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FLASH GENE
Symbol FGFR3 contributors: mct/pgu - updated : 29-03-2017
HGNC name fibroblast growth factor receptor 3
HGNC id 3690
Corresponding disease
ACH achondroplasia
BSCGS2 Beare-Stevenson cutis gyrata syndrome 3
CATSHL camptodactyly, tall stature and hearing loss syndrome
CRS10 craniosynostosis, syndromatic 10
CRS5B craniosynostosis, syndromatic 5B
CRS8 craniosynostosis, syndromatic 8
CRSCNS craniosynostosis, non syndromatic
FENS FGFR3 epidermal nevus syndrome
HCH hypochondroplasia
LADD2 lacrimoauriculodentodigital syndrome 2
SADDAN severe achondroplasia with developmental delay and acanthosis nigricans
TNTP1 thanatophoric dysplasia, type 1
TNTP2 thanatophoric dysplasia, type 2
Location 4p16.3      Physical location : 1.795.038 - 1.810.599
Synonym name
  • tyrosine kinase JTK4
  • hydroxyaryl-protein kinase
  • CD333 antigen
  • Synonym symbol(s) CEK2, JTK4, CD333, HSFGFR3EX
    EC.number 2.7.10.1
    DNA
    TYPE functioning gene
    STRUCTURE 15.56 kb     18 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence cytosine-phosphate-guanine/HTF
    Binding site   transcription factor
    text structure
  • binding sites for sp1, AP2, Krox24, IgHC4 and ZESTE
  • SHOX strongly activate the extended FGFR3 promoter)
  • MAPPING cloned Y linked N status confirmed
    Map pter - D4S115 - D4S168 - D4S113 - FGFR3 ,[D4S99 - D4S98 ] - D4S114 - D4S166 - WHSC2 - D4S43 - cen
    Text see D4S10
    Physical map
    PCDH18 4q31.2-q32 protocadherin 18 LOC389255 4 similar to RSTI689 LOC152687 4p16.3 hypothetical protein LOC152687 AMBN 4q21 ameloblastin, enamel matrix protein FLJ90036 4p16.3 hypothetical protein FLJ90036 LOC391611 4 similar to Zinc finger protein 208 ZNF141 4p16.3 zinc finger protein 141 (clone pHZ-44) FLJ14297 4p16.3 hypothetical protein FLJ14297 FLJ20265 4p16.3 hypothetical protein FLJ20265 PDE6B 4p16.3 phosphodiesterase 6B, cGMP-specific, rod, beta (congenital stationary night blindness 3, autosomal dominant) ATP5I 4p16.3 ATP synthase, H+ transporting, mitochondrial F0 complex, subunit e MYL5 4p16.3 myosin, light polypeptide 5, regulatory FLJ22269 4p16.3 hypothetical protein FLJ22269 RNF3 4p16.3 ring finger protein 3 CPLX1 4p16.3 complexin 1 GAK 4p16 cyclin G associated kinase MGC4618 4p16.3 hypothetical protein MGC4618 DGKQ 4p16.3 diacylglycerol kinase, theta 110kDa SLC26A1 4p16.3 solute carrier family 26 (sulfate transporter), member 1 IDUA 4p16.3 iduronidase, alpha-L- FGFRL1 4p16 fibroblast growth factor receptor-like 1 LOC285498 4p16.3 hypothetical protein LOC285498 LOC132969 4p16.3 similar to hornerin SPON2 4p16.3 spondin 2, extracellular matrix protein CTBP1 4p16 C-terminal binding protein 1 MGC21675 4p16.3 hypothetical protein MGC21675 MAEA 4p16.3 macrophage erythroblast attacher KIAA1530 4p16.3 KIAA1530 protein FLJ34443 4p16.3 hypothetical protein FLJ34443 HSPX153 4p16.3 HPX-153 homeobox LOC345375 4p16.3 similar to CG32656-PA LOC152877 4p16.3 similar to RIKEN cDNA 5430419M09 SLBP 4p16 stem-loop (histone) binding protein LOC92305 4p16.3 hypothetical protein BC009331 TACC3 4p16.3 transforming, acidic coiled-coil containing protein 3 FGFR3 4p16.3 fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism) LETM1 4p16.3 leucine zipper-EF-hand containing transmembrane protein 1 WHSC1 4p16.3 Wolf-Hirschhorn syndrome candidate 1 WHSC2 4p16.3 Wolf-Hirschhorn syndrome candidate 2 LOC389195 4 hypothetical gene supported by BC038466; BC047038 FLJ37478 4p16.3 hypothetical protein FLJ37478 POLN 4p16.3 polymerase (DNA directed) nu MGC4701 4p16.3 hypothetical protein MGC4701 MXD4 4p16.3 MAX dimerization protein 4 KIAA1643 4p16.3 KIAA1643 protein LOC339985 4p16.3 hypothetical gene supported by BC010180 RNF4 4p16.3 ring finger protein 4 C4orf8 4p16.3 chromosome 4 open reading frame 8 TNIP2 4p16.3 TNFAIP3 interacting protein 2 LOC389196 4 LOC389196 SH3BP2 4p16.3 SH3-domain binding protein 2 ADD1 4p16.3 adducin 1 (alpha) TETRAN 4p16.3 tetracycline transporter-like protein C4orf9 4p16.3 chromosome 4 open reading frame 9 GPRK2L 4p16.3 G protein-coupled receptor kinase 2-like (Drosophila) HD 4p16.3 huntingtin (Huntington disease) LOC345222 4p16.3 hypothetical gene supported by BC043530 RGS12 4p16.3 regulator of G-protein signalling 12 HGFAC 4p16.3 HGF activator FLJ33718 4p16.3 hypothetical protein FLJ33718
