Affinage

FGFR4

Fibroblast growth factor receptor 4 · UniProt P22455

Length
802 aa
Mass
88.0 kDa
Annotated
2026-06-09
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGFR4 is a receptor tyrosine kinase whose ligand-activated kinase signals through Shp2, PLCγ, PI3K/AKT, MAPK/ERK, and STAT pathways to drive cell transformation, proliferation, and survival (PMID:10918587). Productive FGF19 (and FGF21) engagement of FGFR4 strictly requires the co-receptor KLB, which mediates ligand binding to the receptor (PMID:22442730, PMID:36179047). In the liver, FGFR4 transduces FGF19/FGF4 signals to suppress bile acid biosynthesis and control plasma lipid homeostasis, acting through an intracellular FGFR4–LRH-1 node that downregulates CYP7A1/CYP8B1 downstream of FXR, while remaining dispensable for FGF19's glucose-handling effects (PMID:21437243, PMID:39393353, PMID:17664243). FGFR4 also acts as a cardiac signaling receptor: FGF23 binding (without klotho) on cardiomyocytes induces hypertrophy and increased contractility, and FGFR4 loss or blockade protects against left ventricular hypertrophy (PMID:28512310). In contrast, FGFR4 acts in concert with FGFR1/FGFR3 in the kidney for FGF23-mediated phosphate handling, where it is not the principal mediator (PMID:18753255, PMID:21139072). FGFR4 promotes survival through several substrate-directed mechanisms: it directly phosphorylates MST1 at Y433 to suppress MST1/2-dependent apoptosis (PMID:30903103), phosphorylates GSK-3β to activate β-catenin/TCF4 signaling and protect cells from ferroptosis (PMID:35562334), and tyrosine-phosphorylates IKKβ to inhibit its kinase activity and downregulate NF-κB signaling (PMID:21203561). During muscle regeneration, Fgfr4 is the transcriptional output of a MyoD–Tead2–Fgfr4 axis, and its loss impairs myotube differentiation (PMID:16267055). Activated FGFR4 is internalized by clathrin-mediated endocytosis and trafficked through early endosomes to recycling and trans-Golgi compartments, with endocytosis required for AKT and ERK signaling (PMID:27615514). Constitutively activating mutations (K650E, Y367C) and FGF19/FGFR4 dependency render tumor cells oncogenically addicted to FGFR4, supporting development of selective covalent inhibitors; the membrane-proximal G388R polymorphism exposes a STAT3 recruitment motif that enhances STAT3 phosphorylation and tumor cell motility (PMID:10918587, PMID:19946327, PMID:26675719, PMID:25776529). Acquired resistance to selective FGFR4 inhibitors arises through gatekeeper/hinge-1 kinase domain mutations or FGFR3-mediated redundancy (PMID:31575540, PMID:36179047).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Established that FGFR4 is a bona fide oncogenic kinase whose activity drives signaling through multiple canonical RTK effectors, defining the molecular basis of its downstream output.

    Evidence Activated K650E mutant overexpression in NIH3T3/PC12 with transformation, neurite outgrowth, and phospho-effector Westerns

    PMID:10918587

    Open questions at the time
    • Used an engineered activation-loop mutant rather than physiological ligand activation
    • Did not distinguish which effectors are required for transformation versus passively phosphorylated
  2. 2005 High

    Placed Fgfr4 as the transcriptional endpoint of a defined myogenic regulatory cascade, explaining its requirement in muscle regeneration.

    Evidence Fgfr4-null mice with staged regeneration plus promoter reporter, M-CAT mutagenesis, and ChIP defining MyoD–Tead2–Fgfr4

    PMID:16267055

    Open questions at the time
    • Downstream FGFR4 effectors mediating myotube differentiation not resolved
    • Relevant FGF ligand in regenerating muscle not identified
  3. 2007 High

    Defined hepatocyte FGFR4 as a systemic regulator of lipid metabolism and a determinant of fatty liver susceptibility, linking the receptor to whole-body metabolic control.

    Evidence FGFR4 KO mice with hepatocyte-specific transgenic rescue and metabolic phenotyping on normal/high-fat diet

    PMID:17664243

    Open questions at the time
    • The ligand and intracellular pathway connecting hepatic FGFR4 to lipid control not defined in this study
    • Mechanism of glucose intolerance phenotype unexplained
  4. 2008 High

    Clarified the tissue-specific division of labor among FGFRs by showing FGFR4 is not the principal renal FGF23 receptor, refining the receptor's physiological scope.

    Evidence FGFR4 KO crossed onto Hyp background with serum phosphate and 1,25(OH)2D readouts

    PMID:18753255

    Open questions at the time
    • Did not exclude redundant contribution with other FGFRs (later addressed)
    • Single disease-model background
  5. 2010 High

    Resolved the apparent dispensability of FGFR4 in renal FGF23 signaling by demonstrating functional redundancy with FGFR3 and a feedback loop to bone FGF23 expression.

