View source for Biology:Fibroblast growth factor receptor 2

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Fibroblast growth factor receptor 2''' ('''FGFR2''') also known as '''CD332''' ([[Biology:Cluster of differentiation|cluster of differentiation]] 332) is a [[Biology:Protein|protein]] that in humans is encoded by the ''FGFR2'' [[Biology:Gene|gene]] residing on [[Biology:Chromosome 10|chromosome 10]].<ref name="pmid2172978">{{cite journal | vauthors = Houssaint E, Blanquet PR, Champion-Arnaud P, Gesnel MC, Torriglia A, Courtois Y, Breathnach R | title = Related fibroblast growth factor receptor genes exist in the human genome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 20 | pages = 8180–4 | date = Oct 1990 | pmid = 2172978 | pmc = 54916 | doi = 10.1073/pnas.87.20.8180 | bibcode = 1990PNAS...87.8180H | doi-access = free }}</ref><ref name="pmid1697263">{{cite journal | vauthors = Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M, Burgess WH, Jaye M, Schlessinger J | title = Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors | journal = The EMBO Journal | volume = 9 | issue = 9 | pages = 2685–92 | date = Sep 1990 | pmid = 1697263 | pmc = 551973 | doi =  10.1002/j.1460-2075.1990.tb07454.x}}</ref> FGFR2 is a receptor for [[Biology:Fibroblast growth factor|fibroblast growth factor]].

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.<ref>{{cite web | title = Entrez Gene: FGFR2 fibroblast growth factor receptor 2 (bacteria-expressed kinase, keratinocyte growth factor receptor, craniofacial dysostosis 1, Crouzon syndrome, Pfeiffer syndrome, Jackson–Weiss syndrome)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2263}}</ref> FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three [[Biology:Immunoglobulin domain|immunoglobulin domain]]s, a single hydrophobic membrane-spanning segment and a [[Biology:Cytoplasm|cytoplasm]]ic [[Biology:Tyrosine kinase|tyrosine kinase]] domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and [[Biology:Cellular differentiation|differentiation]]. This particular family member is a high-affinity receptor for acidic, basic and/or [[Biology:Keratinocyte|keratinocyte]] growth factor, depending on the isoform.

== Function ==

FGFR2 has important roles in embryonic development and tissue repair, especially bone and blood vessels. Like the other members of the fibroblast growth factor receptor family, these [[Biology:Receptor (biochemistry)|receptor]]s signal by binding to their [[Chemistry:Ligand|ligand]] and [[Chemistry:Dimer|dimer]]isation (pairing of receptors), which causes the tyrosine kinase domains to initiate a cascade of intracellular signals. On a molecular level these signals mediate cell division, growth and differentiation.

== Isoforms ==

FGFR2 has two naturally occurring isoforms, FGFR2IIIb and FGFR2IIIc, created by splicing of the third immunoglobulin-like domain. FGFR2IIIb is predominantly found in [[Biology:Ectoderm|ectoderm]] derived tissues and [[Biology:Endothelium|endothelial]] organ lining, i.e. skin and internal organs.<ref name="pmid8393815">{{cite journal | vauthors = Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P | title = Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2) | journal = Developmental Biology | volume = 158 | issue = 2 | pages = 475–86 | date = Aug 1993 | pmid = 8393815 | doi = 10.1006/dbio.1993.1205 }}</ref> FGFR2IIIc is found in mesenchyme, which includes craniofacial bone and for this reason the mutations of this gene and isoform are associated with craniosynostosis.

== Interactions ==

Fibroblast growth factor receptor 2 has been shown to interact with FGF1.<ref name="pmid10618369">{{cite journal | vauthors = Stauber DJ, DiGabriele AD, Hendrickson WA | title = Structural interactions of fibroblast growth factor receptor with its ligands | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 1 | pages = 49–54 | date = Jan 2000 | pmid = 10618369 | pmc = 26614 | doi = 10.1073/pnas.97.1.49 | bibcode = 2000PNAS...97...49S | doi-access = free }}</ref><ref name="pmid11069186">{{cite journal | vauthors = Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL | title = Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin | journal = Nature | volume = 407 | issue = 6807 | pages = 1029–34 | date = Oct 2000 | pmid = 11069186 | doi = 10.1038/35039551 | bibcode = 2000Natur.407.1029P | s2cid = 4418272 }}</ref><ref name="pmid8576175">{{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 = Jan 1996 | pmid = 8576175 | doi = 10.1074/jbc.271.3.1726 | s2cid = 27191391 | doi-access = free }}</ref>

