Fibroblast growth factor receptor 2

PDB rendering based on 1djs.

Available structures

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

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 10:
121.48 – 121.6 Mb

Chr 7:
130.16 – 133.12 Mb

PubMed search

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. doi:10.1128/mcb.17.10.5739. 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.

PDB gallery

1djs: LIGAND-BINDING PORTION OF FIBROBLAST GROWTH FACTOR RECEPTOR 2 IN COMPLEX WITH FGF1

1e0o: CRYSTAL STRUCTURE OF A TERNARY FGF1-FGFR2-HEPARIN COMPLEX

1ev2: CRYSTAL STRUCTURE OF FGF2 IN COMPLEX WITH THE EXTRACELLULAR LIGAND BINDING DOMAIN OF FGF RECEPTOR 2 (FGFR2)

1gjo: THE FGFR2 TYROSINE KINASE DOMAIN

1ii4: CRYSTAL STRUCTURE OF SER252TRP APERT MUTANT FGF RECEPTOR 2 (FGFR2) IN COMPLEX WITH FGF2

1iil: CRYSTAL STRUCTURE OF PRO253ARG APERT MUTANT FGF RECEPTOR 2 (FGFR2) IN COMPLEX WITH FGF2

1nun: Crystal Structure Analysis of the FGF10-FGFR2b Complex

1oec: FGFR2 KINASE DOMAIN

1wvz: Solution Structure of the D2 Domain of the Fibroblast Growth Factor

2fdb: Crystal Structure of Fibroblast growth factor (FGF)8b in complex with FGF Receptor (FGFR) 2c

Proteins: clusters of differentiation (see also list of human clusters of differentiation)

1-50	CD1 a-c 1A 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50

51-100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100

101-150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150

151-200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD180 CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200

201-250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249

251-300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD263 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299

301-350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350

Protein kinases: tyrosine kinases (EC 2.7.10)

Receptor tyrosine kinases (EC 2.7.10.1)

Growth factor receptors

EGF receptor family	EGFR ERBB2 ERBB3 ERBB4

Insulin receptor family	IGF1R INSR INSRR

PDGF receptor family	CSF1R FLT3 KIT PDGFR (PDGFRA PDGFRB)

FGF receptor family	FGFR1 FGFR2 FGFR3 FGFR4

VEGF receptors family	VEGFR1 VEGFR2 VEGFR3

HGF receptor family	MET RON

Trk receptor family	NTRK1 NTRK2 NTRK3

EPH receptor family

LTK receptor family

TIE receptor family

ROR receptor family

ROR1
ROR2

DDR receptor family

DDR1
DDR2

PTK7 receptor family

PTK7

RYK receptor family

MuSK receptor family

MUSK

ROS receptor family

ROS1

AATYK receptor family

AATYK
AATYK2

AXL receptor family

RET receptor family

uncatagorised

STYK1

Non-receptor tyrosine kinases (EC 2.7.10.2)

ABL family	ABL1 ARG

ACK family	ACK1 TNK1

CSK family	CSK MATK

FAK family	FAK PYK2

FES family	FES FER

FRK family	FRK BRK SRMS

JAK family	JAK1 JAK2 JAK3 TYK2

SRC-A family	SRC FGR FYN YES1

SRC-B family	BLK HCK LCK LYN

TEC family	TEC BMX BTK ITK TXK

SYK family	SYK ZAP70

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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