    Evidence Compound Fgfr3/Fgfr4 KO on Hyp background with phosphate, 1,25(OH)2D, and Fgf23 measurements

    PMID:21139072

    Open questions at the time
    • Quantitative contribution of each FGFR not separated
    • Mechanism of compensatory FGF23 feedback unresolved
  6. 2010 High

    Identified an unexpected negative-regulatory branch in which FGFR4 directly inhibits NF-κB signaling by phosphorylating IKKβ, broadening FGFR4's substrate repertoire beyond canonical mitogenic effectors.

    Evidence Yeast two-hybrid, reciprocal Co-IP/MS, in vitro IKKβ kinase assay, EMSA, and nuclear fractionation

    PMID:21203561

    Open questions at the time
    • Physiological context where FGFR4 restrains NF-κB not established
    • IKKβ phospho-site not mapped
  7. 2011 High

    Dissected which FGF19 functions depend on FGFR4, separating bile acid suppression and hepatocyte proliferation from glucose/lipid effects.

    Evidence Fgfr4 KO mice combined with an FGF19 variant selectively impaired in FGFR4 activation; proliferation and bile acid readouts

    PMID:21437243

    Open questions at the time
    • Receptor mediating FGF19 metabolic effects not identified here
    • Downstream transcriptional mediators of bile acid suppression not defined
  8. 2012 High

    Established the KLB co-receptor requirement and ligand-binding selectivity that govern which endocrine FGFs activate FGFR4.

    Evidence Quantitative binding kinetics with KLB and FGFR1 genetic ablation plus tissue signaling readouts

    PMID:22442730

    Open questions at the time
    • Structural basis of differential FGF19 vs FGF21 affinity not resolved
    • Stoichiometry of FGF–KLB–FGFR4 complex not determined
  9. 2012 High

    Demonstrated FGFR4 is genetically required for FGF19-driven hepatocarcinogenesis and is druggable by ligand-blocking antibody, validating it as an oncology target.

    Evidence FGF19 Tg × FGFR4 KO epistasis plus LD1 blocking antibody in binding, colony, and xenograft assays

    PMID:22615798

    Open questions at the time
    • Did not define the survival pathway downstream of FGF19/FGFR4 in tumors
    • Antibody efficacy in patients not addressed
  10. 2015 High

    Provided a mechanistic explanation for the cancer-associated G388R polymorphism, showing it exposes a STAT3 recruitment motif that potentiates STAT3 signaling.

    Evidence Transmembrane domain analysis, STAT3 Co-IP with Arg388 vs Gly388, phospho-STAT3 assays, and knock-in/transgenic mice

    PMID:26675719

    Open questions at the time
    • Extent to which STAT3 enhancement explains all G388R phenotypes unclear
    • Interplay with other downstream pathways not quantified
  11. 2015 High

    Delivered the first highly selective covalent FGFR4 inhibitor exploiting a unique cysteine, enabling specific targeting of FGF19-amplified tumors.

    Evidence BLU9931 selectivity profiling, irreversible inhibition assay, and HCC xenograft models

    PMID:25776529

    Open questions at the time
    • Resistance liabilities not yet characterized in this study
    • Durability of response in vivo limited
  12. 2016 High

    Mapped activated FGFR4's proximal interactome and endocytic itinerary, linking clathrin-mediated internalization to productive AKT/ERK signaling.

    Evidence BirA*-FGFR4 proximity proteomics, 3D-SIM microscopy, and clathrin heavy-chain depletion with phospho-readouts

    PMID:27615514

    Open questions at the time
    • Functional roles of most of the 291 proximal proteins not validated
    • How endosomal compartmentalization differentially shapes each pathway not resolved
  13. 2017 High

    Defined a klotho-independent cardiac role in which FGF23 activates FGFR4 to drive pathological hypertrophy, extending FGFR4 biology to the heart.

    Evidence FGFR4 KO mice, selective inhibitor, and 5/6 nephrectomy CKD rat model with cardiac functional readouts

    PMID:28512310

    Open questions at the time
    • Cardiac intracellular effectors of FGF23/FGFR4 not fully mapped
    • Cofactor for klotho-independent activation not defined
  14. 2018 High

    Identified MST1 as a direct FGFR4 substrate (Y433), revealing a mechanism by which FGFR4 suppresses Hippo-pathway-dependent apoptosis.

    Evidence Kinase substrate screen, MS phospho-site mapping, Y433F mutagenesis, and apoptosis assays in HER2+ breast cancer cells

    PMID:30903103

    Open questions at the time
    • Generality of MST1 phosphorylation across FGFR4-dependent tissues unknown
    • Structural basis of FGFR4–MST1 recognition not determined
  15. 2019 High

    Defined the clinical resistance mechanism to selective FGFR4 inhibition as on-target kinase domain mutations, while confirming persistent pathway dependence.

    Evidence Clinical sequencing of fisogatinib-resistant HCC tumors with in vitro/in vivo validation and pan-FGFR inhibitor rescue

    PMID:31575540

    Open questions at the time
    • Frequency and co-occurrence of these mutations across patients not quantified
    • Strategies to pre-empt gatekeeper mutations not established
  16. 2022 High

    Showed FGFR4 phosphorylates GSK-3β to activate β-catenin/TCF4 signaling that suppresses ferroptosis and drives anti-HER2 resistance, connecting FGFR4 to redox/iron metabolism.

