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MGP001074

UniProt Annotations

Entry Information
Gene Namefibroblast growth factor receptor 3
Protein EntryFGFR3_HUMAN
UniProt IDP22607
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=4; Name=1; Synonyms=IIIc; IsoId=P22607-1; Sequence=Displayed; Name=2; Synonyms=IIIb; IsoId=P22607-2; Sequence=VSP_002988; Name=3; Synonyms=FGFR3deltaTM; IsoId=P22607-3; Sequence=VSP_002989; Name=4; IsoId=P22607-4; Sequence=VSP_040945; Note=No experimental confirmation available.;
Catalytic ActivityATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE- ProRule:PRU10028, ECO:0000269|PubMed:12297284, ECO:0000269|PubMed:17145761}.
DiseaseAchondroplasia (ACH) [MIM:100800]: A frequent form of short-limb dwarfism. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. {ECO:0000269|PubMed:7758520, ECO:0000269|PubMed:7847369, ECO:0000269|PubMed:8078586}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseBladder cancer (BLC) [MIM:109800]: A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas that begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. {ECO:0000269|PubMed:11314002}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3.
DiseaseCamptodactyly tall stature and hearing loss syndrome (CATSHL syndrome) [MIM:610474]: Autosomal dominant syndrome characterized by permanent and irreducible flexion of one or more fingers of the hand and/or feet, tall stature, scoliosis and/or a pectus excavatum, and hearing loss. Affected individuals have developmental delay and/or mental retardation, and several of these have microcephaly. Radiographic findings included tall vertebral bodies with irregular borders and broad femoral metaphyses with long tubular shafts. On audiological exam, each tested member have bilateral sensorineural hearing loss and absent otoacoustic emissions. The hearing loss was congenital or developed in early infancy, progressed variably in early childhood, and range from mild to severe. Computed tomography and magnetic resonance imaging reveal that the brain, middle ear, and inner ear are structurally normal. {ECO:0000269|PubMed:17033969}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseCervical cancer (CERCA) [MIM:603956]: A malignant neoplasm of the cervix, typically originating from a dysplastic or premalignant lesion previously present at the active squamocolumnar junction. The transformation from mild dysplastic to invasive carcinoma generally occurs slowly within several years, although the rate of this process varies widely. Carcinoma in situ is particularly known to precede invasive cervical cancer in most cases. Cervical cancer is strongly associated with infection by oncogenic types of human papillomavirus. Note=The gene represented in this entry is involved in disease pathogenesis.
DiseaseCrouzon syndrome with acanthosis nigricans (CAN) [MIM:612247]: Classic Crouzon disease which is caused by mutations in the FGFR2 gene is characterized by craniosynostosis (premature fusion of the skull sutures), and facial hypoplasia. Crouzon syndrome with acanthosis nigricans (a skin disorder characterized by pigmentation anomalies), CAN, is considered to be an independent disorder from classic Crouzon syndrome. CAN is characterized by additional more severe physical manifestation, such as Chiari malformation, hydrocephalus, and atresia or stenosis of the choanas, and is caused by a specific mutation (Ala-391 to Glu) in the transmembrane domain of FGFR3. It is proposed to have an autosomal dominant mode of inheritance. {ECO:0000269|PubMed:17935505, ECO:0000269|PubMed:7493034}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseHypochondroplasia (HCH) [MIM:146000]: Autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. {ECO:0000269|PubMed:10215410, ECO:0000269|PubMed:10777366, ECO:0000269|PubMed:11055896, ECO:0000269|PubMed:12707965, ECO:0000269|PubMed:7670477, ECO:0000269|PubMed:9452043}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseKeratinocytic non-epidermolytic nevus (KNEN) [MIM:162900]: Epidermal nevi of the common, non-organoid and non- epidermolytic type are benign skin lesions and may vary in their extent from a single (usually linear) lesion to widespread and systematized involvement. They may be present at birth or develop early during childhood. {ECO:0000269|PubMed:16841094}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseKeratosis, seborrheic (KERSEB) [MIM:182000]: A common benign skin tumor. Seborrheic keratoses usually begin with the appearance of one or more sharply defined, light brown, flat macules. The lesions may be sparse or numerous. As they initially grow, they develop a velvety to finely verrucous surface, followed by an uneven warty surface with multiple plugged follicles and a dull or lackluster