The spliced isoforms, however differ in binding:<ref name="pmid8663044">{{cite journal | vauthors = Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M | title = Receptor specificity of the fibroblast growth factor family | journal = The Journal of Biological Chemistry | volume = 271 | issue = 25 | pages = 15292–7 | date = Jun 1996 | pmid = 8663044 | doi = 10.1074/jbc.271.25.15292 | s2cid = 31736768 | doi-access = free }}</ref>

* FGFR2IIIb binds to FGF-1, -3, [[Biology:FGF7|-7]], -10, [[Biology:FGF22|-22]]
* FGFR2IIIc binds to FGF-1, [[Biology:Basic fibroblast growth factor|-2]], -4, -6, -8, -9, -17 and [[Biology:FGF18|-18]]

These differences in binding are not surprising, since FGF ligand is known to bind to the second and third [[Biology:Immunoglobulin domain|immunoglobulin domain]] of the receptor.

== Clinical significance ==

Mutations (changes) are associated with numerous medical conditions that include abnormal bone development (e.g. craniosynostosis syndromes) and cancer.

=== Craniosynostosis syndromes ===

FGFR2 mutations are the cause of several craniosynostosis syndromes:<ref>{{Cite web |title=FGFR2-related craniosynostosis (Concept Id: CN231480) |url=https://www.ncbi.nlm.nih.gov/medgen/850742 |access-date=2023-07-17 |website=www.ncbi.nlm.nih.gov |language=en}}</ref>

* Acrocephalosyndactyly type 1 ([[Medicine:Apert syndrome|Apert syndrome]])
* [[Medicine:Beare–Stevenson cutis gyrata syndrome|Beare-Stevenson cutis gyrata syndrome]]
* [[Medicine:Crouzon syndrome|Crouzon syndrome]]
* [[Medicine:Jackson–Weiss syndrome|Jackson-Weiss syndrome]]
* [[Medicine:Pfeiffer syndrome|Pfeiffer syndrome]]

=== Cancer ===

* [[Medicine:Breast cancer|Breast cancer]], a mutation or single nucleotide polymorphism (SNP) in [[Biology:Intron|intron]] 2 of the FGFR2 [[Biology:Gene|gene]] is associated with a higher breast cancer risk; however the risk is only mildly increased from about 10% lifetime breast cancer risk in the average woman in the industrialized world, to 12-14% risk in carriers of the SNP.<ref>{{cite journal | vauthors = Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M, Gerhard DS, Fraumeni JF, Hoover RN, Thomas G, Chanock SJ | title = A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer | journal = Nature Genetics | volume = 39 | issue = 7 | pages = 870–4 | date = Jul 2007 | pmid = 17529973 | doi = 10.1038/ng2075 | pmc = 3493132 }}</ref>

Missense mutations of FGFR2 have been found in [[Medicine:Endometrial cancer|endometrial cancer]] and [[Medicine:Melanoma|melanoma]].<ref name = "Katoh_2014" >{{cite journal | vauthors = Katoh M, Nakagama H | title = FGF receptors: cancer biology and therapeutics | journal = Medicinal Research Reviews | volume = 34 | issue = 2 | date = Mar 2014 | pmid = 23696246 | doi = 10.1002/med.21288 | pages=280–300| s2cid = 27412585 }}</ref>

==As a drug target==
AZD4547 is a tyrosine kinase inhibitor which targets FGFR1-3. It has demonstrated early evidence of efficacy in gastric cancer patients with high level FGFR2 amplification (Cancer Discovery 2016). FPA144 is a [[Biology:Monoclonal antibody|monoclonal antibody]] that binds to FGFR2b (a form of FGFR2) and preventing binding of certain FGFs. In 2014, a clinical trial began to treat gastric tumours that overexpress FGFR2b.<ref>[https://clinicaltrials.gov/ct2/show/NCT02318329 Open-Label, Dose-Finding Study Evaluating Safety and PK of FPA144 in Patients With Advanced Solid Tumors]</ref>
Another approach of FGFR2 targeting is use of allosteric inhibitors. Alofanib is a novel first-in-class allosteric small-molecular inhibitor of FGFR2. It binds to the extracellular domain of FGFR2 and has an inhibitory effect on FGF2-induced [[Biology:Phosphorylation|phosphorylation]]. Principal benefits of allosteric inhibitors are high selectivity and low [[Medicine:Toxicity|toxicity]] [Tsimafeyeu et al. ESMO Asia 2016]. A phase Ib clinical study protocol has been selected for ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research, better known as the ‘Flims’ Workshop and clinical study of safety and preliminary efficacy of alofanib will be initiated at the beginning of 2017.

