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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
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
  • FGF receptors FGFR3, FGFR4 control alveolar elastogenesis
  • 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