Fibroblast growth factor receptor 3

Last updated
FGFR3
PDB 1ry7 EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FGFR3 , ACH, CD333, CEK2, HSFGFR3EX, JTK4, fibroblast growth factor receptor 3
External IDs OMIM: 134934 MGI: 95524 HomoloGene: 55437 GeneCards: FGFR3
Orthologs
SpeciesHumanMouse
Entrez

2261

14184

Ensembl

ENSG00000068078

ENSMUSG00000054252

UniProt

P22607

Q61851

RefSeq (mRNA)

NM_000142
NM_001163213
NM_022965
NM_001354809
NM_001354810

Contents

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
View/Edit Human View/Edit Mouse

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 ] eg. 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

Related Research Articles

Achondroplasia is a genetic disorder with an autosomal dominant pattern of inheritance whose primary feature is dwarfism. In those with the condition, the arms and legs are short, while the torso is typically of normal length. Those affected have an average adult height of 131 centimetres for males and 123 centimetres (4 ft) for females. Other features can include an enlarged head and prominent forehead. Complications can include sleep apnea or recurrent ear infections. Achondroplasia includes short-limb skeletal dysplasia with severe combined immunodeficiency.

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

<span class="mw-page-title-main">Crouzon syndrome</span> Genetic disorder of the skull and face

Crouzon syndrome is an autosomal dominant genetic disorder known as a branchial arch syndrome. Specifically, this syndrome affects the first branchial arch, which is the precursor of the maxilla and mandible. Since the branchial arches are important developmental features in a growing embryo, disturbances in their development create lasting and widespread effects.

<span class="mw-page-title-main">Craniosynostosis</span> Premature fusion of bones in the skull

Craniosynostosis is a condition in which one or more of the fibrous sutures in a young infant's skull prematurely fuses by turning into bone (ossification), thereby changing the growth pattern of the skull. Because the skull cannot expand perpendicular to the fused suture, it compensates by growing more in the direction parallel to the closed sutures. Sometimes the resulting growth pattern provides the necessary space for the growing brain, but results in an abnormal head shape and abnormal facial features. In cases in which the compensation does not effectively provide enough space for the growing brain, craniosynostosis results in increased intracranial pressure leading possibly to visual impairment, sleeping impairment, eating difficulties, or an impairment of mental development combined with a significant reduction in IQ.

<span class="mw-page-title-main">Thanatophoric dysplasia</span> Severe form of genetic dwarfism that is usually lethal

Thanatophoric dysplasia is a severe skeletal disorder characterized by a disproportionately small ribcage, extremely short limbs and folds of extra skin on the arms and legs.

<span class="mw-page-title-main">Chromosome 4</span> Human chromosome

Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 193 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.

Crouzonodermoskeletal syndrome is a disorder characterized by the premature joining of certain bones of the skull (craniosynostosis) during development and a skin condition called acanthosis nigricans.

<span class="mw-page-title-main">Pfeiffer syndrome</span> Genetic disorder of the skull

Pfeiffer syndrome is a rare genetic disorder, characterized by the premature fusion of certain bones of the skull (craniosynostosis), which affects the shape of the head and face. The syndrome includes abnormalities of the hands and feet, such as wide and deviated thumbs and big toes.

Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their function lead to a range of developmental defects. These growth factors typically act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to heparin and to heparan sulfate. Thus, some are sequestered in the extracellular matrix of tissues that contains heparan sulfate proteoglycans and are released locally upon injury or tissue remodeling.

<span class="mw-page-title-main">FGF1</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 1, (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1 gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycosylated 17-18 kDa protein. Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1. Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.

<span class="mw-page-title-main">Receptor tyrosine kinase</span> Class of enzymes

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

The fibroblast growth factor receptors (FGFR) are, as their name implies, receptors that bind to members of the fibroblast growth factor (FGF) family of proteins. Some of these receptors are involved in pathological conditions. For example, a point mutation in FGFR3 can lead to achondroplasia.

<span class="mw-page-title-main">Fibroblast growth factor receptor 2</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 is a protein that in humans is encoded by the FGFR2 gene residing on chromosome 10. FGFR2 is a receptor for fibroblast growth factor.

<span class="mw-page-title-main">Fibroblast growth factor receptor 1</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 1 (FGFR1), also known as basic fibroblast growth factor receptor 1, fms-related tyrosine kinase-2 / Pfeiffer syndrome, and CD331, is a receptor tyrosine kinase whose ligands are specific members of the fibroblast growth factor family. FGFR1 has been shown to be associated with Pfeiffer syndrome, and clonal eosinophilias.

<span class="mw-page-title-main">Fibroblast growth factor receptor 4</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor receptor 4 is a protein that in humans is encoded by the FGFR4 gene. FGFR4 has also been designated as CD334.

<span class="mw-page-title-main">Fibroblast growth factor 8</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 8(FGF-8) is a protein that in humans is encoded by the FGF8 gene.

<span class="mw-page-title-main">FGF9</span> Protein-coding gene in the species Homo sapiens

Glia-activating factor is a protein that in humans is encoded by the FGF9 gene.

Zoltan Vajo is a Hungarian/American scientist, best known for his contributions to the Human Genome Project, including cloning the COQ7 gene, characterizing the human CLK-1 timing protein cDNA and its potential effect on aging, and research on the molecular and genetic background of skeletal dysplasias and fibroblast growth factor receptor 3 disorders, including Achondroplasia, SADDAN, Thanatophoric dysplasia, Muenke coronal craniosynostosis and Crouzon syndrome as well as more recently on genetically engineered insulin analog molecules, including their structure, metabolic effects and cellular processing and the role of recombinant DNA technology in the treatment of diabetes.

