Affinage

FGFR3

Fibroblast growth factor receptor 3 · UniProt P22607

Length
806 aa
Mass
87.7 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGFR3 is a receptor tyrosine kinase that signals through ligand-induced or constitutive dimerization and activation-loop tyrosine phosphorylation to engage MAPK/ERK, STAT1/STAT3, PI3K, PLC-γ and Shp2 effectors (PMID:10918587, PMID:19901323). Dimerization is stabilized by intracellular receptor-receptor contacts: the juxtamembrane domain stabilizes unliganded dimers when linked to the transmembrane segment, and transmembrane-domain mutations such as G375C/G380R promote ligand-independent dimerization and phosphorylation (PMID:10587515, PMID:21324899, PMID:25688803). In the developing skeleton FGFR3 acts as a negative regulator of chondrocyte proliferation and differentiation, signaling through ERK to suppress Indian hedgehog—its loss elevating IHH and producing chondroma-like lesions (PMID:10646125, PMID:26091072)—and inhibiting BMP signaling by driving Smurf1-mediated ubiquitination and degradation of the BMP type I receptor BMPR1a, a function independent of FGFR3 kinase activity (PMID:24657641). FGFR3 signaling also coordinates membranous ossification, synchondrosis closure, and the cartilage-to-bone transition during growth and fracture repair, acting in part through paracrine effects of mutant chondrocytes on osteoblasts and osteoclasts (PMID:18923003, PMID:22367969, PMID:32916123). Gain-of-function FGFR3 mutations cause achondroplasia and thanatophoric dysplasia, and extracellular-domain-targeting peptide inhibitors and statins reverse these skeletal phenotypes in disease models (PMID:10587515, PMID:23014564, PMID:25231866). In cancer, activating FGFR3 mutations substitute for Ras to drive MAPK signaling in urothelial carcinoma (PMID:15897885), oncogenic FGFR3-TACC3 fusions confer constitutive kinase activity and metabolic reprogramming through a PIN4–peroxisome–ROS–PGC1α axis (PMID:26869289, PMID:29323298), and FGFR3 transphosphorylates EGFR to sustain PI3K/AKT signaling (PMID:33794187). FGFR3 is internalized by both clathrin-dependent and clathrin-independent routes, modulating signaling duration (PMID:21779335).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1995 Medium

    Established that FGFR3 mutations are pleiotropic—affecting skin as well as the skeleton—when a transmembrane-domain substitution was found in Crouzon syndrome with acanthosis nigricans, broadening the disease scope of FGFR3 beyond dwarfism.

    Evidence Mutation analysis / DNA sequencing in unrelated patient families

    PMID:7493034

    Open questions at the time
    • No functional reconstitution of the Ala391Glu allele
    • Mechanism linking the receptor mutation to the skin phenotype unresolved
  2. 1999 High

    Resolved how a transmembrane-domain mutation activates FGFR3 by showing G375C/G369C causes ligand-independent dimerization and phosphorylation, linking constitutive receptor activity to growth-plate disorganization and dwarfism in vivo.

    Evidence Biochemical dimerization/phosphorylation assays plus knock-in mouse with growth-plate histology

    PMID:10587515

    Open questions at the time
    • Did not map the full downstream effector cascade
    • Stat activation correlative within the model
  3. 2000 High

    Defined the downstream signaling repertoire of activated FGFR3 by showing a constitutively active kinase-domain mutant engages Shp2, PLC-γ, MAPK, Stat1/Stat3 and PI3K and transforms cells, establishing the effector network.

    Evidence In vitro signaling assays, NIH3T3 transformation, PC12 neurite outgrowth with K650E mutant

    PMID:10918587

    Open questions at the time
    • Effectors defined with a single hyperactive mutant
    • Quantitative contribution of each pathway not dissected
  4. 2000 Medium

    Provided a cellular mechanism for FGFR3-mediated inhibition of chondrocytes, showing the active receptor blocks proliferation and differentiation and alters integrin-dependent matrix preference.

    Evidence Stable expression of FGFR3Ach (G380R) in chondrocytic cells with proliferation, differentiation and apoptosis assays

    PMID:10646125

    Open questions at the time
    • Single cell line and lab
    • Did not identify the transcriptional mediators of growth arrest
  5. 2003 Medium

    Identified a CNS role for FGFR3 as a marker and repressor of astrocyte GFAP expression, extending its biology beyond cartilage.

    Evidence Fgfr3-null mouse with GFAP immunostaining of grey-matter astrocytes

    PMID:12441294

    Open questions at the time
    • Downstream pathway controlling GFAP repression unknown
    • Ligand driving astrocytic signaling not identified
  6. 2005 Medium

    Placed FGFR3 firmly upstream of MAPK in tumorigenesis by demonstrating mutual exclusivity of FGFR3 and Ras mutations in urothelial carcinoma, implying both activate the same oncogenic pathway.

    Evidence Mutation screening of bladder tumours and cell lines with statistical epistasis analysis

    PMID:15897885

    Open questions at the time
    • Correlative genetic epistasis, not functional
    • Did not establish dependency of tumours on the pathway
  7. 2007 Medium

    Revealed compartment-specific activation, showing intracellular-domain mutants are prematurely phosphorylated in the Golgi and impair receptor glycosylation, linking mutation class to subcellular signaling site.