    Evidence Genome-wide CRISPR screen, phospho-GSK-3β Westerns, GSH/ROS/iron measurements, and PDX/organoid validation

    PMID:35562334

    Open questions at the time
    • Direct kinetics of FGFR4–GSK-3β phosphorylation not characterized
    • Generalizability beyond anti-HER2 resistant breast cancer unclear
  17. 2022 High

    Revealed a KLB-dependent FGFR3/FGFR4 redundancy that underlies de novo resistance to FGFR4-selective inhibitors in HCC.

    Evidence Co-association assays, KLB mutagenesis, genome-wide CRISPR screen, and genetic inactivation of KLB/FGFR3/FGFR4

    PMID:36179047

    Open questions at the time
    • Conditions selecting FGFR3 versus FGFR4 dependence not defined
    • Combination strategies to overcome redundancy not tested clinically
  18. 2024 High

    Defined an intrahepatic FXR–FGF4–FGFR4–LRH-1 axis acting as a first-line bile acid checkpoint upstream of the peripheral FGF15/19 system.

    Evidence ChIP of FXR at the Fgf4 promoter, FGF4 gain/loss-of-function in vivo, LRH-1 epistasis, and cholestasis model

    PMID:39393353

    Open questions at the time
    • Molecular link between FGFR4 activation and LRH-1 not detailed
    • Relative contribution of intrahepatic versus endocrine arms in humans unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FGFR4's many divergent substrate-directed activities (MST1, GSK-3β, IKKβ, STAT3) are selected and balanced within a given cell, and how these integrate with its endocytic trafficking, remains unresolved.
  • No unified model of substrate selection by activated FGFR4
  • Context-dependent switching between pro-survival and NF-κB-suppressive outputs not explained
  • Structural determinants linking trafficking state to effector engagement undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060089 molecular transducer activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
FGF19FGF23FRS2GSK3BIKKBKLBMST1STAT3
Complex memberships
FGFR4–KLB co-receptor complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Activated FGFR4 (via K650E activation-loop mutation, membrane-targeted) can transform NIH3T3 cells, induce neurite outgrowth in PC12 cells, stimulate phosphorylation of Shp2, PLC-γ, and MAPK, activate Stat1 and Stat3, and stimulate PI3K activity, demonstrating FGFR4 kinase-dependent oncogenic signaling through multiple effector proteins. Activated mutant overexpression in NIH3T3 and PC12 cells; Western blot for phosphorylation of downstream effectors; PI3K activity assay Oncogene High 10918587
2002 A G388R polymorphism in the transmembrane domain of FGFR4 increases tumor cell motility; MDA-MB-231 cells expressing FGFR4 Arg388 exhibited increased motility relative to cells expressing FGFR4 Gly388. Cell motility assay comparing isogenic cell lines expressing FGFR4 Gly388 vs Arg388 Cancer research Medium 11830541
2007 FGFR4 activity in hepatocytes is required for suppression of systemic hyperlipidemia and mediates high-fat diet-induced fatty liver disease; FGFR4-deficient mice show hyperlipidemia and glucose intolerance on normal diet, but are protected from high-fat diet-induced fatty liver, and hepatocyte-specific restoration of FGFR4 rescues plasma lipid levels and restores fatty liver susceptibility. FGFR4 knockout mice; hepatocyte-specific transgenic FGFR4 rescue; metabolic phenotyping on normal and high-fat diet Diabetes High 17664243
2008 Neither FGFR3 nor FGFR4 is the principal mediator of FGF23 renal effects (phosphaturia, 1,25(OH)2D suppression); ablation of FGFR4 failed to correct hypophosphatemia in Hyp mice. FGFR4 knockout crossed with Hyp mice; serum phosphate and 1,25(OH)2D measurement Journal of the American Society of Nephrology High 18753255
2008 FGFR4 exists in a novel splice form (FGFR4(-16)) lacking exon 16 (part of kinase domain) in myogenic cells. Unlike FGFR1, induced homodimerization of FGFR4 does not result in receptor tyrosine phosphorylation; however, coexpression with a chimeric FGFR1 protein enables FGFR4 tyrosine phosphorylation, suggesting FGFR4 phosphorylation requires a heterologous kinase. Both forms are N-glycosylated. Molecular cloning of splice variant; forced dimerization assay; Western blot for tyrosine phosphorylation; glycosylation analysis Journal of cellular physiology Medium 18186042
2009 The FGFR4 Y367C mutation in MDA-MB453 breast cancer cells causes constitutive receptor phosphorylation and constitutive activation of the MAPK cascade (enhanced Erk1/2 phosphorylation), rendering cells insensitive to ligand stimulation or antagonistic antibody inhibition; ectopic expression of Y367C in HEK293 cells confirmed high pErk and enhanced proliferation. Mutant cloning and ectopic expression in HEK293; phospho-Western for FGFR4 and Erk1/2; proliferation assay; antibody inhibition assay Oncogene Medium 19946327