<span class="mw-page-title-main">Severe achondroplasia with developmental delay and acanthosis nigricans</span> Medical condition

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is a very rare genetic disorder. This disorder is one that affects bone growth and is characterized by skeletal, brain, and skin abnormalities. Those affected by the disorder are severely short in height and commonly possess shorter arms and legs. In addition, the bones of the legs are often bowed and the affected have smaller chests with shorter rib bones, along with curved collarbones. Other symptoms of the disorder include broad fingers and extra folds of skin on the arms and legs. Developmentally, many individuals who suffer from the disorder show a higher level in delays and disability. Seizures are also common due to structural abnormalities of the brain. Those affected may also suffer with apnea, the slowing or loss of breath for short periods of time.

Clair A. Francomano is an American medical geneticist and academic specializing in Ehlers–Danlos syndromes. She is Professor of Medical and Molecular Genetics at Indiana University.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000068078 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000054252 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Keegan K, Johnson DE, Williams LT, Hayman MJ (February 1991). "Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3". Proceedings of the National Academy of Sciences of the United States of America. 88 (4): 1095–9. Bibcode:1991PNAS...88.1095K. doi: 10.1073/pnas.88.4.1095 . PMC   50963 . PMID   1847508.
  6. 1 2 Wang Y, Liu Z, Liu Z, Zhao H, Zhou X, Cui Y, Han J (May 2013). "Advances in research on and diagnosis and treatment of achondroplasia in China". Intractable & Rare Diseases Research. 2 (2): 45–50. doi:10.5582/irdr.2013.v2.2.45. PMC   4204580 . PMID   25343101.
  7. 1 2 3 "FGFR3 gene". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 2018-09-27.
  8. ↑ "Entrez Gene: FGFR3 fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)".
  9. ↑ Foldynova-Trantirkova S, Wilcox WR, Krejci P (January 2012). "Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias". Human Mutation. 33 (1): 29–41. doi:10.1002/humu.21636. PMC   3240715 . PMID   22045636.
  10. ↑ Kelleher FC, O'Sullivan H, Smyth E, McDermott R, Viterbo A (October 2013). "Fibroblast growth factor receptors, developmental corruption and malignant disease". Carcinogenesis. 34 (10): 2198–205. doi: 10.1093/carcin/bgt254 . PMID   23880303.
  11. ↑ Hafner C, Hartmann A, Vogt T (July 2007). "FGFR3 mutations in epidermal nevi and seborrheic keratoses: lessons from urothelium and skin". The Journal of Investigative Dermatology. 127 (7): 1572–3. doi: 10.1038/sj.jid.5700772 . PMID   17568799.
  12. ↑ di Martino E, Tomlinson DC, Williams SV, Knowles MA (October 2016). "A place for precision medicine in bladder cancer: targeting the FGFRs". Future Oncology (London, England). 12 (19): 2243–63. doi:10.2217/fon-2016-0042. PMC   5066128 . PMID   27381494.
  13. ↑ Oo HZ, Seiler R, Black PC, Daugaard M (October 2018). "Post-translational modifications in bladder cancer: Expanding the tumor target repertoire". Urologic Oncology. 38 (12): 858–866. doi:10.1016/j.urolonc.2018.09.001. PMID   30342880. S2CID   53041768.
  14. ↑ Mata, Douglas A.; Benhamida, Jamal K.; Lin, Andrew L.; Vanderbilt, Chad M.; Yang, Soo-Ryum; Villafania, Liliana B.; Ferguson, Donna C.; Jonsson, Philip; Miller, Alexandra M.; Tabar, Viviane; Brennan, Cameron W.; Moss, Nelson S.; Sill, Martin; Benayed, Ryma; Mellinghoff, Ingo K.; Rosenblum, Marc K.; Arcila, Maria E.; Ladanyi, Marc; Bale, Tejus A. (2020). "Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions". Acta Neuropathologica Communications. 8 (1): 186. doi: 10.1186/s40478-020-01058-6 . PMC   7653727 . PMID   33168106.
  15. ↑ "Achondroplasia". Genetic and Rare Diseases Information Center (GARD).
  16. 1 2 "FGFR3 gene". Genetics Home Reference. U.S. National Library of Medicine.
  17. 1 2 "Learning about Achondroplasia". National Human Genome Research Institute. Retrieved July 15, 2016.
  18. 1 2 3 Karczeski B, Cutting GR (1993). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). Thanatophoric Dysplasia. PMID   20301540 . Retrieved 2018-11-17.{{cite book}}: |work= ignored (help)
  19. ↑ Nissenbaum M, Chung SM, Rosenberg HK, Buck BE (August 1977). "Thanatophoric dwarfism. Two case reports and survey of the literature". Clinical Pediatrics. 16 (8): 690–7. doi:10.1177/000992287701600803. PMID   872478. S2CID   30837380.
  20. ↑ "Muenke syndrome (Concept Id: C1864436)". MedGen. NCBI. Retrieved March 18, 2023.
  21. ↑ "Orphanet: Muenke syndrome". Orphanet. Retrieved March 18, 2023.
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  23. 1 2 Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM (January 1996). "Expression and biological activity of mouse fibroblast growth factor-9". The Journal of Biological Chemistry. 271 (3): 1726–31. doi: 10.1074/jbc.271.3.1726 . PMID   8576175.
  24. 1 2 Chellaiah A, Yuan W, Chellaiah M, Ornitz DM (December 1999). "Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity". The Journal of Biological Chemistry. 274 (49): 34785–94. doi: 10.1074/jbc.274.49.34785 . PMID   10574949.

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