    Evidence Transfection of FGFR3 mutant panel with phosphorylation/glycosylation Western blots

    PMID:17320202

    Open questions at the time
    • Functional consequence of Golgi signaling for disease not established
    • Single-lab cell-culture observation
  8. 2009 High

    Systematically mapped the FGFR3 phosphotyrosine network in a disease cell context, identifying activation-loop tyrosines and 52 inhibitor-sensitive substrates including Syndecan-1.

    Evidence Label-free quantitative phosphoproteomics with FGFR3 inhibitor PD173074 in multiple myeloma cells

    PMID:19901323

    Open questions at the time
    • Direct vs indirect substrates not all distinguished
    • Functional role of individual network nodes untested
  9. 2011 High

    Distinguished FGFR3 trafficking from FGFR1 by showing FGFR3 uses both clathrin-dependent and clathrin/dynamin-independent endocytosis, with internalization route shaping degradation and signaling duration.

    Evidence Clathrin depletion, dominant-negative dynamin, live imaging and signaling assays versus FGFR1

    PMID:21779335

    Open questions at the time
    • Molecular machinery of the clathrin-independent route not defined
    • Link between trafficking and disease signaling unexplored
  10. 2011 Medium

    Quantified the biophysical basis of the achondroplasia mutation, showing G380R alters heterodimerization probability with wild-type receptor at low ligand.

    Evidence Cell-based dimerization assay using a truncated kinase-dead FGFR3 construct

    PMID:21324899

    Open questions at the time
    • Indirect measure via dominant-negative depletion
    • Single lab
  11. 2008 High

    Defined the skeletal output and physiological limits of FGFR3: it promotes synchondrosis closure and BMP-dependent ossification, but is not the principal renal mediator of FGF23 signaling, narrowing its endocrine role.

    Evidence Chondrocyte-specific Fgfr3 activation mice and Fgfr3/Fgfr4-null × Hyp crosses with histology and physiological readouts

    PMID:18753255 PMID:18923003

    Open questions at the time
    • Direct BMP target genes not all defined
    • Redundancy among FGFRs in other tissues not fully mapped
  12. 2012 High

    Dissected the cellular geography of skeletal disease by showing FGFR3 gain-of-function impairs both endochondral and membranous bone and acts on bone via a paracrine signal from cartilage rather than direct osteoblast effects.

    Evidence Ubiquitous, chondrocyte-specific and osteoblast-specific Fgfr3(Y367C) knock-in mice with histomorphometry

    PMID:22367969 PMID:24419316

    Open questions at the time
    • Identity of the paracrine signal to osteoblasts/osteoclasts not defined
    • Mechanism of membranous defect unresolved
  13. 2013 High

    Defined a bona fide oncogenic FGFR3 species by showing the FGFR3-TACC3 fusion, but not wild-type overexpression, is tumorigenic and escapes miR-99a regulation.

    Evidence Whole transcriptome sequencing, proliferation assays, xenografts and miRNA binding analysis in glioblastoma

    PMID:23298836

    Open questions at the time
    • Mechanism of constitutive activation not yet resolved in this study
    • Downstream signaling of fusion not characterized here
  14. 2014 High

    Established a kinase-independent FGFR3 function and a developmental regulatory node by showing FGFR3 drives Smurf1-mediated BMPR1a degradation to inhibit BMP signaling and chondrogenesis, with Bmpr1a deletion rescuing Fgfr3-null overgrowth.

    Evidence Genetic epistasis rescue, ubiquitination and Smad phosphorylation assays

    PMID:24657641

    Open questions at the time
    • How FGFR3 recruits Smurf1 to BMPR1a not mechanistically resolved
    • Relative weight of kinase-dependent vs -independent outputs in vivo unclear
  15. 2014 High

    Demonstrated druggability of FGFR3 in skeletal disease via an extracellular-domain-binding peptide that inhibits kinase activity, promotes chondrogenesis and rescues TDII mice.

    Evidence Phage display, in vitro kinase inhibition, differentiation assay and in vivo TDII rescue

    PMID:23014564

    Open questions at the time
    • Peptide pharmacology and selectivity not fully characterized
    • Translational development beyond model not addressed
  16. 2014 High

    Identified a pharmacological corrective strategy by showing statins rescue cartilage and bone-growth phenotypes in patient iPSC chondrocytes and ACH mice.

    Evidence Patient iPSC-derived chondrocyte models and ACH mouse statin treatment

    PMID:25231866

    Open questions at the time
    • Molecular target linking statins to FGFR3 signaling not defined
    • Long-term in vivo efficacy not assessed
  17. 2015 Medium

    Resolved the dimer-stabilizing role of the juxtamembrane domain, showing it stabilizes unliganded FGFR3 dimers additively with a pathogenic TM mutation when tethered to the TM segment.

    Evidence Quantitative FRET dimerization assays with deletion/chimeric constructs

    PMID:25688803

    Open questions at the time
    • Structural detail of JM-mediated contacts not defined
    • Single biophysical lab
  18. 2015 High

    Placed FGFR3 upstream of an ERK→IHH axis in cartilage homeostasis by showing Fgfr3 loss reduces ERK, derepresses IHH and causes chondromas, reversible by IHH or MEK inhibition.