2010 FGFR4 interacts with IKKβ (identified by yeast two-hybrid, confirmed by co-immunoprecipitation and mass spectrometry), and activated FGFR4 induces tyrosine phosphorylation of IKKβ (kinase-dead FGFR4 does not). FGFR4 activation following TNFα treatment results in inhibition of NF-κB signaling: decreased nuclear NF-κB, reduced NF-κB transcriptional activation (EMSA), and inhibition of IKKβ kinase activity toward GST-IκBα in vitro. Yeast two-hybrid; co-immunoprecipitation; mass spectrometry; in vitro IKKβ kinase assay; EMSA; nuclear fractionation PloS one High 21203561
2011 FGFR4 activation mediates FGF19-induced hepatocyte proliferation and suppression of bile acid biosynthesis, but is not required for FGF19's effects on glucose and lipid metabolism in obese mice; demonstrated using Fgfr4-deficient mice and an FGF19 variant (FGF19v) specifically impaired in FGFR4 activation. Fgfr4 knockout mice; FGF19v variant with selective FGFR4 impairment; hepatocyte proliferation and bile acid biosynthesis assays; metabolic phenotyping in high-fat and ob/ob mice PloS one High 21437243
2012 FGFR4 is required for FGF19-driven hepatocarcinogenesis in vivo; FGF19 transgenic mice crossed with FGFR4 knockout mice fail to develop liver tumors. An anti-FGFR4 blocking antibody (LD1) inhibits FGF1 and FGF19 binding to FGFR4, blocks FGFR4-mediated signaling, colony formation, and proliferation in vitro, and suppresses tumor growth in vivo. Genetic epistasis (FGF19 Tg × FGFR4 KO); blocking monoclonal antibody (LD1); ligand binding assay; colony formation; proliferation; xenograft tumor model PloS one High 22615798
2012 FGF21 binds FGFR1-KLB complex with much higher affinity than FGFR4-KLB, while FGF19 binds both FGFR1-KLB and FGFR4-KLB with comparable affinity; FGF21-FGFR4-KLB interaction is negligible at physiological concentrations. KLB is an indispensable co-receptor mediating FGF19 and FGF21 binding to FGFRs. Quantitative binding kinetics assay; downstream signaling and early response gene expression in mouse tissues; KLB and FGFR1 ablation PloS one High 22442730
2013 Ponatinib (AP24534) inhibits wild-type and mutated FGFR4 with nanomolar IC50 in Ba/F3 TEL-FGFR4 chimeric constructs, suppresses FGFR4 and STAT3 phosphorylation in RMS cells, and inhibits RMS tumor growth in a mouse model expressing mutated FGFR4. Ba/F3 TEL-FGFR4 chimeric construct; phospho-Western for FGFR4 and STAT3; apoptosis assay; xenograft mouse model PloS one Medium 24124571
2014 FGFR4 silencing in colon cancer cell lines decreases STAT3 activity and reduces expression of anti-apoptotic c-FLIP; STAT3 silencing likewise reduces c-FLIP, indicating FGFR4 regulates c-FLIP expression via STAT3. RNAi knockdown; Western blot for STAT3 activity and c-FLIP; caspase-dependent apoptosis assay Cell death & disease Medium 24503538
2015 BLU9931 is a potent, irreversible, and exquisitely selective covalent inhibitor of FGFR4 (sparing FGFR1-3 and other kinases) that inhibits FGF19/FGFR4 signaling and demonstrates antitumor activity in HCC xenograft models with FGF19 amplification or overexpression. Kinase selectivity profiling; irreversible inhibition assay; HCC xenograft mouse models Cancer discovery High 25776529
2015 The FGFR4 G388R polymorphism alters the transmembrane spanning segment, exposing a membrane-proximal cytoplasmic STAT3 binding motif Y390-(P)XXQ393. This motif recruits STAT3 to the inner cell membrane, enhancing STAT3 tyrosine phosphorylation. Validated in Fgfr4 SNP knock-in mice and transgenic mouse models for breast and lung cancers. Structural/biochemical analysis of transmembrane domain; STAT3 co-immunoprecipitation with Arg388 vs Gly388 receptor; phospho-STAT3 assay; Fgfr4 knock-in mice; cancer transgenic mouse models Nature High 26675719
2016 FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT signaling in basal-like breast cancer cells; FGF19 (autocrine ligand secreted by a subset of cells) activates FGFR4 and drives AKT phosphorylation and cell growth. siRNA knockdown of FGFR4 and FGF19; anti-FGF19 antibody neutralization; AKT phosphorylation by Western blot; cell growth assay Oncotarget Medium 27192118