appearance. {ECO:0000269|PubMed:15772091}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseLacrimo-auriculo-dento-digital syndrome (LADDS) [MIM:149730]: An autosomal dominant ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Lacrimo-auriculo-dento-digital syndrome is characterized by aplastic/hypoplastic lacrimal and salivary glands and ducts, cup-shaped ears, hearing loss, hypodontia and enamel hypoplasia, and distal limb segments anomalies. In addition to these cardinal features, facial dysmorphism, malformations of the kidney and respiratory system and abnormal genitalia have been reported. Craniosynostosis and severe syndactyly are not observed. {ECO:0000269|PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseMuenke syndrome (MNKS) [MIM:602849]: A condition characterized by premature closure of coronal suture of skull during development (coronal craniosynostosis), which affects the shape of the head and face. It may be uni- or bilateral. When bilateral, it is characterized by a skull with a small antero- posterior diameter (brachycephaly), often with a decrease in the depth of the orbits and hypoplasia of the maxillae. Unilateral closure of the coronal sutures leads to flattening of the orbit on the involved side (plagiocephaly). The intellect is normal. In addition to coronal craniosynostosis some affected individuals show skeletal abnormalities of hands and feet, sensorineural hearing loss, mental retardation and respiratory insufficiency. {ECO:0000269|PubMed:11746040, ECO:0000269|PubMed:9042914, ECO:0000269|PubMed:9950359}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseMultiple myeloma (MM) [MIM:254500]: A malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. {ECO:0000269|PubMed:11529856, ECO:0000269|PubMed:9207791}. Note=The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving FGFR3 is found in multiple myeloma. Translocation t(4;14)(p16.3;q32.3) with the IgH locus.
DiseaseTesticular germ cell tumor (TGCT) [MIM:273300]: A common malignancy in males representing 95% of all testicular neoplasms. TGCTs have various pathologic subtypes including: unclassified intratubular germ cell neoplasia, seminoma (including cases with syncytiotrophoblastic cells), spermatocytic seminoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma. {ECO:0000269|PubMed:19855393}. Note=The gene represented in this entry may be involved in disease pathogenesis.
DiseaseThanatophoric dysplasia 1 (TD1) [MIM:187600]: A neonatal lethal skeletal dysplasia. Affected individuals manifest severe shortening of the limbs with macrocephaly, narrow thorax, short ribs, and curved femurs. {ECO:0000269|PubMed:10360402, ECO:0000269|PubMed:10671061, ECO:0000269|PubMed:7773297, ECO:0000269|PubMed:8589699, ECO:0000269|PubMed:8845844, ECO:0000269|PubMed:9790257}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseThanatophoric dysplasia 2 (TD2) [MIM:187601]: A neonatal lethal skeletal dysplasia causing severe shortening of the limbs, narrow thorax and short ribs. Patients with thanatophoric dysplasia type 2 have straight femurs and cloverleaf skull. {ECO:0000269|PubMed:7773297}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainThe second and third Ig-like domains directly interact with fibroblast growth factors (FGF) and heparan sulfate proteoglycans. {ECO:0000269|PubMed:14732692}.
Enzyme RegulationPresent in an inactive conformation in the absence of bound ligand. Ligand binding leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by SU5402. {ECO:0000269|PubMed:14732692, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17509076}.
FunctionTyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of cell proliferation, differentiation and apoptosis. Plays an essential role in the regulation of chondrocyte differentiation, proliferation and apoptosis, and is required for normal skeleton development. Regulates both osteogenesis and postnatal bone mineralization by osteoblasts. Promotes apoptosis in chondrocytes, but can also promote cancer cell proliferation. Required for normal development of the inner ear. Phosphorylates PLCG1, CBL and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Plays a role in the regulation of vitamin D metabolism. Mutations that lead to constitutive kinase activation or impair normal FGFR3 maturation, internalization and degradation lead to aberrant signaling. Over-expressed or constitutively activated FGFR3 promotes activation of PTPN11/SHP2, STAT1, STAT5A and STAT5B. Secreted isoform 3 retains its capacity to bind FGF1 and FGF2 and hence may interfere with FGF signaling. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14534538, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17145761, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:19088846, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}.