    Evidence Postnatal chondrocyte-specific Fgfr3 deletion with ERK assays and pharmacological epistasis

    PMID:26091072

    Open questions at the time
    • Direct transcriptional link between ERK and IHH not defined
    • Relationship to BMPR1a pathway not integrated
  19. 2016 High

    Explained how the FGFR3-TACC3 fusion is constitutively active, showing the TACC3 coiled-coil drives FGFR3 autophosphorylation and MAPK activation while FGFR3 kinase activity is essential for transformation and TACC3 drives nuclear localization.

    Evidence TiO2-LC-MS/MS phosphoproteomics, kinase-dead and domain-deletion mutants, transformation and localization assays

    PMID:26869289

    Open questions at the time
    • Nuclear function of the fusion not defined
    • In vivo relevance of nuclear localization untested
  20. 2018 High

    Uncovered a metabolic mechanism of FGFR3-TACC3 oncogenesis, showing the fusion phosphorylates PIN4 to trigger peroxisome biogenesis and ROS that converge on PGC1α to drive mitochondrial respiration and tumor growth.

    Evidence Transcriptional clustering, metabolic and ROS assays, phosphoproteomics and PGC1α activity assays in tumors and cell lines

    PMID:29323298

    Open questions at the time
    • Generalizability beyond fusion-positive tumours unclear
    • Direct PIN4-to-peroxisome signaling steps incomplete
  21. 2018 Medium

    Linked FGFR3 mutation to tumour-promoting immune modulation, showing FGFR3 S249C suppresses early neutrophil influx during bladder carcinogenesis, with neutrophil depletion phenocopying the effect.

    Evidence FGFR3-mutant urothelium mice with carcinogen exposure and antibody-mediated neutrophil depletion

    PMID:30043421

    Open questions at the time
    • Molecular mediator of neutrophil suppression unknown
    • Single carcinogen model
  22. 2019 Medium

    Connected FGFR3 to contact-inhibition loss by defining an ERK→ETV5→TAZ axis driving proliferation in mutant bladder cancer.

    Evidence FGFR3 inhibition/activation and ETV5 knockdown with proliferation and anchorage-independent growth assays

    PMID:30952872

    Open questions at the time
    • Direct binding of ETV5 to TAZ regulatory elements not shown
    • In vivo validation absent
  23. 2019 Medium

    Extended FGFR3 function to lymphatic biology, showing FGFR3 promotes lymphatic endothelial cell formation via BMPR1a–pSmad1/5 signaling, with loss exacerbating inflammation and heterotopic ossification.

    Evidence Conditional Fgfr3 knockout, lineage tracing and FGF9 rescue in a heterotopic ossification model

    PMID:34282140

    Open questions at the time
    • Cell-type-specific BMPR1a regulation versus chondrocyte degradation paradigm not reconciled
    • Single lab
  24. 2020 High

    Identified an isoform-specific oncogenic mechanism, showing the FGFR3Δ7-9 splice variant phosphorylates TET2 at Y1902 to trigger its degradation, lowering PTEN and activating AKT in hepatocellular carcinoma, whereas wild-type FGFR3 does not bind TET2.

    Evidence Mass spectrometry, co-IP, phosphosite mapping (Y1902F), ubiquitination assay and xenografts

    PMID:33097695

    Open questions at the time
    • Prevalence of this splice variant across tumours unclear
    • Structural basis of variant-specific TET2 binding undefined
  25. 2020 Medium

    Established FGFR3 as a positive regulator of cranial osteogenesis, showing zebrafish fgfr3 loss delays osteoblast expansion and alters matrix during skull-vault formation, complementing mammalian membranous-bone phenotypes.

    Evidence fgfr3 loss-of-function zebrafish with in vivo imaging and single-cell RNA-seq

    PMID:32379366

    Open questions at the time
    • Signaling pathway underlying osteoblast delay not defined
    • Conservation of mechanism to mammals not directly tested
  26. 2020 Medium

    Defined a periosteal requirement for FGFR3 in fracture repair, showing mutant periosteal cells fail terminal chondrocyte hypertrophy and cartilage-to-bone transformation, rescuable by wild-type cell transplantation.

    Evidence Conditional Fgfr3Y637C knock-in fracture model with periosteal cell transplantation

    PMID:32916123

    Open questions at the time
    • Molecular block to hypertrophic transition not defined
    • Single lab
  27. 2020 Medium

    Revealed FGFR3 as a driver of therapy resistance via receptor cross-talk, showing FGFR3 transphosphorylates EGFR to activate PI3K/AKT and confer cisplatin resistance in ovarian cancer.

    Evidence FGFR3 overexpression/silencing with EGFR phosphorylation and PI3K/AKT readouts and xenografts

    PMID:33794187

    Open questions at the time
    • Direct vs indirect EGFR transphosphorylation not resolved
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FGFR3's kinase-dependent (MAPK/ERK, STAT, PI3K) and kinase-independent (Smurf1-BMPR1a) outputs are integrated to set the balance between chondrocyte suppression, osteogenic promotion, and oncogenic signaling across tissues remains unresolved.
  • No unified model linking endocytic route, signaling duration and pathway choice
  • Mechanism of context-dependent positive vs negative skeletal effects unexplained
  • Recruitment logic of Smurf1 and substrate selection by mutant/fusion forms undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0060089 molecular transducer activity 4 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
BMPR1AEGFRPIN4SDC1SMURF1TACC3TET2

