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词条 Fibroblast growth factor receptor 3
释义

  1. Function

  2. Mutations

  3. Disease linkage

     Bladder Cancer  Achondroplasia  Thanatophoric dysplasia  

  4. As a drug target

  5. Interactions

  6. See also

  7. References

  8. Further reading

  9. External links

{{Infobox_gene}}Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene.[1] 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.[2]

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.[3] 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 influencing 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.[3] 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.[4]

Mutations

Gain of function mutations in this gene can develop dysfunctional proteins "impede cartilage growth and development and affect chondrocyte proliferation and calcification"[2] 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.[5] 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.[3]

FGFR3 mutations are also linked with spermatocytic seminoma, which occur more frequently in older men.[6]

Disease linkage

Defects in the FGFR3 gene has been associated with several conditions, including craniosynostosis and seborrheic keratosis[7]

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.[8]

Post-translational modification of FGFR3 occur in bladder cancer that do not occur in normal cells and can be targeted by immunotherapeutic antibodies.[9]

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.[10][11] Only a single copy of the mutated FGFR3 gene results in achondroplasia.[15] 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.[11][12]

Thanatophoric dysplasia

Thanatophoric dysplasia is a genetic disorder caused by loss of function mutations in FGFR3 that is often fatal during the perinatal period because the child cannot breathe.[13][14] 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.[13] TD type II is a result of a substitution in a Lsy650Glu which is located in the tyrosine kinase area of FGFR3.[13]

As a drug target

FGFR3 inhibitors are in early clinical trials as a cancer treatment,[15] eg. BGJ398 for urothelial carcinoma.[16] The FGFR3 receptor has a tyrosine kinase signaling pathway that is associated with many biological developments embryonically and in tissues. [15] 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. [15]

Interactions

Fibroblast growth factor receptor 3 has been shown to interact with FGF1[17][18] and FGF9.[17][18]

See also

  • Cluster of differentiation
  • Fibroblast growth factor receptor

References

1. ^{{cite journal | vauthors = Keegan K, Johnson DE, Williams LT, Hayman MJ | title = Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 4 | pages = 1095–9 | date = February 1991 | pmid = 1847508 | pmc = 50963 | doi = 10.1073/pnas.88.4.1095 }}
2. ^1 {{cite journal | vauthors = Wang Y, Liu Z, Liu Z, Zhao H, Zhou X, Cui Y, Han J | title = Advances in research on and diagnosis and treatment of achondroplasia in China | journal = Intractable & Rare Diseases Research | volume = 2 | issue = 2 | pages = 45–50 | date = May 2013 | pmid = 25343101 | pmc = 4204580 | doi = 10.5582/irdr.2013.v2.2.45 }}
3. ^1 2 {{Cite web|url=https://ghr.nlm.nih.gov/gene/FGFR3|title=FGFR3 gene | work = Genetics Home Reference |publisher=U.S. National Library of Medicine |access-date=2018-09-27}}
4. ^{{cite web | title = Entrez Gene: FGFR3 fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2261| access-date = }}
5. ^{{cite journal | vauthors = Foldynova-Trantirkova S, Wilcox WR, Krejci P | title = Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias | journal = Human Mutation | volume = 33 | issue = 1 | pages = 29–41 | date = January 2012 | pmid = 22045636 | pmc = 3240715 | doi = 10.1002/humu.21636 }}
6. ^{{cite journal | vauthors = Kelleher FC, O'Sullivan H, Smyth E, McDermott R, Viterbo A | title = Fibroblast growth factor receptors, developmental corruption and malignant disease | journal = Carcinogenesis | volume = 34 | issue = 10 | pages = 2198–205 | date = October 2013 | pmid = 23880303 | doi = 10.1093/carcin/bgt254 }}
7. ^{{cite journal | vauthors = Hafner C, Hartmann A, Vogt T | title = FGFR3 mutations in epidermal nevi and seborrheic keratoses: lessons from urothelium and skin | journal = The Journal of Investigative Dermatology | volume = 127 | issue = 7 | pages = 1572–3 | date = July 2007 | pmid = 17568799 | doi = 10.1038/sj.jid.5700772 }}
8. ^{{cite journal | vauthors = di Martino E, Tomlinson DC, Williams SV, Knowles MA | title = A place for precision medicine in bladder cancer: targeting the FGFRs | journal = Future Oncology (London, England) | volume = 12 | issue = 19 | pages = 2243–63 | date = October 2016 | pmid = 27381494 | pmc = 5066128 | doi = 10.2217/fon-2016-0042 }}
9. ^{{cite journal | vauthors = Oo HZ, Seiler R, Black PC, Daugaard M | title = Post-translational modifications in bladder cancer: Expanding the tumor target repertoire | journal = Urologic Oncology | volume = | issue = | pages = | date = October 2018 | pmid = 30342880 | doi = 10.1016/j.urolonc.2018.09.001 }}
10. ^{{cite web | title = Achondroplasia | url=http://rarediseases.info.nih.gov/diseases/8173/achondroplasia | work = Genetic and Rare Diseases Information Center (GARD) }}
11. ^1 {{cite web | title = FGFR3 gene |url=https://ghr.nlm.nih.gov/gene/FGFR3#conditions | work = Genetics Home Reference | publisher = U.S. National Library of Medicine }}
12. ^1 {{cite web |title=Learning about Achondroplasia |url=https://www.genome.gov/19517823/ | work = National Human Genome Research Institute |accessdate=July 15, 2016}}
13. ^1 2 {{cite book | vauthors = Karczeski B, Cutting GR |title=Thanatophoric Dysplasia|date=1993|url=https://www.ncbi.nlm.nih.gov/books/NBK1366/|work=GeneReviews | veditors = Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A |publisher=University of Washington, Seattle|pmid=20301540|access-date=2018-11-17 }}
14. ^{{cite journal | vauthors = Nissenbaum M, Chung SM, Rosenberg HK, Buck BE | title = Thanatophoric dwarfism. Two case reports and survey of the literature | journal = Clinical Pediatrics | volume = 16 | issue = 8 | pages = 690–7 | date = August 1977 | pmid = 872478 | doi = 10.1177/000992287701600803 }}
15. ^1 2 {{cite journal | vauthors = Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, Matsangou M, Costa R, Carneiro B, Villaflor VM, Cristofanilli M, Giles FJ | title = Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application | journal = Oncotarget | volume = 8 | issue = 9 | pages = 16052–16074 | date = February 2017 | pmid = 28030802 | pmc = 5362545 | doi = 10.18632/oncotarget.14109 }}
16. ^{{cite journal | vauthors = Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, Galsky MD, Wolf J, Dittrich C, Keam B, Delord JP, Schellens JH, Gravis G, Medioni J, Maroto P, Sriuranpong V, Charoentum C, Burris HA, Grünwald V, Petrylak D, Vaishampayan U, Gez E, De Giorgi U, Lee JL, Voortman J, Gupta S, Sharma S, Mortazavi A, Vaughn DJ, Isaacs R, Parker K, Chen X, Yu K, Porter D, Graus Porta D, Bajorin DF | title = FGFR3 Alterations | journal = Cancer Discovery | volume = 8 | issue = 7 | pages = 812–821 | date = July 2018 | pmid = 29848605 | doi = 10.1158/2159-8290.CD-18-0229 | lay-summary = https://www.cancertherapyadvisor.com/bladder-cancer/urothelial-carcinoma-fgfr3-inhibitor-new-treatment-option/article/769963/ | lay-source = Cancer Therapy Advisor }}
17. ^1 {{cite journal | vauthors = Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM | title = Expression and biological activity of mouse fibroblast growth factor-9 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 3 | pages = 1726–31 | date = January 1996 | pmid = 8576175 | doi = 10.1074/jbc.271.3.1726 }}
18. ^1 {{cite journal | vauthors = Chellaiah A, Yuan W, Chellaiah M, Ornitz DM | title = Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity | journal = The Journal of Biological Chemistry | volume = 274 | issue = 49 | pages = 34785–94 | date = December 1999 | pmid = 10574949 | doi = 10.1074/jbc.274.49.34785 }}