2017 FGF23 activates FGFR4 directly on cardiac myocytes to induce hypertrophic myocyte growth and left ventricular hypertrophy (LVH) in rodents; specific FGFR4 blockade attenuates established LVH in a 5/6 nephrectomy CKD rat model; FGFR4 knockout mice are protected from age-related LVH. Additionally, FGF23 increases cardiac contractility via FGFR4. FGFR4 selective inhibitor; FGFR4 knockout mice; 5/6 nephrectomy CKD rat model; cardiac hypertrophy and contractility measurements Scientific reports High 28512310
2018 FGFR4 phosphorylates MST1 at Y433 in a kinase activity-dependent manner; Y433F mutation blocks this phosphorylation and increases MST1/2 activation (threonine phosphorylation of MST1/2 and MOB1). FGFR4 knockdown or inhibition in HER2+ breast cancer cells leads to MST1 nuclear localization, generation of cleaved autophosphorylated MST1, and apoptosis in an MST2-dependent manner. Kinase substrate screen; mass spectrometry identification of Y433 phosphorylation; Y433F mutation; phospho-Western for MST1/2 and MOB1; nuclear fractionation; FGFR4 knockdown and pharmacological inhibition in breast cancer cells Cell death and differentiation High 30903103
2018 FGFR4 activation leads to phosphorylation of FRS2 and downstream activation of MAPK/ERK signaling, which drives enhanced glycolytic flux (increased glucose uptake, lactate release, ECAR) and chemoresistance in doxorubicin-resistant breast cancer cells. Gene expression microarray; shRNA knockdown; phospho-Western for FRS2 and ERK; glucose uptake and lactate assays; ECAR measurement by Seahorse Cellular physiology and biochemistry Medium 29763898
2018 FGFR4 activation by FGF19 upregulates AKT signaling in breast cancer cells; FGFR4 knockout by genetic methods suppresses breast tumor progression and metastasis in orthotopic and experimental metastasis mouse models. FGFR4 inhibitor BLU9931; FGF19 genetic knockout; orthotopic mouse tumor model; experimental metastasis model; AKT phosphorylation Western blot Molecular carcinogenesis Medium 30074276
2005 Fgfr4 null mice show defective muscle regeneration; myotube differentiation is delayed and poorly coordinated, with muscle replaced by fat and calcifications by 14 days post-injury. A transcriptional pathway was identified: MyoD directly activates Tead2 (via E-box binding confirmed by ChIP), and Tead2 directly activates the Fgfr4 promoter via an M-CAT motif (mutation of M-CAT abolishes activation), defining a MyoD-Tead2-Fgfr4 axis in muscle regeneration. Fgfr4 null mice with staged muscle regeneration; co-transfection reporter assay with Tead2 and Fgfr4 promoter; M-CAT motif mutagenesis; ChIP for MyoD at Tead2 E-boxes; immunostaining The Journal of biological chemistry High 16267055
2016 Proximity biotin labeling of activated FGFR4 identified 291 proximal proteins including known signaling effectors (FRS2, PLCγ, RSK2, NCK2) and multiple endosomal transport proteins. Activated FGFR4 uses clathrin-mediated endocytosis for internalization and is sorted from early endosomes to the recycling compartment and trans-Golgi network. Depletion of clathrin heavy chain accumulates FGFR4 at the cell surface, increases active FGFR4 and PLCγ levels, but diminishes AKT and ERK signaling. BirA*-FGFR4 proximity labeling; quantitative mass spectrometry; confocal and 3D-SIM microscopy; clathrin heavy chain depletion; phospho-Western for signaling effectors Journal of proteome research High 27615514
2019 Acquired clinical resistance to FGFR4 inhibitor fisogatinib (BLU-554) in HCC patients is caused by on-target mutations in the gatekeeper and hinge-1 residues of the FGFR4 kinase domain, confirmed to mediate resistance in vitro and in vivo; continued FGF19-FGFR4 pathway dependence is demonstrated by efficacy of a pan-FGFR inhibitor against these resistant mutants. Clinical sequencing of resistant patient tumors; in vitro resistance validation; xenograft in vivo models with resistant mutants; pan-FGFR inhibitor rescue Cancer discovery High 31575540
2022 KLB (klotho beta) associates with both FGFR3 and FGFR4 to mediate pro-survival FGF19 signaling in HCC; KLB mutants defective in interacting with FGFR3 or FGFR4 cannot support HCC cell growth or survival. FGFR3 restricts the activity of FGFR4-selective inhibitors, providing a mechanism for de novo resistance. Biochemical co-association assays; KLB mutagenesis; genome-wide CRISPR loss-of-function screening; genetic inactivation of KLB, FGFR3, FGFR4; cell proliferation and survival assays Proceedings of the National Academy of Sciences High 36179047