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 A missense mutation Ala391Glu in the FGFR3 transmembrane domain was identified in Crouzon syndrome with acanthosis nigricans, demonstrating that transmembrane domain mutations in FGFR3 can cause non-skeletal (skin) disorders in addition to dwarfing conditions, and revealing pleiotropic effects of FGFR3 mutations. Mutation analysis / DNA sequencing in unrelated patient families Nature genetics Medium 7493034
1999 The G375C (human)/G369C (mouse) substitution in the FGFR3 transmembrane domain causes ligand-independent dimerization and phosphorylation of FGFR3 in cells, leading to achondroplasia-like dwarfism in mice with expanded resting zone, narrowed proliferating and hypertrophic zones in growth plates, activation of Stat proteins, upregulation of cell-cycle inhibitors, increased osteoclast activity, and upregulation of osteoblast differentiation genes. Biochemical assay (dimerization, phosphorylation), mouse genetic model (knock-in), histological and molecular analysis of growth plate The Journal of clinical investigation High 10587515
2000 Constitutively active FGFR3 (K650E activation loop mutation, TDII-like) phosphorylates Shp2, PLC-gamma, and MAPK, activates Stat1 and Stat3, stimulates PI3-kinase activity, transforms NIH3T3 cells, and induces neurite outgrowth in PC12 cells, defining downstream effectors of FGFR3 kinase activation. In vitro kinase/signaling assays, NIH3T3 transformation assay, PC12 neurite outgrowth assay, Western blot for downstream effectors Oncogene High 10918587
2000 Stable expression of constitutively active FGFR3Ach (G380R) in CFK2 chondrocytic cells severely inhibits proliferation and prevents differentiation, induces abnormal apoptosis upon serum deprivation, and alters integrin subunit expression leading to a switch in substrate preference from fibronectin to type II collagen, providing a cellular mechanism for FGFR3-mediated inhibition of chondrocyte proliferation. Stable transfection of chondrocytic cell line, proliferation assays, differentiation assays, apoptosis assays, integrin expression analysis Journal of bone and mineral research Medium 10646125
2003 Fgfr3 marks astrocytes and their neuroepithelial precursors in the developing CNS, and FGFR3 signaling normally represses GFAP expression in grey matter (protoplasmic) astrocytes, as demonstrated by strong upregulation of GFAP in grey matter astrocytes of Fgfr3-null mice. Fgfr3 knockout mouse analysis, in vitro and in vivo immunostaining, cell co-expression analysis Development (Cambridge, England) Medium 12441294
2005 FGFR3 mutations and Ras gene mutations are mutually exclusive in urothelial cell carcinoma (UCC), indicating that FGFR3 activating mutations and Ras mutations represent alternative means to activate the MAPK pathway and confer the same oncogenic phenotype. Mutation screening of 98 bladder tumours and 31 cell lines for FGFR3, HRAS, NRAS, and KRAS2 mutations; statistical mutual exclusivity analysis Oncogene Medium 15897885
2007 FGFR3 intracellular domain mutations (but not extracellular or transmembrane domain mutations) induce premature tyrosine phosphorylation of the receptor in the Golgi apparatus and inhibit receptor glycosylation, suggesting that premature kinase activation prevents glycosylation and leads to elevated Golgi-associated signaling. HEK cell transfection with various FGFR3 mutants, Western blotting for phosphorylation and glycosylation state Biochimica et biophysica acta Medium 17320202
2008 FGFR3 and MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers; chondrocyte-specific activation of Fgfr3 in mice induced premature synchondrosis closure, enhanced osteoblast differentiation around synchondroses, increased Bmp ligand mRNA expression, and decreased Bmp antagonist mRNA expression in a MAPK-dependent manner. Mouse genetic models (chondrocyte-specific Fgfr3 activation), histology, gene expression analysis Human molecular genetics High 18923003
2008 FGFR3 (and FGFR4) do not mediate the principal renal effects of FGF23: ablation of FGFR3 alone or together with FGFR4 failed to correct hypophosphatemia or restore 1,25(OH)2D in Hyp mice, while FGFR1 co-localizes with Klotho in distal tubule, suggesting FGFR1 as the primary mediator of FGF23 renal effects. Genetic knockout (Fgfr3-null, Fgfr4-null) crossed with Hyp mouse model, serum phosphate and 1,25(OH)2D measurements, immunohistochemistry Journal of the American Society of Nephrology : JASN Medium 18753255
2009 FGFR3 activation by FGF1 ligand in multiple myeloma KMS11 cells induces phosphorylation of tandem tyrosines in the kinase domain activation loop; mass spectrometry identified 52 proteins with pY sites sensitive to the FGFR3 inhibitor PD173074, including Syndecan-1/CD138, defining the FGFR3 phosphotyrosine signaling network. Label-free quantitative phosphoproteomic mass spectrometry, FGFR3 inhibitor treatment, pervanadate stimulation Proceedings of the National Academy of Sciences of the United States of America High 19901323
