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Fibroblast growth factor receptor 2 (FGFR2) also known as CD332 (cluster of differentiation 332) is a protein that in humans is encoded by the FGFR2 gene residing on chromosome 10.^[1]^[2] FGFR2 is a receptor for 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.^[3] 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 immunoglobulin 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, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or 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 receptors signal by binding to their ligand and dimerisation (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 ectoderm derived tissues and endothelial organ lining, i.e. skin and internal organs.^[4] 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.^[5]^[6]^[7]

The spliced isoforms, however differ in binding:^[8]

FGFR2IIIb binds to FGF-1, -3, -7, -10, -22
FGFR2IIIc binds to FGF-1, -2, -4, -6, -8, -9, -17 and -18

These differences in binding are not surprising, since FGF ligand is known to bind to the second and third 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

Apert syndrome, the best-known type of acrocephalosyndactyly. This condition is characterized by abnormalities of the skull and face, such as a cleft palate, and the hands and feet.
Antley-Bixler syndrome (characterized by trapezoidal, craniofacial and skeletal synostosis, plus camptodactyly). Inherited as a recessive trait.
Pfeiffer syndrome (another type of acrocephalosyndactyly). Inherited as a dominant trait, includes broad thumbs and large toes.
Crouzon syndrome (a craniofacial disorder with no clinically significant hand or foot problems)..^[9] Cleft palate can be a feature of this syndrome. Inherited as a dominant trait.

Jackson-Weiss syndrome

Cancer

Breast cancer, a mutation or single nucleotide polymorphism (SNP) in intron 2 of the FGFR2 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.^[10]

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. ^[11] On a molecular level, mutations that affect FGFR2IIIc are associated with marked changes in osteoblast proliferation and differentiation.^[12] 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.^[13] 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.^[14]

References

^ Houssaint E, Blanquet PR, Champion-Arnaud P, Gesnel MC, Torriglia A, Courtois Y, Breathnach R (Oct 1990). "Related fibroblast growth factor receptor genes exist in the human genome". Proceedings of the National Academy of Sciences of the United States of America 87 (20): 8180–4. doi:10.1073/pnas.87.20.8180. PMC 54916. PMID 2172978.
^ Dionne CA, Crumley G, Bellot F, Kaplow JM, Searfoss G, Ruta M, Burgess WH, Jaye M, Schlessinger J (Sep 1990). "Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors". The EMBO Journal 9 (9): 2685–92. PMC 551973. PMID 1697263.
^ "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)".
^ Orr-Urtreger A, Bedford MT, Burakova T, Arman E, Zimmer Y, Yayon A, Givol D, Lonai P (Aug 1993). "Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2)". Developmental Biology 158 (2): 475–86. doi:10.1006/dbio.1993.1205. PMID 8393815.
^ Stauber DJ, DiGabriele AD, Hendrickson WA (Jan 2000). "Structural interactions of fibroblast growth factor receptor with its ligands". Proceedings of the National Academy of Sciences of the United States of America 97 (1): 49–54. doi:10.1073/pnas.97.1.49. PMC 26614. PMID 10618369.
^ Pellegrini L, Burke DF, von Delft F, Mulloy B, Blundell TL (Oct 2000). "Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin". Nature 407 (6807): 1029–34. doi:10.1038/35039551. PMID 11069186.
^ Santos-Ocampo S, Colvin JS, Chellaiah A, Ornitz DM (Jan 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.
^ Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Gao G, Goldfarb M (Jun 1996). "Receptor specificity of the fibroblast growth factor family". The Journal of Biological Chemistry 271 (25): 15292–7. doi:10.1074/jbc.271.25.15292. PMID 8663044.
^ Sagong B, Jung da J, Baek JI, Kim MA, Lee J, Lee SH, Kim UK, Lee KY (2014). "Identification of causative mutation in a Korean family with Crouzon syndrome using whole exome sequencing". Annals of Clinical and Laboratory Science 44 (4): 476–83. PMID 25361936.
^ 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 (Jul 2007). "A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer". Nature Genetics 39 (7): 870–4. doi:10.1038/ng2075. PMID 17529973.
^ Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Review Genetics (12): 167-178.
^ Lee KM, Santos-Ruiz L, Ferretti P (Mar 2010). "A single-point mutation in FGFR2 affects cell cycle and Tgfbeta signalling in osteoblasts". Biochimica Et Biophysica Acta 1802 (3): 347–55. doi:10.1016/j.bbadis.2009.11.006. PMID 20004243.
^ Webster MK, Donoghue DJ (Oct 1997). "Enhanced signaling and morphological transformation by a membrane-localized derivative of the fibroblast growth factor receptor 3 kinase domain". Molecular and Cellular Biology 17 (10): 5739–47. PMC 232422. PMID 9315632.
^ Hajihosseini MK, Duarte R, Pegrum J, Donjacour A, Lana-Elola E, Rice DP, Sharpe J, Dickson C (Feb 2009). "Evidence that Fgf10 contributes to the skeletal and visceral defects of an Apert syndrome mouse model". Developmental Dynamics 238 (2): 376–85. doi:10.1002/dvdy.21648. PMID 18773495.

