Fibroblast growth factor receptor 3

FGFR3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1RY7, 2LZL, 4K33
Identifiers
Aliases	FGFR3, ACH, CD333, CEK2, HSFGFR3EX, JTK4, fibroblast growth factor receptor 3
External IDs	OMIM: 134934 MGI: 95524 HomoloGene: 55437 GeneCards: FGFR3
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4p16.3 Start 1,793,293 bp[1] End 1,808,872 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 B2|5 17.83 cM Start 33,879,018 bp[2] End 33,894,412 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia external globus pallidus internal globus pallidus optic nerve skin of abdomen human penis inferior olivary nucleus pancreatic ductal cell nipple ventral tegmental area Top expressed in dorsal tegmental nucleus lens medial vestibular nucleus ventral tegmental area hair follicle mammillary body superior colliculus dorsomedial hypothalamic nucleus left lung lobe globus pallidus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity kinase activity protein binding transmembrane receptor protein tyrosine kinase activity fibroblast growth factor binding fibroblast growth factor-activated receptor activity ATP binding protein tyrosine kinase activity phosphatidylinositol-4,5-bisphosphate 3-kinase activity 1-phosphatidylinositol-3-kinase activity identical protein binding receptor tyrosine kinase transmembrane signaling receptor activity Cellular component cytoplasm integral component of membrane Golgi apparatus membrane focal adhesion plasma membrane integral component of plasma membrane transport vesicle extracellular region cell surface endoplasmic reticulum cytoplasmic vesicle nucleus receptor complex Biological process bone mineralization chondrocyte differentiation phosphorylation negative regulation of developmental growth cell-cell signaling bone morphogenesis endochondral ossification bone maturation fibroblast growth factor receptor apoptotic signaling pathway MAPK cascade positive regulation of phosphatidylinositol 3-kinase activity positive regulation of phospholipase activity fibroblast growth factor receptor signaling pathway protein phosphorylation chondrocyte proliferation positive regulation of cell population proliferation positive regulation of ERK1 and ERK2 cascade protein autophosphorylation peptidyl-tyrosine phosphorylation endochondral bone growth positive regulation of MAPK cascade apoptotic process phosphatidylinositol phosphate biosynthetic process phosphatidylinositol-3-phosphate biosynthetic process positive regulation of tyrosine phosphorylation of STAT protein skeletal system development positive regulation of protein kinase B signaling negative regulation of signal transduction cell differentiation negative regulation of apoptotic process transmembrane receptor protein tyrosine kinase signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2261 14184 Ensembl ENSG00000068078 ENSMUSG00000054252 UniProt P22607 Q61851 RefSeq (mRNA) NM_000142 NM_001163213 NM_022965 NM_001354809 NM_001354810 NM_001163215 NM_001163216 NM_001163217 NM_001205270 NM_008010 NM_001359036 NM_001359037 RefSeq (protein) NP_000133 NP_001156685 NP_075254 NP_001341738 NP_001341739 n/a Location (UCSC) Chr 4: 1.79 – 1.81 Mb Chr 5: 33.88 – 33.89 Mb PubMed search [3] [4]
Wikidata
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Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene.^[5] FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.^[6]

The FGFR3 gene produces various forms of the FGFR3 protein; the location varies depending on the isoform of the FGFR3 protein. Since the different forms are found within different tissues the protein is responsible for multiple growth factor interactions.^[7] Gain of function mutations in FGFR3 inhibits chondrocyte proliferation and underlies achondroplasia and hypochondroplasia.

Function

The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals which ultimately influence cell mitogenesis and differentiation.

This particular family member binds both acidic and basic fibroblast growth factor and plays a role in bone development and maintenance. The FGFR3 protein plays a role in bone growth by regulating ossification.^[7] Alternative splicing occurs and additional variants have been described, including those utilizing alternate exon 8 rather than 9, but their full-length nature has not been determined.^[8]

Mutations

Simplification on the mutation 46 XX 4q16.3 (female), 46XY 4q16.3 (male). Gain of function mutations in this gene can develop dysfunctional proteins "impede cartilage growth and development and affect chondrocyte proliferation and calcification"^[6] which can lead to craniosynostosis and multiple types of skeletal dysplasia (osteochondrodysplasia).