2011 FGFR3 is internalized by both clathrin-dependent and clathrin-independent/dynamin-independent mechanisms, unlike FGFR1 which relies predominantly on clathrin-mediated endocytosis; clathrin depletion only partially inhibits FGFR3 internalization and has minimal effect on FGFR3 degradation and signaling duration. Clathrin depletion, dominant-negative dynamin mutants, live-cell imaging, signaling assays (Western blot), comparison with FGFR1 PloS one High 21779335
2011 FGFR3 G380R (achondroplasia) transmembrane domain mutation causes the mutant receptor to form heterodimers with wild-type FGFR3 at lower probability than wild-type homodimers at low ligand concentrations, as demonstrated using a kinase-dead truncated FGFR3 construct that depletes the active receptor pool. Cell-based dimerization assay using truncated kinase-dead FGFR3 construct, phosphorylation assay The Journal of biological chemistry Medium 21324899
2012 FGFR3 gain-of-function mutations cause abnormal membranous ossification in addition to endochondral ossification defects in achondroplasia: Fgfr3(Y367C/+) mice exhibit partial premature fusion of coronal sutures and non-ossified gaps in frontal bones, demonstrating that FGFR3 signaling affects both endochondral and membranous bone formation. Fgfr3(Y367C/+) knock-in mouse model, craniofacial morphological analysis, comparison with human ACH patient imaging Human molecular genetics Medium 24419316
2012 Activating Fgfr3 mutation (Y367C) in chondrocytes affects trabecular bone formation via a paracrine mechanism during growth: the bone formation defect (reduced trabecular bone volume and thickness, increased osteoclast recruitment, defective osteoblast mineralization) is only observed when the mutation is expressed in cartilage (not in mature osteoblasts), and primary osteoblast proliferation/differentiation is not directly affected by Fgfr3 activation. Three mouse models expressing Fgfr3(Y367C/+) ubiquitously, chondrocyte-specific, or osteoblast-specific; histomorphometry, osteoclast and osteoblast activity assays Human molecular genetics High 22367969
2012 A 12-amino-acid peptide (P3: VSPPLTLGQLLS) identified by phage display binds specifically to the extracellular domain of FGFR3, inhibits FGFR3 tyrosine kinase activity and ERK/MAPK downstream signaling, promotes chondrogenic differentiation of ATDC5 cells, and reverses neonatal lethality and bone growth retardation in TDII mice. Phage display library screening with FGFR3 as bait, in vitro kinase inhibition assay, chondrogenic cell differentiation assay, mouse model (TDII) rescue experiment Human molecular genetics High 23014564
2013 The FGFR3-TACC3 fusion gene (from tandem duplication on 4p16.3) generates an oncogenic protein in glioblastoma that is tumorigenic, while wild-type FGFR3 overexpression is not; the fusion escapes miR-99a regulation via 3'-UTR deletion and promotes cell proliferation and tumor progression. Whole transcriptome sequencing, cell culture proliferation assays, mouse xenograft model, miRNA binding analysis The Journal of clinical investigation High 23298836
2014 FGFR3 promotes degradation of BMP type I receptor (BMPR1a) through Smurf1-mediated ubiquitination, thereby inhibiting BMP signaling and chondrogenic differentiation; chondrocyte-specific deletion of Bmpr1a rescues the bone overgrowth in Fgfr3-deficient mice; this BMPR1a degradation occurs independently of FGFR3 tyrosine kinase activity. Genetic rescue (chondrocyte-specific Bmpr1a knockout in Fgfr3-null mice), in vitro chondrogenic differentiation assays, Smad phosphorylation assays, ubiquitination assay, mouse growth plate analysis Biochimica et biophysica acta High 24657641
2014 Statin treatment corrects degraded cartilage formation in iPSC-derived chondrocytes from thanatophoric dysplasia type I and achondroplasia patients, and rescues bone growth in ACH model mice, demonstrating that statins can pharmacologically counteract FGFR3 gain-of-function skeletal dysplasia phenotypes. Patient-specific iPSC differentiation to chondrocytes, ACH mouse model treatment, histological and molecular analysis Nature High 25231866
2015 The FGFR3 juxtamembrane (JM) domain stabilizes unliganded FGFR3 dimers in the membrane through receptor-receptor contacts; this stabilization is additive with the contribution of a pathogenic TM domain mutation, and requires the JM domain to be linked to the FGFR3 TM domain (not merely membrane-anchored). Quantitative FRET-based dimerization assay in cell membranes, deletion/chimeric constructs Journal of molecular biology Medium 25688803
2015 FGFR3 deficiency in chondrocytes leads to formation of chondroma-like lesions (enchondromas and osteochondromas) via decreased ERK activity and upregulation of Indian hedgehog (IHH) signaling; MEK inhibition increases Ihh expression, and IHH signaling inhibitor treatment reduces chondroma-like lesion occurrence in Fgfr3-deficient mice. Postnatal chondrocyte-specific Fgfr3 deletion mouse model, ERK activity assay, gene expression analysis, pharmacological rescue with IHH inhibitor and MEK inhibitor PLoS genetics High 26091072
