InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: FGFR3

Summary

InnateDB Protein

IDBP-360832.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

FGFR3

Protein Name

fibroblast growth factor receptor 3

Synonyms

ACH; CD333; CEK2; HSFGFR3EX; JTK4;

Species

Homo sapiens

Ensembl Protein

ENSP00000412903

InnateDB Gene

IDBG-6932 (FGFR3)

Protein Structure

UniProt Annotation

Function

Tyrosine-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:0000269PubMed:10611230, ECO:0000269PubMed:11294897, ECO:0000269PubMed:11703096, ECO:0000269PubMed:14534538, ECO:0000269PubMed:16410555, ECO:0000269PubMed:16597617, ECO:0000269PubMed:17145761, ECO:0000269PubMed:17311277, ECO:0000269PubMed:17509076, ECO:0000269PubMed:17561467, ECO:0000269PubMed:19088846, ECO:0000269PubMed:19286672, ECO:0000269PubMed:8663044}.

Subcellular Localization

Isoform 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.Isoform 2: Cell membrane {ECO:0000250}; Single-pass type I membrane protein {ECO:0000250}.Isoform 3: Secreted.Isoform 4: Cell membrane {ECO:0000250}; Single-pass type I membrane protein {ECO:0000250}.

Disease Associations

Achondroplasia (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:0000269PubMed:7758520, ECO:0000269PubMed:7847369, ECO:0000269PubMed:8078586}. Note=The disease is caused by mutations affecting the gene represented in this entry.Crouzon 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:0000269PubMed:17935505, ECO:0000269PubMed:7493034}. Note=The disease is caused by mutations affecting the gene represented in this entry.Thanatophoric 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:0000269PubMed:10360402, ECO:0000269PubMed:10671061, ECO:0000269PubMed:7773297, ECO:0000269PubMed:8589699, ECO:0000269PubMed:8845844, ECO:0000269PubMed:9790257}. Note=The disease is caused by mutations affecting the gene represented in this entry.Thanatophoric 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:0000269PubMed:7773297}. Note=The disease is caused by mutations affecting the gene represented in this entry.Hypochondroplasia (HCH) [MIM:146000]: Autosomal dominant disease and is characterized by disproportionate short stature. It resembles achondroplasia, but with a less severe phenotype. {ECO:0000269PubMed:10215410, ECO:0000269PubMed:10777366, ECO:0000269PubMed:11055896, ECO:0000269PubMed:12707965, ECO:0000269PubMed:7670477, ECO:0000269PubMed:9452043}. Note=The disease is caused by mutations affecting the gene represented in this entry.Bladder 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:0000269PubMed:11314002}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Somatic mutations can constitutively activate FGFR3.Cervical 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.Camptodactyly 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:0000269PubMed:17033969}. Note=The disease is caused by mutations affecting the gene represented in this entry.Multiple 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:0000269PubMed:11529856, ECO:0000269PubMed: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.Lacrimo-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:0000269PubMed:16501574}. Note=The disease is caused by mutations affecting the gene represented in this entry.Keratinocytic 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:0000269PubMed:16841094}. Note=The disease is caused by mutations affecting the gene represented in this entry.Muenke 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:0000269PubMed:11746040, ECO:0000269PubMed:9042914, ECO:0000269PubMed:9950359}. Note=The disease is caused by mutations affecting the gene represented in this entry.Keratosis, 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:0000269PubMed:15772091}. Note=The disease is caused by mutations affecting the gene represented in this entry.Testicular 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:0000269PubMed:19855393}. Note=The gene represented in this entry may be involved in disease pathogenesis.

Tissue Specificity

Expressed 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:0000269PubMed:1664411}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 46 experimentally validated interaction(s) in this database.
They are also associated with 2 interaction(s) predicted by orthology.

Experimentally validated
Total	46 [view]
Protein-Protein	46 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	2 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005007	fibroblast growth factor-activated receptor activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0017134	fibroblast growth factor binding

Biological Process

GO:0001501	skeletal system development
GO:0001958	endochondral ossification
GO:0002062	chondrocyte differentiation
GO:0003416	endochondral bone growth
GO:0006468	protein phosphorylation
GO:0007173	epidermal growth factor receptor signaling pathway
GO:0007259	JAK-STAT cascade
GO:0008284	positive regulation of cell proliferation
GO:0008286	insulin receptor signaling pathway
GO:0008543	fibroblast growth factor receptor signaling pathway
GO:0010518	positive regulation of phospholipase activity
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0030282	bone mineralization
GO:0035988	chondrocyte proliferation
GO:0038095	Fc-epsilon receptor signaling pathway
GO:0042511	positive regulation of tyrosine phosphorylation of Stat1 protein
GO:0042517	positive regulation of tyrosine phosphorylation of Stat3 protein
GO:0043410	positive regulation of MAPK cascade
GO:0043552	positive regulation of phosphatidylinositol 3-kinase activity
GO:0045087	innate immune response
GO:0046777	protein autophosphorylation
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0048015	phosphatidylinositol-mediated signaling
GO:0048640	negative regulation of developmental growth
GO:0060349	bone morphogenesis
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0070977	bone maturation
GO:1902178	fibroblast growth factor receptor apoptotic signaling pathway

Cellular Component

GO:0005576	extracellular region
GO:0005783	endoplasmic reticulum
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0005925	focal adhesion
GO:0016021	integral component of membrane
GO:0016023	cytoplasmic membrane-bounded vesicle

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003598 Immunoglobulin subtype 2
IPR003599 Immunoglobulin subtype
IPR007110 Immunoglobulin-like domain
IPR011009 Protein kinase-like domain
IPR013098 Immunoglobulin I-set
IPR013151 Immunoglobulin
IPR016248 Fibroblast growth factor receptor family
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714
PF07679
PF00047

PRINTS

PR00109

PIRSF

PIRSF000628

SMART

SM00220
SM00408
SM00409
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References