In achondroplasia, the FGFR3 gene has a missense mutation at nucleotide 1138 resulting from either a G>A or G>C.^[9] This point mutation in the FGFR3 gene causes hydrogen bonds to form between two arginine side chains leading to ligand-independent stabilization of FGFR3 dimers. Overactivity of FGFR3 inhibits chondrocyte proliferation and restricts long bone length.^[7]

FGFR3 mutations are also linked with spermatocytic tumor, which occur more frequently in older men.^[10]

Disease linkage

Defects in the FGFR3 gene has been associated with several conditions, including craniosynostosis and seborrheic keratosis.^[11]

Bladder cancer

Mutations of FGFR3, FGFR3–TACC3 and FGFR3–BAIAP2L1 fusion proteins are frequently associated with bladder cancer, while some FGFR3 mutations are also associated with a better prognosis. Hence FGFR3 represents a potential therapeutic target for the treatment of bladder cancer.^[12]

Post-translational modification of FGFR3 occur in bladder cancer that do not occur in normal cells and can be targeted by immunotherapeutic antibodies.^[13]

Glioblastoma

FGFR3-TACC3 fusions have been identified as the primary mitogenic drivers in a subset of glioblastomas (approximately 4%) and other gliomas and may be associated with slightly improved overall survival.^[14] The FGFR3-TACC3 fusion represents a possible therapeutic target in glioblastoma.

Achondroplasia

Achondroplasia is a dominant genetic disorder caused by mutations in FGFR3 that make the resulting protein overactive. Individuals with these mutation have a head size that is larger than normal and are significantly shorter in height.^[15][16] Only a single copy of the mutated FGFR3 gene results in achondroplasia.^[17] It is generally caused by spontaneous mutations in germ cells; roughly 80 percent of the time, parents with children that have this disorder are normal size.^[16][17]

Thanatophoric dysplasia

Thanatophoric dysplasia is a genetic disorder caused by gain-of-function mutations in FGFR3 that is often fatal during the perinatal period because the child cannot breathe.^[18][19] There are two types. TD type I is caused by a stop codon mutation that is located in part of the gene coding for the extracellular domain of the protein.^[18] TD type II is a result of a substitution in a Lsy650Glu which is located in the tyrosine kinase area of FGFR3.^[18]

Muenke syndrome

Muenke syndrome, a disorder characterized by craniosynostosis, is caused by protein changes on FGFR3. The specific pathogenic variant c.749C>G changes the protein p.Pro250Arg, in turn resulting in this condition.^[20] Characteristics of Muenke syndrome include coronal synostosis (usually bilateral), midfacial retrusion, strabismus, hearing loss, and developmental delay. Turribrachycephaly, cloverleaf skull, and frontal bossing are also possible.^[21]

As a drug target

FGFR3 inhibitors are in early clinical trials as a cancer treatment,^{[citation needed]} e.g. BGJ398 for urothelial carcinoma.^[22] The FGFR3 receptor has a tyrosine kinase signaling pathway that is associated with many biological developments embryonically and in tissues.^{[citation needed]} Studying the tyrosine kinase signaling pathway that FGFR3 displays has played a crucial role in the development of research of several cell activities such as cell proliferation and cellular resistance to anti-cancer medications.^{[citation needed]}

Interactions

Fibroblast growth factor receptor 3 has been shown to interact with FGF8^[23][24] and FGF9.^[23][24]

See also

• Cluster of differentiation
• Fibroblast growth factor receptor

References

Further reading

External links

• GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes
• GeneReviews/NIH/NCBI/UW entry on Muenke Syndrome
• GeneReviews/NIH/NCBI/UW entry on Hypochondroplasia
• FGFR3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P22607 (Fibroblast growth factor receptor 3) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.