InteractionP05230:FGF1; NbExp=3; IntAct=EBI-348399, EBI-698068; P08238:HSP90AB1; NbExp=2; IntAct=EBI-348399, EBI-352572;
PtmAutophosphorylated. Binding of FGF family members together with heparan sulfate proteoglycan or heparin promotes receptor dimerization and autophosphorylation on tyrosine residues. Autophosphorylation occurs in trans between the two FGFR molecules present in the dimer. Phosphorylation at Tyr-724 is essential for stimulation of cell proliferation and activation of PIK3R1, STAT1 and MAP kinase signaling. Phosphorylation at Tyr-760 is required for interaction with PIK3R1 and PLCG1. {ECO:0000269|PubMed:11294897, ECO:0000269|PubMed:19286672}.
PtmN-glycosylated in the endoplasmic reticulum. The N-glycan chains undergo further maturation to an Endo H-resistant form in the Golgi apparatus. {ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:17311277, ECO:0000269|PubMed:17509076}.
PtmUbiquitinated. Is rapidly ubiquitinated after ligand binding and autophosphorylation, leading to receptor internalization and degradation. Subject to both proteasomal and lysosomal degradation. {ECO:0000269|PubMed:12297284, ECO:0000269|PubMed:17509076}.
Sequence CautionSequence=BAD92678.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305};
SimilarityBelongs to the protein kinase superfamily. Tyr protein kinase family. Fibroblast growth factor receptor subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
SimilarityContains 3 Ig-like C2-type (immunoglobulin-like) domains. {ECO:0000305}.
Subcellular LocationIsoform 1: Cell membrane; Single-pass type I membrane protein. Cytoplasmic vesicle. Endoplasmic reticulum. Note=The activated receptor is rapidly internalized and degraded. Detected in intracellular vesicles after internalization of the autophosphorylated receptor.
Subcellular LocationIsoform 2: Cell membrane {ECO:0000250}; Single-pass type I membrane protein {ECO:0000250}.
Subcellular LocationIsoform 3: Secreted.
Subcellular LocationIsoform 4: Cell membrane {ECO:0000250}; Single-pass type I membrane protein {ECO:0000250}.
SubunitMonomer. Homodimer after ligand binding. Interacts with FGF1, FGF2, FGF4, FGF6; FGF8, FGF9, FGF10, FGF17, FGF18, FGF19, FGF20 and FGF23 (in vitro). Interacts with KLB. Affinity for fibroblast growth factors (FGFs) is increased by heparan sulfate glycosaminoglycans that function as coreceptors. Likewise, KLB increases the affinity for FGF19 and FGF21. Interacts with PIK3R1, PLCG1, SOCS1 and SOCS3. Isoform 3 forms disulfide-linked dimers. {ECO:0000269|PubMed:10611230, ECO:0000269|PubMed:11703096, ECO:0000269|PubMed:14732692, ECO:0000269|PubMed:16410555, ECO:0000269|PubMed:16597617, ECO:0000269|PubMed:17561467, ECO:0000269|PubMed:17623664, ECO:0000269|PubMed:19286672, ECO:0000269|PubMed:8663044}.
Tissue SpecificityExpressed in brain, kidney and testis. Very low or no expression in spleen, heart, and muscle. In 20- to 22- week old fetuses it is expressed at high level in kidney, lung, small intestine and brain, and to a lower degree in spleen, liver, and muscle. Isoform 2 is detected in epithelial cells. Isoform 1 is not detected in epithelial cells. Isoform 1 and isoform 2 are detected in fibroblastic cells. {ECO:0000269|PubMed:1664411}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/FGFRID99.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/fgfr3/";
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