2022 FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance in breast cancer; suppression of FGFR4 diminishes glutathione synthesis and Fe2+ efflux via the β-catenin/TCF4-SLC7A11/FPN1 axis, leading to excessive ROS and labile iron pool accumulation and triggering ferroptosis. m6A hypomethylation regulates FGFR4 expression. Genome-wide CRISPR/Cas9 screening (in vitro and in vivo); phospho-Western for GSK-3β; β-catenin/TCF4 signaling assay; glutathione and ROS measurements; iron pool quantification; patient-derived xenografts and organoids Nature communications High 35562334
2022 BCL-XL inhibition activates a rescue response involving rapid FGF2 secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1; FGFR4 inhibition prevents MCL-1 upregulation and sensitizes colorectal cancer stem cells to BCL-XL inhibition. Compound library screen for synergy; FGF2 secretion measurement; MCL-1 protein stability assay; FGFR4 inhibition; in vitro and in vivo (xenograft) validation Cell reports Medium 35172148
2022 A dual-warhead covalent FGFR4 inhibitor (CXF-009) covalently targets both Cys477 and Cys552 of FGFR4; the co-crystal structure confirms dual-warhead covalent binding mode and that single cysteine mutants (C477A or C552A) remain potently inhibited by the dual-warhead compound. Crystal structure of FGFR4-CXF-009 complex; covalent binding assay; kinase selectivity profiling; single cysteine mutant inhibition assay Communications chemistry High 36697897
2024 Hepatic FXR directly targets Fgf4 to produce an intrahepatic FGF4 paracrine signal that downregulates Cyp7a1 and Cyp8b1 via an FGFR4-LRH-1 intracellular signaling node, functioning as a first-line checkpoint for bile acid homeostasis upstream of the peripheral FXR-FGF15/19 axis. ChIP identifying FXR binding to Fgf4 promoter; FGF4 gain/loss-of-function in vivo; FGFR4 signaling assays; LRH-1 epistasis; Cyp7a1/Cyp8b1 expression as readout; cholestasis model Cell metabolism High 39393353
2010 Compound deletion of Fgfr3 and Fgfr4 in Hyp mice partially corrects hypophosphatemia and increases 1,25(OH)2D, demonstrating that FGFR3 and FGFR4 act in concert with FGFR1 to mediate renal FGF23 effects; loss of FGFR3/4 function leads to compensatory feedback stimulation of Fgf23 expression in bone. Compound Fgfr3/Fgfr4 knockout on Hyp background; serum phosphate, 1,25(OH)2D, FGF23 measurements; NPT2a/NPT2c mRNA expression American journal of physiology. Endocrinology and metabolism High 21139072
2020 Inhibition of FGFR4 signaling in breast cancer PDX and bulk/single-cell RNA sequencing causes molecular subtype switching, linking FGFR4-regulated gene expression to luminal-to-HER2-enriched subtype transition and metastasis. FGFR4 inhibitor treatment of PDX in vivo; bulk tumor gene expression analysis; single-cell RNA sequencing The Journal of clinical investigation Medium 32573490
2023 EIF4A3 modulates FGFR4 splicing in HCC; EIF4A3 silencing alters FGFR4 expression and splicing, blocks cellular response to FGF19 (the natural FGFR4 ligand), and restoration of full-length unspliced FGFR4 rescues the proliferation defect caused by EIF4A3 silencing, placing FGFR4 downstream of EIF4A3 in a splicing regulatory axis. EIF4A3 siRNA and CRISPR knockdown; RNA-seq; FGFR4 splicing analysis; FGF19 stimulation assay; FGFR4 full-length rescue experiment; xenograft in vivo Clinical and translational medicine Medium 36419260
2023 FGF19/FGFR4 and HGF/c-MET jointly upregulate ETV4 expression through the ERK1/2 pathway in HCC cells; ETV4 in turn transactivates FGFR4 expression, creating a FGF19-ETV4-FGFR4 positive feedback loop that promotes HCC metastasis. Luciferase reporter and ChIP assays for ETV4 transactivation of FGFR4; ERK1/2 pathway inhibitor; knockdown experiments; orthotopic HCC models; flow cytometry for immune cell changes Journal of hepatology Medium 36907560
2023 METTL16 regulates PRDM15 protein expression via YTHDF1-dependent translation (m6A modification); PRDM15 then binds the FGFR4 promoter to regulate FGFR4 expression in cholangiocarcinoma cells, defining a METTL16-PRDM15-FGFR4 signaling axis. MeRIP-Seq; ChIP-qPCR of PRDM15 at FGFR4 promoter; immunoprecipitation; CRISPR/siRNA knockdown; rescue experiments; in vivo xenograft Journal of experimental & clinical cancer research Medium 37817227
2018 FGFR4 inhibitor treatment activates NF-κB via non-canonical signaling, leading to EZH2 accumulation, which confers resistance; combined inhibition of FGFR4 (Roblitinib) and EZH2 (CPI-169) synergistically induces HCC cell apoptosis and suppresses tumor growth via repression of YAP signaling. RNA-seq; ChIP-seq; NF-κB signaling assay; EZH2 knockdown; combination drug treatment in vitro and zebrafish/mouse xenograft models; YAP signaling readout Journal of experimental & clinical cancer research Medium 37085881