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - - - - - epithelial cells 1995 7495869
  • also called FGFR3b
  • activated by FGF1, FGF3
  • does not cooperate with the FGFR3c isoform in endochondral bone development
  • - - 370 - 125 mesenchymal cells 2011 21894939
  • also called FGFR3c
  • activated by FGF1, FGF4, FGF5, FGF6, FGF8
  • main transducer of the balance between cell proliferation and differentiation during normal chondrocyte development
  • FGF1 and FGF2 elicit a similar FGFR3c response at low, but not at high, concentrations
  • BGN binds to FGFR3c and FGF1 (PMID: 25260943)
  • 17 splicing 4304 87.7 806 in the inner retina, in fibroblastic cells 1995 7495869
  • also called variant 1, isoform 1 or isoform IIIc
  • 3 Ig-like domains
  • missing exon 8
  • using exon 9
  • alternative splicing choice between IIIb and IIIc exons of the is not strictly tissue-specific: epithelial cells show exclusively IIIb transcripts while fibroblastic cells show a mixture of IIIb and IIIc transcripts
  • 15 - 3968 75 694 maybe secreted 2009 18923003
  • variant 2
  • two Ig-like domains
  • - - 390 86 782 undifferenciated chondrocytes 2001 11134040
  • also called FGFR3-DAB
  • lacking the acid-box domain
  • - splicing - - - tumour and tumour cell lines 2003 14520460
  • also called FGFR3 IIIS
  • soluble
  • regulate FGF and FGFR trafficking and function, possibly contributing to the development of a malignant phenotype
  • - - 4310 - 808 in epithelial cells and fibroblastic cells 1995 7495869
  • isoform IIIb
  • alternative splicing choice between IIIb and IIIc exons of the is not strictly tissue-specific: epithelial cells show exclusively IIIb transcripts while fibroblastic cells show a mixture of IIIb and IIIc transcripts
  • EXPRESSION
    Type
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly
    Digestiveintestinelarge intestine  lowly Homo sapiens
     intestinesmall intestinejejunum   Homo sapiens
    Nervousbrain    
    Reproductivemale systemtestis    Homo sapiensAdult
    Skeletonaxialskull   
    Urinarybladder    
     kidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivecartilage   
    Epithelialabsorptive excretorydigestive epithelium (mucosa)   Homo sapiens
    Muscularstriatumcardiac highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte
    Digestiveenterocyte Homo sapiens
    DigestivePaneth Homo sapiens
    Muscularmyocyte Homo sapiens
    Reproductivespermatogonia Homo sapiensAdult
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text kidney, lung, small intestine, brain, lowly in spleen, liver, muscle, cartilage, skull
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a signal peptide, three Ig-like domains
  • an acidic region between the first and second Ig loops
  • a single membrane-spanning segment
  • two C-terminal intracellular split tyrosine-kinase domains
  • conjugated GlycoP
    isoforms Precursor
    HOMOLOGY
    interspecies homolog to murine Fgfr3
    Homologene
    FAMILY
  • protein kinase superfamily
  • Tyr protein kinase family
  • fibroblast growth factor receptor subfamily
  • CATEGORY signaling growth factor , receptor membrane
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,lysosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • ectodomain cleavage is followed by intramembrane cleavage (S2) to generate a soluble intracellular domain that is released into the cytosol and can translocate to the nucleus (mechanism for the nuclear localization of FGFR3 in response to ligand activation, which may occur in both development and disease)