2016 The FGFR3-TACC3 fusion protein is constitutively phosphorylated at key activating FGFR3 tyrosine residues (shown by TiO2-LC-MS/MS phosphopeptide enrichment); the TACC3 coiled-coil domain drives constitutive phosphorylation and increased MAPK activation, cellular transformation, and IL3-independent proliferation; FGFR3 kinase activity (not TACC3 phospho-tyrosines) is essential for oncogenic effects; nuclear localization is driven by the TACC3 domain independently of kinase activity. TiO2-LC-MS/MS phosphopeptide analysis, kinase-dead K508R mutant, domain deletion constructs, NIH3T3 transformation assay, Ba/F3 IL3-independence assay, nuclear localization imaging Molecular cancer research : MCR High 26869289
2018 The FGFR3-TACC3 (F3-T3) fusion activates oxidative phosphorylation and mitochondrial biogenesis in cancer cells; F3-T3 phosphorylates the phosphopeptide PIN4 as an intermediate step, which triggers peroxisome biogenesis and new protein synthesis; this converges on PGC1α through production of intracellular reactive oxygen species, enabling mitochondrial respiration and tumor growth. Transcriptional clustering analysis, metabolic assays (oxidative phosphorylation), ROS measurements, phosphoproteomics (PIN4 phosphorylation), peroxisome biogenesis assays, PGC1α activity assays, sensitivity to oxidative metabolism inhibitors Nature High 29323298
2018 FGFR3 S249C mutation in urothelium suppresses acute inflammatory response (neutrophil influx) at early tumor initiation stages in response to the carcinogen OH-BBN, thereby promoting bladder tumor development; early neutrophil depletion phenocopies the FGFR3 mutation effect on later inflammatory and tumorigenic outcomes. Genetically engineered mice expressing FGFR3 S249C or K644E in urothelium, carcinogen treatment (OH-BBN), neutrophil depletion with anti-Ly6G antibody, histological and inflammatory analysis at multiple timepoints The Journal of pathology Medium 30043421
2019 FGFR3 signaling induces a MAPK/ERK-mediated increase in ETV5 transcription factor levels, which in turn elevates TAZ (a Hippo pathway co-transcriptional regulator), causing loss of contact-inhibition of proliferation; ETV5 knockdown in FGFR3-mutant bladder cancer cells reduces proliferation and anchorage-independent growth. FGFR3 inhibition/activation in bladder cancer cell lines, siRNA knockdown of ETV5, Western blot for ETV5 and TAZ levels, proliferation and anchorage-independent growth assays, MAPK pathway analysis Scientific reports Medium 30952872
2019 FGFR3 signaling via the BMPR1a pathway promotes lymphatic endothelial cell (LEC) formation; FGFR3 deficiency in LECs leads to decreased lymphangiogenesis through a BMPR1a-pSmad1/5-dependent mechanism, exacerbating local inflammation and heterotopic ossification after trauma. Conditional Fgfr3 knockout in Col2+ cells and Prox1+ LECs, lineage tracing, HO mouse model (Achilles tenotomy), signaling analysis (pSmad1/5), FGF9 local administration rescue Nature communications Medium 34282140
2020 FGFR3Δ7-9 splice variant (lacking exons 7-9) directly interacts with and phosphorylates TET2 at Y1902, leading to ubiquitination and proteasome-mediated degradation of TET2, thereby reducing PTEN expression and activating AKT to promote hepatocellular carcinoma proliferation. Wild-type FGFR3 does not interact with TET2. Mass spectrometry, co-immunoprecipitation, in vitro phosphorylation assay (Y1902 site), phospho-deficient mutant (Y1902F), ubiquitination assay, in vitro and xenograft in vivo proliferation assays Cell death & disease High 33097695
2020 fgfr3 loss-of-function in zebrafish causes delay in osteoblast expansion and differentiation during skull vault development, together with changes in extracellular matrix, establishing FGFR3 as a positive regulator of osteogenesis in cranial membranous bone formation. Fgfr3 loss-of-function zebrafish (fgfr3lof/lof), in vivo imaging, single-cell RNA sequencing of osteoblast lineage Journal of bone and mineral research Medium 32379366
2020 FGFR3 overexpression in DDP-resistant ovarian cancer cells enhances cisplatin resistance by phosphorylating EGFR and thereby activating the PI3K/AKT pathway; FGFR3 silencing suppresses EGFR phosphorylation and PI3K/AKT activation and restores DDP sensitivity in vitro and in nude mouse xenografts. Co-expression analysis, siRNA knockdown, FGFR3 overexpression, Western blot for EGFR phosphorylation and PI3K/AKT, cell viability assays, nude mouse xenograft Biochemical pharmacology Medium 33794187
2020 FGFR3 in periosteal cells (PCs) is required for terminal chondrocyte hypertrophy and cartilage-to-bone transformation during fracture healing; Fgfr3Y637C/+ PCs fail to undergo this transformation and cause pseudarthrosis/fibrocartilage, while transplantation of wild-type PCs rescues this defect. Conditional knock-in Fgfr3Y637C/+ (Prx1Cre), fracture model, periosteal cell transplantation, histological and lineage analysis Stem cell reports Medium 32916123