External links

GeneReviews/NIH/NCBI/UW entry on FGFR-Related Craniosynostosis Syndromes
Fibroblast Growth Factor Receptor 2 at the US National Library of Medicine Medical Subject Headings (MeSH)
FGFR2 human gene location in the UCSC Genome Browser.
FGFR2 human gene details in the UCSC Genome Browser.

UpToDate Contents

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1. 頭蓋骨縫合早期癒合症候群 craniosynostosis syndromes
2. 再発性または転移性子宮体癌の治療 treatment of recurrent or metastatic endometrial cancer
3. 頭蓋骨縫合早期癒合症の概要 overview of craniosynostosis
4. 外陰部異常を有する幼児の評価 evaluation of the infant with ambiguous genitalia
5. 肺移植：死亡ドナーの評価およびマネージメント lung transplantation deceased donor evaluation and management

English Journal

Increased FGF1-FGFRc expression in idiopathic pulmonary fibrosis.

MacKenzie B1, Korfei M1, Henneke I1, Sibinska Z1, Tian X1, Hezel S1, Dilai S1, Wasnick R1, Schneider B1, Wilhelm J1, El Agha E1, Klepetko W2, Seeger W1,3, Schermuly R1,3, Günther A1,3,4, Bellusci S5,6,7,8.
Respiratory research.Respir Res.2015 Jul 3;16(1):83. [Epub ahead of print]
BACKGROUND: Recent clinical studies show that tyrosine kinase inhibitors slow the rate of lung function decline and decrease the number of acute exacerbations in patients with Idiopathic Pulmonary Fibrosis (IPF). However, in the murine bleomycin model of fibrosis, not all tyrosine kinase signaling i
PMID 26138239

Fibroblast growth factor (FGF) signaling in myofibroblasts differs from lipofibroblasts during alveolar septation in mice.

McGowan SE1, McCoy DM2.
American journal of physiology. Lung cellular and molecular physiology.Am J Physiol Lung Cell Mol Physiol.2015 Jul 2:ajplung.00013.2015. doi: 10.1152/ajplung.00013.2015. [Epub ahead of print]
Pulmonary alveolar fibroblasts produce extracellular matrix in a temporally and spatially regulated pattern to yield a durable, yet pliable gas-exchange surface. Proliferation ensures a sufficient complement of cells, but they must differentiate into functionally distinct subtypes: contractile myofi
PMID 26138642

Identification of in vivo DNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development.

Sun J1, Rockowitz S1, Xie Q1, Ashery-Padan R2, Zheng D3, Cvekl A4.
Nucleic acids research.Nucleic Acids Res.2015 Jul 2. pii: gkv589. [Epub ahead of print]
The transcription factor Pax6 is comprised of the paired domain (PD) and homeodomain (HD). In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific subpopulations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification
PMID 26138486

Japanese Journal

Polymorphisms in Second Intron of the FGFR2 Gene Are Associated with the Risk of Early-Onset Breast Cancer in Chinese Han Women

FU Fangmeng,WANG Chuan,HUANG Meng,SONG Chuangui,LIN Shunguo,HUANG Heguang
Tohoku journal of experimental medicine 226(3), 221-229, 2012-03-01
NAID 10030197506

Composite likelihood-based meta-analysis of breast cancer association studies

Politopoulos Ioannis,Gibson Jane,Tapper William [他]
Journal of human genetics 56(5), 377-382, 2011-05
NAID 40018810310

Related Pictures

★リンクテーブル★

リンク元	「線維芽細胞増殖因子受容体2」「type 2 fibroblast growth factor receptor」
拡張検索	「FGFR2 gene」
関連記事	「FGF」