  • basic FUNCTION
  • receptor tyrosine kinase class IV, negative regulator of bone growth, playing an important role in the control of chondrocyte proliferation and differentiation, a process critical for normal development of the skeleton
  • essential regulator of endochondral bone growth
  • promotion and inhibition of chondrocyte proliferation and differentiation depending on the time during development (mouse)
  • negative regulation of endochondral ossification
  • involved in lysosomal degradation through c-Cbl mediated ubiquination(defective in achondroplasia)
  • potential molecular targets with its ligand FGF18, for intervention in tissue engineering aimed at cartilage repair and regeneration of damaged cartilage
  • requires SNAI1 during bone development and disease as the inhibition of SNAI1 abolishes its signaling even through achondroplastic- and thanatophoric-activating FGFR3 forms
  • potential tumor suppressor gene in melanoma
  • FGF18 and FGFR3 are involved, possibly as partners, in the control of intestinal precursor cell proliferation
  • with MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers (resposible of spinal canal and foramen magnum stenosis)
  • activated FGFR3 implicated in cell adaptation, including Sprouty4 (SPRY4)up regulation to inhibit the receptor-mediated ERKs activation from the endoplasmic reticulum
  • transcriptional regulation of FGFR3 might play a so far underestimated role in the development of short stature
  • FGFR3 signaling may potentially regulate intestinal crypt stem cell numbers by regulating the differentiation of the Paneth cell phenotype
  • FGFR3 signaling also modulates other effectors and/or pathways that are required to induce Paneth cell DEFA5 expression in addition to its effects on TCF4/CTNNB activity)
  • FGFR1, FGFR2, FGFR3, differentially control the normal generation of oligodendrocyte progenitor (OLP) from the embryonic ventral forebrain
  • is internalized by both clathrin-dependent and clathrin-independent mechanisms
  • specific role for FGFR3 in the cell cycle and chondrocyte differentiation
  • impaired FGFR3 signaling pathways may affect trabecular bone formation via a paracrine mechanism during growth
  • is likely a negative regulator of endochondral bone growth
  • receptor tyrosine kinase that control cell proliferation, differentiation, and survival
  • role of FGFR3 in regulating lipid metabolism to maintain tumor growth and survival
  • regulates microtubule formation and cell surface mechanical properties in the developing organ of Corti
  • transduces biochemical signals via lateral dimerization in the plasma membrane, and plays an important role in human development and disease
  • has a tumor suppressor-like function in chondrogenesis
  • FGF8 and FGFR3 may play an important role in the onset of deep zone necrosis and pathogenesis in osteochondropathy Kashin-Beck disease in adolescent children
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • IHH (negative regulator of IHH)
  • STAT protein, PTHLH
  • ligand FGF18
  • interacting with RPS6KA3 (association is critical for FGFR3-dependent tyrosine phosphorylation at Y529 and Y707 of RPS6KA3 as well as its subsequent activation and RPS6KA3 is important for FGFR3-induced hematopoietic transformation)
  • FGFR3 is a novel transcriptional target of SHOX
  • ligands for FGFR3, FGF1, FGF2, and FGF9
  • associates with Hsp90 and CDC37
  • direct target of canonical Wnt signaling (Reinhold 2007)
  • GLG1 is involved in FGF18 signalling via FGFR3C
  • FGF1 induces regulated intramembrane proteolysis (RIP) of FGFR3
  • by binding FGFR1 and/or FGFR3, FGF21 prevents GH-mediated stimulation of chondrocyte proliferation and differentiation
  • FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, SREBF1, that in turn regulates the expression of SCD