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer discovery 268 25776529
2002 Cancer progression and tumor cell motility are associated with the FGFR4 Arg(388) allele. Cancer research 238 11830541
2000 Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 222 10918587
2022 N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nature communications 194 35562334
2012 Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PloS one 183 22615798
2023 FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. Journal of hepatology 175 36907560
2011 FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways. PloS one 156 21437243
2012 Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PloS one 154 22442730
2017 FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. Journal of experimental & clinical cancer research : CR 150 28069043
1993 Amplification of fgfr4 gene in human breast and gynecological cancers. International journal of cancer 132 8099571
2019 FGF19-FGFR4 Signaling in Hepatocellular Carcinoma. Cells 127 31167419
2007 FGFR4 prevents hyperlipidemia and insulin resistance but underlies high-fat diet induced fatty liver. Diabetes 119 17664243
2008 FGFR3 and FGFR4 do not mediate renal effects of FGF23. Journal of the American Society of Nephrology : JASN 113 18753255
2017 FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Scientific reports 103 28512310
2019 Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma. Cancer discovery 98 31575540
2004 Involvement of the FGFR4 Arg388 allele in head and neck squamous cell carcinoma. International journal of cancer 91 15197773
2005 Fgfr4 is required for effective muscle regeneration in vivo. Delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway. The Journal of biological chemistry 86 16267055
2014 Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer. Cell death & disease 83 24503538
2013 Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534). PloS one 83 24124571
2020 FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease. The Journal of clinical investigation 79 32573490
2020 Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression. Frontiers in cell and developmental biology 74 32154250
2020 miR-486-3p mediates hepatocellular carcinoma sorafenib resistance by targeting FGFR4 and EGFR. Cell death & disease 73 32313144
2010 Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. American journal of physiology. Endocrinology and metabolism 73 21139072
2020 FGFR4: A promising therapeutic target for breast cancer and other solid tumors. Pharmacology & therapeutics 71 32492514
2016 Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival. Oncotarget 71 27192118
2018 Fibroblast Growth Factor Receptor 4 (FGFR4) Selective Inhibitors as Hepatocellular Carcinoma Therapy: Advances and Prospects. Journal of medicinal chemistry 70 30403487
2005 Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth. Clinical cancer research : an official journal of the American Association for Cancer Research 69 15709206
2018 FGF19 amplification reveals an oncogenic dependency upon autocrine FGF19/FGFR4 signaling in head and neck squamous cell carcinoma. Oncogene 67 30518874
1995 Novel FGF receptor (Z-FGFR4) is dynamically expressed in mesoderm and neurectoderm during early zebrafish embryogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 66 8589434
2015 Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma. Diseases (Basel, Switzerland) 64 28943626
2015 Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site. Nature 56 26675719
2013 FGFR4 role in epithelial-mesenchymal transition and its therapeutic value in colorectal cancer. PloS one 56 23696849
2009 The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells. Oncogene 56 19946327
2024 Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress. Cell metabolism 52 39393353
2010 The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling. PloS one 51 21203561
2021 FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis. Oncogene 50 34163030
2018 Forkhead box C1 promotes colorectal cancer metastasis through transactivating ITGA7 and FGFR4 expression. Oncogene 50 29884889
2019 FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis. Cell death and differentiation 49 30903103
2018 FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 48 29763898
2018 FGFR4 provides the conduit to facilitate FGF19 signaling in breast cancer progression. Molecular carcinogenesis 48 30074276
2014 Targeted inhibition of the FGF19-FGFR4 pathway in hepatocellular carcinoma; translational safety considerations. Liver international : official journal of the International Association for the Study of the Liver 45 24393342
2022 DCZ0415, a small-molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/β-catenin pathway in colorectal cancer. Molecular oncology 44 35194944
2018 Functional screening of FGFR4-driven tumorigenesis identifies PI3K/mTOR inhibition as a therapeutic strategy in rhabdomyosarcoma. Oncogene 44 29487419
2010 FGFR4 transmembrane domain polymorphism and cancer risk: a meta-analysis including 8555 subjects. European journal of cancer (Oxford, England : 1990) 43 20638838
2024 Targeting the FGF19-FGFR4 pathway for cholestatic, metabolic, and cancerous diseases. Journal of internal medicine 36 38212977
2023 FGF19-mediated ELF4 overexpression promotes colorectal cancer metastasis through transactivating FGFR4 and SRC. Theranostics 33 36923538
2015 High Expression of FGFR4 Enhances Tumor Growth and Metastasis in Nasopharyngeal Carcinoma. Journal of Cancer 33 26535066
2020 Discovery of Dual FGFR4 and EGFR Inhibitors by Machine Learning and Biological Evaluation. Journal of chemical information and modeling 32 32926776
2022 FGFR redundancy limits the efficacy of FGFR4-selective inhibitors in hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America 31 36179047
2020 Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma. Cancers 31 33182650
2018 TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 29490293
2008 Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer. Oral oncology 31 18487077
2020 Development of a Potent and Specific FGFR4 Inhibitor for the Treatment of Hepatocellular Carcinoma. Journal of medicinal chemistry 30 33030342
2020 FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer. Cancers 30 33066597
2011 FGFR4 Gly388Arg polymorphism contributes to prostate cancer development and progression: a meta-analysis of 2618 cases and 2305 controls. BMC cancer 30 21349172