「線維芽細胞増殖因子受容体2」

Fibroblast growth factor receptor 2
	PDB rendering based on 1djs.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1DJS, 1E0O, 1EV2, 1GJO, 1II4, 1IIL, 1NUN, 1OEC, 1WVZ, 2FDB, 2PSQ, 2PVF, 2PVY, 2PWL, 2PY3, 2PZ5, 2PZP, 2PZR, 2Q0B, 3B2T, 3CAF, 3CLY, 3CU1, 3DAR, 3EUU, 3OJ2, 3OJM, 3RI1, 4J23, 4J95, 4J96, 4J97, 4J98, 4J99
Identifiers
Symbols	FGFR2 ; BBDS; BEK; BFR-1; CD332; CEK3; CFD1; ECT1; JWS; K-SAM; KGFR; TK14; TK25
External IDs	OMIM: 176943 MGI: 95523 HomoloGene: 22566 ChEMBL: 4142 GeneCards: FGFR2 Gene
EC number	2.7.10.1
Gene ontology
Molecular function	• protein tyrosine kinase activity; • fibroblast growth factor-activated receptor activity; • protein binding; • ATP binding; • heparin binding; • fibroblast growth factor binding; • protein homodimerization activity;
Cellular component	• extracellular region; • nucleus; • nucleoplasm; • cytoplasm; • Golgi apparatus; • plasma membrane; • integral component of plasma membrane; • cell cortex; • cell surface; • membrane; • integral component of membrane; • cytoplasmic membrane-bounded vesicle; • extracellular matrix; • intracellular membrane-bounded organelle; • excitatory synapse;
Biological process	• negative regulation of transcription from RNA polymerase II promoter; • angiogenesis; • ureteric bud development; • in utero embryonic development; • epithelial to mesenchymal transition; • positive regulation of mesenchymal cell proliferation; • outflow tract septum morphogenesis; • membranous septum morphogenesis; • apoptotic process; • epidermal growth factor receptor signaling pathway; • cell-cell signaling; • axonogenesis; • neuromuscular junction development; • positive regulation of cell proliferation; • insulin receptor signaling pathway; • fibroblast growth factor receptor signaling pathway; • regulation of smoothened signaling pathway; • post-embryonic development; • embryonic pattern specification; • organ morphogenesis; • regulation of cell fate commitment; • positive regulation of phospholipase activity; • morphogenesis of embryonic epithelium; • peptidyl-tyrosine phosphorylation; • orbitofrontal cortex development; • ventricular zone neuroblast division; • pyramidal neuron development; • gland morphogenesis; • positive regulation of Wnt signaling pathway; • bone mineralization; • lung development; • epithelial cell differentiation; • midbrain development; • otic vesicle formation; • hair follicle morphogenesis; • lacrimal gland development; • regulation of osteoblast proliferation; • multicellular organism growth; • organ growth; • fibroblast growth factor receptor signaling pathway involved in negative regulation of apoptotic process in bone marrow; • fibroblast growth factor receptor signaling pathway involved in hemopoiesis; • fibroblast growth factor receptor signaling pathway involved in positive regulation of cell proliferation in bone marrow; • fibroblast growth factor receptor signaling pathway involved in orbitofrontal cortex development; • Fc-epsilon receptor signaling pathway; • regulation of multicellular organism growth; • regulation of fibroblast growth factor receptor signaling pathway; • inner ear morphogenesis; • odontogenesis; • positive regulation of MAPK cascade; • innate immune response; • cell fate commitment; • regulation of osteoblast differentiation; • positive regulation of cell cycle; • negative regulation of mitotic nuclear division; • positive regulation of transcription from RNA polymerase II promoter; • protein autophosphorylation; • neurotrophin TRK receptor signaling pathway; • phosphatidylinositol-mediated signaling; • lung alveolus development; • mesodermal cell differentiation; • synaptic vesicle transport; • embryonic digestive tract morphogenesis; • embryonic organ morphogenesis; • digestive tract development; • embryonic organ development; • reproductive structure development; • positive regulation of smooth muscle cell proliferation; • embryonic cranial skeleton morphogenesis; • skeletal system morphogenesis; • epidermis morphogenesis; • branching morphogenesis of a nerve; • mesenchymal cell differentiation; • positive regulation of epithelial cell proliferation; • negative regulation of epithelial cell proliferation; • regulation of smooth muscle cell differentiation; • positive regulation of cell division; • ventricular cardiac muscle tissue morphogenesis; • positive regulation of cardiac muscle cell proliferation; • limb bud formation; • bone development; • bone morphogenesis; • coronal suture morphogenesis; • branching involved in prostate gland morphogenesis; • branching involved in salivary gland morphogenesis; • bud elongation involved in lung branching; • lung lobe morphogenesis; • lung-associated mesenchyme development; • positive regulation of epithelial cell proliferation involved in lung morphogenesis; • prostate gland morphogenesis; • prostate epithelial cord elongation; • prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis; • squamous basal epithelial stem cell differentiation involved in prostate gland acinus development; • fibroblast growth factor receptor signaling pathway involved in mammary gland specification; • lateral sprouting from an epithelium; • mammary gland bud formation; • epithelial cell proliferation involved in salivary gland morphogenesis; • branch elongation involved in salivary gland morphogenesis; • branching involved in labyrinthine layer morphogenesis; • regulation of branching involved in prostate gland morphogenesis; • regulation of morphogenesis of a branching structure; • mesenchymal cell differentiation involved in lung development; • mesenchymal cell proliferation involved in lung development; • endodermal digestive tract morphogenesis; • lens fiber cell development; • regulation of ERK1 and ERK2 cascade; • positive regulation of ERK1 and ERK2 cascade; • positive regulation of canonical Wnt signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;