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends in pharmacological sciences 366 25639674
1995 Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans. Nature genetics 325 7493034
2012 Oncogenic FGFR3 gene fusions in bladder cancer. Human molecular genetics 319 23175443
2005 FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 256 15897885
2000 Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 222 10918587
1999 Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. The Journal of clinical investigation 206 10587515
2013 The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma. The Journal of clinical investigation 192 23298836
2004 Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Experimental cell research 180 15748888
2018 A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature 161 29323298
2014 Statin treatment rescues FGFR3 skeletal dysplasia phenotypes. Nature 157 25231866
2011 Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Human mutation 156 22045636
2023 Role of FGFR3 in bladder cancer: Treatment landscape and future challenges. Cancer treatment reviews 151 36898352
1995 Molecular biology of the vesicular ACh transporter. Trends in neurosciences 139 7610492
2003 Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains. Development (Cambridge, England) 135 12441294
2002 Frequent FGFR3 mutations in urothelial papilloma. The Journal of pathology 134 12237885
2002 ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases. American journal of physiology. Heart and circulatory physiology 119 12388234
2016 FGFR3-TACC3 fusion in solid tumors: mini review. Oncotarget 113 27409839
2008 FGFR3 and FGFR4 do not mediate renal effects of FGF23. Journal of the American Society of Nephrology : JASN 113 18753255
1995 A common FGFR3 gene mutation in hypochondroplasia. Human molecular genetics 109 8589686
2000 Expression of FGFR1, FGFR2 and FGFR3 during early neural development in the chick embryo. Mechanisms of development 108 10585567
2008 FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. Human molecular genetics 107 18923003
2007 Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target. World journal of urology 98 17912529
2013 Biogenesis, trafficking and up-regulation of nicotinic ACh receptors. Biochemical pharmacology 96 23830821
2001 Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. Oncogene 89 11314002
2016 Long noncoding RNA FGFR3-AS1 promotes osteosarcoma growth through regulating its natural antisense transcript FGFR3. Molecular biology reports 85 27022737
2015 Mutations in TERT promoter and FGFR3 and telomere length in bladder cancer. International journal of cancer 82 25809917
2011 The FGFR3 mutation is related to favorable pT1 bladder cancer. The Journal of urology 82 22099989
2015 The integrated role of ACh, ERK and mTOR in the mechanisms of hippocampal inhibitory avoidance memory. Neurobiology of learning and memory 75 25595880
2014 Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma. Cancer biology & therapy 75 25535896
2016 Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation. Molecular cancer research : MCR 74 26869289
2010 Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. American journal of physiology. Endocrinology and metabolism 73 21139072
2020 FGFR3 Mutation Status and FGFR3 Expression in a Large Bladder Cancer Cohort Treated by Radical Cystectomy: Implications for Anti-FGFR3 Treatment?†. European urology 72 32682615
2011 Mechanisms of FGFR3 actions in endocrine resistant breast cancer. International journal of cancer 72 21792889
2011 Somatic mutation of fibroblast growth factor receptor-3 (FGFR3) defines a distinct morphological subtype of high-grade urothelial carcinoma. The Journal of pathology 70 21547910
2016 mTORC1 activation downregulates FGFR3 and PTH/PTHrP receptor in articular chondrocytes to initiate osteoarthritis. Osteoarthritis and cartilage 69 28043938
2014 FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Human molecular genetics 62 24419316
2020 FGFR3 signaling and function in triple negative breast cancer. Cell communication and signaling : CCS 61 31987043
2005 Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation. Molecular cancer 60 15869706
2020 Clinical, molecular, and radiomic profile of gliomas with FGFR3-TACC3 fusions. Neuro-oncology 56 32413119
2020 FGFR3 Alterations in the Era of Immunotherapy for Urothelial Bladder Cancer. Frontiers in immunology 56 33224141
2019 Clinical characterisation of sensory neuropathy with anti-FGFR3 autoantibodies. Journal of neurology, neurosurgery, and psychiatry 55 31690697
2017 Diffuse gliomas with FGFR3-TACC3 fusion have characteristic histopathological and molecular features. Brain pathology (Zurich, Switzerland) 54 28976058
2000 Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytic cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 53 10646125
2001 fgfr3 and regionalization of anterior neural tube in zebrafish. Mechanisms of development 48 11287195
2021 Regulation of Immune Functions by Non-Neuronal Acetylcholine (ACh) via Muscarinic and Nicotinic ACh Receptors. International journal of molecular sciences 47 34202925
2020 MicroRNA-99a Suppresses Breast Cancer Progression by Targeting FGFR3. Frontiers in oncology 47 32038996
2019 FGFR3 promotes the growth and malignancy of melanoma by influencing EMT and the phosphorylation of ERK, AKT, and EGFR. BMC cancer 47 31619201
2015 FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling. PLoS genetics 46 26091072
2010 Overexpression of KLF13 and FGFR3 in oral cancer cells. Cytogenetic and genome research 46 20539070
1995 A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia. American journal of medical genetics 43 7702086
2009 Multiple myeloma phosphotyrosine proteomic profile associated with FGFR3 expression, ligand activation, and drug inhibition. Proceedings of the National Academy of Sciences of the United States of America 41 19901323
2020 LncRNA KCNQ1OT1 accelerates fracture healing via modulating miR-701-3p/FGFR3 axis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40 32060985