2018 The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction. Scientific reports 29 29402970
2023 The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression. Journal of experimental & clinical cancer research : CR 28 37817227
2011 HFE, MTHFR, and FGFR4 genes polymorphisms and breast cancer in Brazilian women. Molecular and cellular biochemistry 28 21625954
2023 CD276-CAR T cells and Dual-CAR T cells targeting CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models. Journal of experimental & clinical cancer research : CR 27 37924157
2022 Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4. Journal of medicinal chemistry 27 35271262
2018 Synergistic effects of TGFβ2, WNT9a, and FGFR4 signals attenuate satellite cell differentiation during skeletal muscle development. Aging cell 27 29869452
2023 Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma. Cell reports. Medicine 26 37774704
2023 KDM6A promotes hepatocellular carcinoma progression and dictates lenvatinib efficacy by upregulating FGFR4 expression. Clinical and translational medicine 26 37846441
2013 Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer. Oncology reports 26 24126887
2024 FGFR4-specific CAR-T cells with inducible caspase-9 suicide gene as an approach to treat rhabdomyosarcoma. Cancer gene therapy 25 39183354
2022 FGFR4-Targeted Chimeric Antigen Receptors Combined with Anti-Myeloid Polypharmacy Effectively Treat Orthotopic Rhabdomyosarcoma. Molecular cancer therapeutics 25 35877472
2021 FGF19/FGFR4 signaling axis confines and switches the role of melatonin in head and neck cancer metastasis. Journal of experimental & clinical cancer research : CR 25 33691750
2002 Fibroblast growth factor receptor 4 (FGFR4) expression in newborn murine calvaria and primary osteoblast cultures. The International journal of developmental biology 25 12141439
2024 CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma. Nature communications 24 39043633
2020 FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy. EBioMedicine 24 32114392
2020 Salvianolic acid B blocks hepatic stellate cell activation via FGF19/FGFR4 signaling. Annals of hepatology 23 32980439
2018 Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation. Toxicological sciences : an official journal of the Society of Toxicology 23 29432567
2008 FGFR4 and its novel splice form in myogenic cells: Interplay of glycosylation and tyrosine phosphorylation. Journal of cellular physiology 23 18186042
2023 FGF19/FGFR4 signaling contributes to hepatocellular carcinoma survival and immune escape by regulating IGF2BP1-mediated expression of PD-L1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 38048735
2019 FGFR4 increases EGFR oncogenic signaling in lung adenocarcinoma, and their combined inhibition is highly effective. Lung cancer (Amsterdam, Netherlands) 22 31027687
2015 Association of FGFR3 and FGFR4 gene polymorphisms with breast cancer in Chinese women of Heilongjiang province. Oncotarget 21 26431494
2023 FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling. Journal of experimental & clinical cancer research : CR 20 37085881
2022 Spliceosomal profiling identifies EIF4A3 as a novel oncogene in hepatocellular carcinoma acting through the modulation of FGFR4 splicing. Clinical and translational medicine 20 36419260
2015 FGFR4 Is a Potential Predictive Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma. Pathobiology : journal of immunopathology, molecular and cellular biology 20 26551585
2009 Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study. BMC cancer 20 19500394
2022 BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer. Cell reports 19 35172148
2017 Functional FGFR4 Gly388Arg polymorphism contributes to oral squamous cell carcinoma susceptibility. Oncotarget 19 29221201
2011 Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease. Biochemical and biophysical research communications 19 21616061
2025 Lgals3 Promotes Calcium Oxalate Crystal Formation and Kidney Injury Through Histone Lactylation-Mediated FGFR4 Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 39903812
2019 Expression of FGF8, FGF18, and FGFR4 in Gastroesophageal Adenocarcinomas. Cells 18 31527546
2018 Making way for suppressing the FGF19/FGFR4 axis in cancer. Future medicinal chemistry 18 30325210
2024 Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles. Journal of medicinal chemistry 17 38604131
2018 Blocking FGFR4 exerts distinct anti-tumorigenic effects in esophageal squamous cell carcinoma. Thoracic cancer 17 30267473
2022 Structure-based design of a dual-warhead covalent inhibitor of FGFR4. Communications chemistry 16 36697897
2021 Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer. Frontiers in pharmacology 16 33981224
2019 FGFR4 does not contribute to progression of chronic kidney disease. Scientific reports 16 31575945
2016 Proximity Labeling Reveals Molecular Determinants of FGFR4 Endosomal Transport. Journal of proteome research 16 27615514
2023 Surfaceome Profiling of Cell Lines and Patient-Derived Xenografts Confirm FGFR4, NCAM1, CD276, and Highlight AGRL2, JAM3, and L1CAM as Surface Targets for Rhabdomyosarcoma. International journal of molecular sciences 15 36768928
2021 Development of nomogram based on immune-related gene FGFR4 for advanced non-small cell lung cancer patients with sensitivity to immune checkpoint inhibitors. Journal of translational medicine 15 33407583
2021 Design, synthesis, and biological evaluation of indazole derivatives as selective and potent FGFR4 inhibitors for the treatment of FGF19-driven hepatocellular cancer. European journal of medicinal chemistry 15 33618175
2021 Dual inhibition of FGFR4 and BCL-xL inhibits multi-resistant ovarian cancer with BCL2L1 gain. Aging 15 34351305
2023 Insight into the design of FGFR4 selective inhibitors in cancer therapy: Prospects and challenges. European journal of medicinal chemistry 14 37976704
2022 TKF, a mexicanolide-type limonoid derivative, suppressed hepatic stellate cells activation and liver fibrosis through inhibition of the YAP/Notch3 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 14 36182796
2021 Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors. European journal of medicinal chemistry 14 34488024
2017 Functional FGFR4 Gly388Arg polymorphism contributes to cancer susceptibility: Evidence from meta-analysis. Oncotarget 14 28445975

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