leukemia inhibitory factor receptor (LIF-R): gene and soluble form of LIF-R, and cytoplasmic domain of LIF-R required for differentiation and growth arrest of myeloid leukemic cells. Leukemia & lymphoma 21 11042511
2021 LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer. Communications biology 20 34716410
2017 LIF endometrial expression is impaired in women with unexplained infertility while LIF-R expression in all infertility sub-groups. Cytokine 20 28432985
2021 Cynaropicrin Shows Antitumor Progression Potential in Colorectal Cancer Through Mediation of the LIFR/STATs Axis. Frontiers in cell and developmental biology 19 33505963
2021 LIFR-α-dependent adipocyte signaling in obesity limits adipose expansion contributing to fatty liver disease. iScience 19 33748712
2017 Opposing Roles of Acetylation and Phosphorylation in LIFR-Dependent Self-Renewal Growth Signaling in Mouse Embryonic Stem Cells. Cell reports 19 28122243
2001 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. Neurochemical research 18 11358282
2000 Expression of leukemia inhibitory factor (LIF) and LIF receptor (LIF-R) in the human adrenal cortex: implications for steroidogenesis. Molecular and cellular endocrinology 18 10854707
2024 Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis. NPJ precision oncology 17 38789520
2018 Synovial tissue quantitative proteomics analysis reveals paeoniflorin decreases LIFR and ASPN proteins in experimental rheumatoid arthritis. Drug design, development and therapy 17 29551890
2018 Quantitative proteome analysis identifies MAP2K6 as potential regulator of LIFR-induced radioresistance in nasopharyngeal carcinoma cells. Biochemical and biophysical research communications 17 30245131
1995 Expression patterns of leukaemia inhibitory factor receptor (LIFR) and the gp130 receptor component in rabbit uterus during early pregnancy. Journal of reproduction and fertility 17 7616497
2020 lncRNA LIFR‑AS1 inhibits gastric carcinoma cell proliferation, migration and invasion by sponging miR‑4698. Molecular medicine reports 16 33355363
2016 LIF and LIF‑R expression in the endometrium of fertile and infertile women: A prospective observational case‑control study. Molecular medicine reports 16 27082016
2010 Neuropoietin activates STAT3 independent of LIFR activation in adipocytes. Biochemical and biophysical research communications 16 20353755
2021 HDAC inhibitors stimulate LIFR when it is repressed by hypoxia or PTHrP in breast cancer. Journal of bone oncology 15 34934614
2023 The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling. International journal of molecular sciences 14 38139260
2022 LncRNA GAS5 Suppresses Colorectal Cancer Progress by Target miR-21/LIFR Axis. Evidence-based complementary and alternative medicine : eCAM 14 36062165
2011 A CD25⁻ positive population of activated B1 cells expresses LIFR and responds to LIF. Frontiers in immunology 14 22566797
2023 OSMR deficiency aggravates pressure overload-induced cardiac hypertrophy by modulating macrophages and OSM/LIFR/STAT3 signalling. Journal of translational medicine 13 37120549
2019 Mutation, methylation and expression analysis of LIFR gene in Indian breast cancer patients. Mutation research 12 31557600
2018 LIFR increases the release of soluble endoglin via the upregulation of MMP14 expression in preeclampsia. Reproduction (Cambridge, England) 12 29363569
2012 Exercise rescued chronic kidney disease by attenuating cardiac hypertrophy through the cardiotrophin-1 -> LIFR/gp 130 -> JAK/STAT3 pathway. European journal of preventive cardiology 12 23064267
2011 Expression of LIF and LIFR in periodontal tissue during orthodontic tooth movement. The Angle orthodontist 12 21446866
2022 Genome-wide screening for differentially methylated long noncoding RNAs identifies LIFR-AS1 as an epigenetically regulated lncRNA that inhibits the progression of colorectal cancer. Clinical epigenetics 11 36316703
2021 Circular RNA circARPP21 Acts as a Sponge of miR-543 to Suppress Hepatocellular Carcinoma by Regulating LIFR. OncoTargets and therapy 11 33584097
2002 Membrane distal cytokine binding domain of LIFR interacts with soluble CNTFR in vitro. FEBS letters 11 11943154
2024 Design, Synthesis, and Pharmacological Evaluation of Dual FXR-LIFR Modulators for the Treatment of Liver Fibrosis. Journal of medicinal chemistry 10 39382988
2023 Cytokimera GIL-11 rescued IL-6R deficient mice from partial hepatectomy-induced death by signaling via non-natural gp130:LIFR:IL-11R complexes. Communications biology 10 37061565
2022 Altered expression of leukemia inhibitory factor (LIF), LIFR, gp130, and IL11 in the embryo implantation site of rat model with prenatal androgen-induced polycystic ovary syndrome. Biochemical and biophysical research communications 10 35306361
2015 Non-truncating LIFR mutation: causal for prominent congenital pain insensitivity phenotype with progressive vertebral destruction? Clinical genetics 10 26285796
2008 Characterization, chromosomal assignment, and role of LIFR in early embryogenesis and stem cell establishment of rabbits. Cloning and stem cells 10 18956948
2017 A possible implication of reduced levels of LIF, LIFR, and gp130 in vasculopathy related to systemic sclerosis. Archives of dermatological research 9 29038846
2022 Circ_0003159 upregulates LIFR expression through competitively binding to miR-221-3p/miR-222-3p to block gastric cancer development. Journal of molecular histology 8 35034206
2022 Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth. Cancers 8 36358818
2016 Neuropathies of Stüve-Wiedemann Syndrome due to mutations in leukemia inhibitory factor receptor (LIFR) gene. Journal of neurology & neuromedicine 8 28058407
2011 Early changes of LIFR and gp130 in sciatic nerve and muscle of diabetic mice. Acta histochemica 8 21565387
2023 PCBP1 regulates LIFR through FAM3C to maintain breast cancer stem cell self-renewal and invasiveness. Cancer biology & therapy 7 37927213
2022 LncRNA LIFR-AS1 overexpression suppressed the progression of serous ovarian carcinoma. Journal of clinical laboratory analysis 7 35778954
2015 Intragenic Deletion in the LIFR Gene in a Long-Term Survivor with Stüve-Wiedemann Syndrome. Molecular syndromology 7 26279654
2005 The N-terminal cytokine binding domain of LIFR is required for CNTF binding and signaling. FEBS letters 7 16051226
2024 IFNT-induced IRF1 enhances bovine endometrial receptivity by transactivating LIFR. Journal of reproductive immunology 6 38432052
2024 COL5A2 drives regorafenib resistance-induced metastatic phenotype via reducing LIFR expression in hepatocellular carcinoma. Acta biochimica et biophysica Sinica 6 38818582
2024 Research progress of multi-target HDAC inhibitors blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway in the treatment of cancer. Bioorganic & medicinal chemistry 5 38964169
2021 Long non-coding RNA LIFR-AS1 regulates the proliferation, migration and invasion of human thyroid cancer cells. 3 Biotech 5 33927978
2025 LIFR-Mediated ERBB2 Signaling Is Essential for Successful Embryo Implantation in Mice. Biomolecules 4 40427591
2025 Harnessing the Estradienone Scaffold to Develop Dual GPBAR1 and LIFR Modulators for Liver Fibrosis. Journal of medicinal chemistry 4 40990291
2024 PTHrP intracrine actions divergently influence breast cancer growth through p27 and LIFR. Breast cancer research : BCR 4 38409028

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