2012 A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. Human molecular genetics 40 23014564
2011 Clathrin- and dynamin-independent endocytosis of FGFR3--implications for signalling. PloS one 40 21779335
2020 FGFR3 in Periosteal Cells Drives Cartilage-to-Bone Transformation in Bone Repair. Stem cell reports 39 32916123
2014 FGFR3 induces degradation of BMP type I receptor to regulate skeletal development. Biochimica et biophysica acta 39 24657641
2012 An activating Fgfr3 mutation affects trabecular bone formation via a paracrine mechanism during growth. Human molecular genetics 39 22367969
2010 Generation of Fgfr3 conditional knockout mice. International journal of biological sciences 39 20582225
2013 FGFR3 has tumor suppressor properties in cells with epithelial phenotype. Molecular cancer 37 23902722
2021 TS-HDS and FGFR3 antibodies in small fiber neuropathy and Dysautonomia. Muscle & nerve 35 33792960
2015 A novel variant of FGFR3 causes proportionate short stature. European journal of endocrinology 35 25777271
2017 Drug-sensitive FGFR3 mutations in lung adenocarcinoma. Annals of oncology : official journal of the European Society for Medical Oncology 34 27998968
2015 FGFR3 unliganded dimer stabilization by the juxtamembrane domain. Journal of molecular biology 34 25688803
2011 FGFR3 heterodimerization in achondroplasia, the most common form of human dwarfism. The Journal of biological chemistry 34 21324899
2009 FGFR3 and TP53 mutation analysis in inverted urothelial papilloma: incidence and etiological considerations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 33 19287463
2009 FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma. The Journal of clinical investigation 32 19422094
2021 FGFR3 phosphorylates EGFR to promote cisplatin-resistance in ovarian cancer. Biochemical pharmacology 31 33794187
2019 Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine 31 30685387
2017 Strong FGFR3 staining is a marker for FGFR3 fusions in diffuse gliomas. Neuro-oncology 31 28379477
2012 FGFR3 targeting strategies for achondroplasia. Expert reviews in molecular medicine 31 22559284
2021 Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway. Nature communications 29 34282140
2018 FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation. The Journal of pathology 29 30043421
2012 FGFR3, PIK3CA and RAS mutations in benign lichenoid keratosis. The British journal of dermatology 29 22188534
2005 Expression of acetylcholine (ACh) and ACh-synthesizing activity in Archaea. Life sciences 29 15936779
2014 FGFR3 mutations, but not FGFR3 expression and FGFR3 copy-number variations, are associated with favourable non-muscle invasive bladder cancer. Virchows Archiv : an international journal of pathology 27 24880661
2010 FGFR3 mutations and the skin: report of a patient with a FGFR3 gene mutation, acanthosis nigricans, hypochondroplasia and hyperinsulinemia and review of the literature. Dermatology (Basel, Switzerland) 27 20453470
2010 FGFR3 mutation affects cell growth, apoptosis and attachment in keratinocytes. Experimental cell research 26 20420824
2009 FGFR3 and PIK3CA mutations in stucco keratosis and dermatosis papulosa nigra. The British journal of dermatology 26 19845664
2007 FGFR3 intracellular mutations induce tyrosine phosphorylation in the Golgi and defective glycosylation. Biochimica et biophysica acta 26 17320202
1998 Modulation of ACh receptor currents by arachidonic acid. Brain research. Molecular brain research 26 9630614
2015 FGFR3 biology and skeletal disease. Connective tissue research 25 26075305
2017 mTORC1 regulates apoptosis and cell proliferation in pterygium via targeting autophagy and FGFR3. Scientific reports 24 28779179
2023 Clinico-pathological and epigenetic heterogeneity of diffuse gliomas with FGFR3::TACC3 fusion. Acta neuropathologica communications 23 36647073
2020 Fgfr3 Is a Positive Regulator of Osteoblast Expansion and Differentiation During Zebrafish Skull Vault Development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 23 32379366
2019 ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer. Scientific reports 23 30952872
2016 FGFR3 and Cyclin D3 as urine biomarkers of bladder cancer recurrence. Biomarkers in medicine 23 26861974
1995 Genomic organization of the mouse fibroblast growth factor receptor 3 (Fgfr3) gene. Genomics 23 8586414
2020 FGFR3△7-9 promotes tumor progression via the phosphorylation and destabilization of ten-eleven translocation-2 in human hepatocellular carcinoma. Cell death & disease 22 33097695
2001 Role of nitric oxide and protein kinase C in ACh-induced cardioprotection. American journal of physiology. Heart and circulatory physiology 22 11406485
2022 FGFR3-TACCs3 Fusions and Their Clinical Relevance in Human Glioblastoma. International journal of molecular sciences 20 35955806
2018 Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma. BMC urology 20 30064409
2018 FGFR3 Antibodies in Neuropathy: What to Do With Them? Journal of clinical neuromuscular disease 20 30124558
2011 FGFR3 is overexpressed waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis and overcomes stroma-induced proliferation. Clinical cancer research : an official journal of the American Association for Cancer Research 20 21521775
2021 Targeted therapies: Expanding the role of FGFR3 inhibition in urothelial carcinoma. Urologic oncology 19 34840077
2022 Dual targeting of FGFR3 and ERBB3 enhances the efficacy of FGFR inhibitors in FGFR3 fusion-driven bladder cancer. BMC cancer 18 35501832
2015 TP53 and FGFR3 Gene Mutation Assessment in Urine: Pilot Study for Bladder Cancer Diagnosis. Anticancer research 18 26254388
2023 Spectroscopic Determination of Acetylcholine (ACh): A Representative Review. Topics in current chemistry (Cham) 17 37169979
2019 Role of FGFR3 in Urothelial Carcinoma. Iranian journal of pathology 17 31528172
2015 Complementary roles of the Cek1 and Cek2 MAP kinases in Candida albicans cell-wall biogenesis. Future microbiology 17 26682470
2013 Temporal and occipital lobe features in children with hypochondroplasia/FGFR3 gene mutation. Pediatric radiology 17 23649205

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