Further reading

{{refbegin|32em}}
  • {{cite journal | vauthors = Duperret EK, Oh SJ, McNeal A, Prouty SM, Ridky TW | title = Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors | journal = Cell Cycle (Georgetown, Tex.) | volume = 13 | issue = 10 | pages = 1551–9 | date = 2014 | pmid = 24626198 | pmc = 4050160 | doi = 10.4161/cc.28492 }}
  • {{cite journal | vauthors = Schweitzer DN, Graham JM, Lachman RS, Jabs EW, Okajima K, Przylepa KA, Shanske A, Chen K, Neidich JA, Wilcox WR | title = Subtle radiographic findings of achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to an Ala391Glu substitution in FGFR3 | journal = American Journal of Medical Genetics | volume = 98 | issue = 1 | pages = 75–91 | date = January 2001 | pmid = 11426459 | doi = 10.1002/1096-8628(20010101)98:1<75::AID-AJMG1010>3.0.CO;2-6 }}
  • {{cite journal | vauthors = Horton WA, Lunstrum GP | title = Fibroblast growth factor receptor 3 mutations in achondroplasia and related forms of dwarfism | journal = Reviews in Endocrine & Metabolic Disorders | volume = 3 | issue = 4 | pages = 381–5 | date = December 2002 | pmid = 12424440 | doi = }}
  • {{cite journal | vauthors = Bonaventure J, Silve C | title = [Hereditary skeletal dysplasias and FGFR3 and PTHR1 signaling pathways] | journal = Medecine Sciences | volume = 21 | issue = 11 | pages = 954–61 | date = November 2005 | pmid = 16274647 | doi = 10.1051/medsci/20052111954 }}
  • {{cite journal | vauthors = Hernández S, Toll A, Baselga E, Ribé A, Azua-Romeo J, Pujol RM, Real FX | title = Fibroblast growth factor receptor 3 mutations in epidermal nevi and associated low grade bladder tumors | journal = The Journal of Investigative Dermatology | volume = 127 | issue = 7 | pages = 1664–6 | date = July 2007 | pmid = 17255960 | doi = 10.1038/sj.jid.5700705 }}
  • {{cite journal | vauthors = Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, Basilico C, Linhardt RJ, Schlessinger J, Mohammadi M | title = Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 4 | pages = 935–40 | date = January 2004 | pmid = 14732692 | pmc = 327120 | doi = 10.1073/pnas.0307287101 }}
{{refend}}

External links

  • [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=craniosynostosis GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes]
  • [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=muenke GeneReviews/NIH/NCBI/UW entry on Muenke Syndrome]
  • [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hypochondroplasia GeneReviews/NIH/NCBI/UW entry on Hypochondroplasia]
  • {{MeshName|FGFR3+protein,+human}}
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2 : Clusters of differentiation|Tyrosine kinase receptors
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