== Mutations ==

FGFR2 mutations are associated with craniosynostosis syndromes, which are skull malformations caused by premature fusion of cranial sutures and other disease features according to the mutation itself. Analysis of chromosomal anomalies in patients led to the identification and confirmation of FGFR2 as a cleft lip and/or palate locus.<ref>Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Review Genetics (12): 167-178.</ref> On a molecular level, mutations that affect FGFR2IIIc are associated with marked changes in [[Biology:Osteoblast|osteoblast]] proliferation and differentiation.<ref name="pmid20004243">{{cite journal | vauthors = Lee KM, Santos-Ruiz L, Ferretti P | title = A single-point mutation in FGFR2 affects cell cycle and Tgfbeta signalling in osteoblasts | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1802 | issue = 3 | pages = 347–55 | date = Mar 2010 | pmid = 20004243 | doi = 10.1016/j.bbadis.2009.11.006 | url = https://hal.archives-ouvertes.fr/hal-00560299/file/PEER_stage2_10.1016%252Fj.bbadis.2009.11.006.pdf }}</ref> Alteration in FGFR2 signalling is thought to underlie the craniosynostosis syndromes. To date, there are two mechanisms of altered FGFR2 signalling. The first is associated with constitutive activation of FGFR, where the FGFR2 receptor is always signalling, regardless of the amount of FGF ligand.<ref name="pmid9315632">{{cite journal | vauthors = Webster MK, Donoghue DJ | title = Enhanced signaling and morphological transformation by a membrane-localized derivative of the fibroblast growth factor receptor 3 kinase domain | journal = Molecular and Cellular Biology | volume = 17 | issue = 10 | pages = 5739–47 | date = Oct 1997 | pmid = 9315632 | pmc = 232422 | doi =  10.1128/mcb.17.10.5739}}</ref> This mechanism is found in patients with Crouzon and Pfeiffer syndrome. The second, which is associated with Apert syndrome is a loss of specificity of the FGFR2 isoform, resulting in the receptor binding to FGFs that it does not normally bind.<ref name="pmid18773495">{{cite journal | vauthors = Hajihosseini MK, Duarte R, Pegrum J, Donjacour A, Lana-Elola E, Rice DP, Sharpe J, Dickson C | title = Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model | journal = Developmental Dynamics | volume = 238 | issue = 2 | pages = 376–85 | date = Feb 2009 | pmid = 18773495 | doi = 10.1002/dvdy.21648 | s2cid = 39997577 | doi-access = free }}</ref>

== See also ==
* [[Biology:Cluster of differentiation|Cluster of differentiation]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = McKeehan WL, Kan M | title = Heparan sulfate fibroblast growth factor receptor complex: structure-function relationships | journal = Molecular Reproduction and Development | volume = 39 | issue = 1 | pages = 69–81; discussion 81–2 | date = Sep 1994 | pmid = 7999363 | doi = 10.1002/mrd.1080390112 | s2cid = 6471340 }}
* {{cite book | vauthors = Johnson DE, Williams LT | title = Structural and functional diversity in the FGF receptor multigene family | volume = 60 | pages = 1–41 | year = 1993 | pmid = 8417497 | doi = 10.1016/S0065-230X(08)60821-0 | isbn = 978-0-12-006660-5 | series = Advances in Cancer Research }}
* {{cite journal | vauthors = Park WJ, Meyers GA, Li X, Theda C, Day D, Orlow SJ, Jones MC, Jabs EW | title = Novel FGFR2 mutations in Crouzon and Jackson–Weiss syndromes show allelic heterogeneity and phenotypic variability | journal = Human Molecular Genetics | volume = 4 | issue = 7 | pages = 1229–33 | date = Jul 1995 | pmid = 8528214 | doi = 10.1093/hmg/4.7.1229 }}
* {{cite journal | vauthors = Marie PJ, Debiais F, Haÿ E | title = Regulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling | journal = Histology and Histopathology | volume = 17 | issue = 3 | pages = 877–85 | year = 2003 | pmid = 12168799 | doi =  10.14670/HH-17.877}}
* {{cite journal | vauthors = Ibrahimi OA, Chiu ES, McCarthy JG, Mohammadi M | title = Understanding the molecular basis of Apert syndrome | journal = Plastic and Reconstructive Surgery | volume = 115 | issue = 1 | pages = 264–70 | date = Jan 2005 | pmid = 15622262 | doi = 10.1097/01.PRS.0000146703.08958.95 | s2cid = 23282194 }}
{{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]
* {{MeshName|Fibroblast+Growth+Factor+Receptor+2}}
* {{UCSC genome browser|FGFR2}}
* {{UCSC gene details|FGFR2}}

{{PDB Gallery|geneid=2263}}
{{Clusters of differentiation}}
{{Tyrosine kinases}}
{{Enzymes}}

[[Category:Clusters of differentiation]]

{{Sourceattribution|Fibroblast growth factor receptor 2}}