  • FGF23 binding to FGFR3 was enhanced in the presence of KL
  • FGFR3 facilitates BMPR1A to degradation through SMURF1-mediated ubiquitination pathway
  • in addition to modulating FGFR3 phosphorylation, PTPN1 and PTPN2 constrain the kinase domain by fostering an inactive-state
  • cell & other
    REGULATION
    activated by oligomerization induced by ligand binding, followed by autophosphorylation at multiple tyrosine residues that are believed to provide docking sites for signaling factors through their respective Src homology 2 (SH2) phosphotyrosine binding domains
    Other regulated by HSP90 that is an important regulator of FGFR3 function
    FGFR3 activation in chondrocytes mimics the activation of major oncogenes signaling via the ERK pathway
    ASSOCIATED DISORDERS
    corresponding disease(s) ACH , CRS10 , CRS5B , CRSCNS , CRS8 , FENS , SADDAN , TNTP1 , TNTP2 , HCH , BSCGS2 , LADD2 , CATSHL
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in transitional cell carcinomas
    tumoral somatic mutation      
    in superficial urothelial cell carcinoma (UCC), in bladder carcinomas (superficial or low-grade)
    constitutional somatic mutation     gain of function
    somatic activating mutations in acanthosis nigricans and seborrheic keratosis
    tumoral     --other  
    dysregulated in multiple myeloma with t(4;14)(p16.3;q32)
    constitutional somatic mutation      
    mosaicism of activating mutation in skin causing epidermal nevi
    constitutional germinal mutation      
    intracellular mutations induce tyrosine phosphorylation in the Golgi, defective glycosylation and could disrupt bone development
    tumoral germinal mutation      
    in seborrheic keratosis and urothelial carcinomas
    tumoral fusion      
    TEL-FGFR3, in t(4;12)(p16;p13) with acute myeloid leukemia
    constitutional somatic mutation      
    somatic activating fibroblast growth factor 3 (FGFR3) mutations in skin can cause seborrheic keratoses
    tumoral       gain of function
    mutation activating in spermatocytic seminomas, paternal age-effect mutations activating a common 'selfish' pathway supporting proliferation in the testis
    constitutional germinal mutation     gain of function
    gain-of-function mutations, would have a stronger effect on the upper arm and leg, since FGFR3 is not targeted by SHOX in that part of the limbs and therefore expressed at higher levels than in the mesomelic segments
    tumoral fusion      
    with BAIAP2L1, in bladder carcinoma 3)
    tumoral fusion      
    to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively in glioblastoma
    constitutional        
    -
    Susceptibility
  • to urinary bladder cancer (UBC)
  • to short stature
  • Variant & Polymorphism SNP
  • rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors
  • p.M528I mutation in FGFR3 segregates with short stature
  • Candidate gene
    Marker
  • nuclear translocation of FGFR3 is frequent and carries clinicopathologic as well as prognostic significances in pancreatic cancer
  • Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies (for multiple myeloma associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants)
    osteoarticularbone 
    HSP90 inhibitors may be useful for treating FGFR3-mediated diseases
    osteoarticularboneosteochondroplasia
    development of tyrosine kinase inhibitors for the treatment of FGFR3-related chondrodysplasias
    osteoarticularbone 
    inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia
    ANIMAL & CELL MODELS
  • chondrocyte-specific activation of Fgfr3 in mice induced premature synchondrosis closure and enhanced osteoblast differentiation around synchondroses
  • FGFR-3-/- mice show a marked deficit in a number of Paneth cell markers and a significant reduction in the number of lysozyme-positive Paneth cell