FGFR2 (fibroblast growth factor receptor 2)

2008-08-01   Masaru Katoh 

Genetics, Cell Biology Section, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Identity

HGNC
LOCATION
10q26.13
LOCUSID
ALIAS
BBDS,BEK,BFR-1,CD332,CEK3,CFD1,ECT1,JWS,K-SAM,KGFR,TK14,TK25
FUSION GENES

DNA/RNA

Note

FGFR2 gene at chromosome 10q26.13 and FGFR1 gene at chromosome 8p12 are paralogs within the human genome.
Atlas Image
Structure and alternative splicing of FGFR2 gene.

Description

FGFR2 gene, consisting of at least 21 exons, encodes multiple isoforms due to alternative splicing. FGFR2b and FGFR2c with extracellular three Ig-like domains, transmembrane domain and cytoplasmic tyrosine kinase domain, are representative FGFR2 isoforms almost identical except the latter half of the third Ig-like domain. Exon 9 and 10, corresponding to the latter half of the third Ig-like domain, are incorporated into FGFR2b and FGFR2c in a mutually exclusive manner. Splicing silencer sequence within intron 8 and splicing activator sequence within intron 9 are implicated in the regulation of splicing preferentiality for FGFR2b and FGFR2c. Exons 20 and 21 of FGFR2 gene are alternative last exons encoding the C-terminal region of FGFR2 isoforms. Wild type FGFR2 transcripts with exon 21 are expressed in normal cells and most tumor cells, while aberrant FGFR2 transcripts with exon 20 are overexpressed in cases with FGFR2 gene amplification due to the exclusion of exon 21 from the FGFR2 amplicon. FGFR2 gene also encodes transmembrane-type FGFR2 isoforms lacking the first Ig-like domain, and secreted-type FGFR2 isoforms.

Transcription

FGFR2b isoform is predominantly expressed in epithelial cells, while FGFR2c isoform preferentially in mesenchymal cells. FGFR2 is expressed in undifferentiated human ES cells, and also in ES-derived embryoid body, endodermal precursors, and neural precursors. FGFR2 is relatively highly expressed in fetal brain. Among adult human tissues, FGFR2 is relatively highly expressed in brain, retina, spinal cord, salivary gland, skin, kidney and uterus. FGFR2 is overexpressed in human breast cancer and gastric cancer due to gene amplification.

Proteins

Note

FGFR2 functions as transmembrane receptor for FGF family members, such as FGF1 (aFGF), FGF2 (bFGF), FGF3, FGF4 (Kaposis sarcoma-derived FGF or KFGF), FGF6, FGF7 (keratinocyte growth factor or KGF), FGF9, FGF10, FGF16, FGF20 and FGF22 FGFR2b and FGFR2c are representative FGFR2 isoforms with distinct ligand specificity.
Atlas Image
Schematic representation of FGF signaling cascades.

Description

FGFR2b and FGFR2c are representative FGFR2 isoforms, consisting of extracellular three Ig-like domains, transmembrane domain, and cytoplasmic tyrosine kinase domain. FGFR2b and FGFR2c are almost identical except the latter half of the third Ig-like domain. The divergence in the latter half of the third Ig-like domain leads to distinct ligand specificity between FGFR2b and FGFR2c. FGFR2b is a high affinity receptor for FGF1, FGF3, FGF7, FGF10 and FGF22, while FGFR2c is a high affinity receptor for FGF1, FGF2, FGF4, FGF6, FGF9, FGF16 and FGF20.

Localisation

FGFR2b and FGFR2c with the N-terminal signal peptide and a single transmembrane domain are localized to the plasma membrane.

Function

FGFR2 is a high affinity receptor for FGFs associated with heparan sulfate proteoglycans (HSPGs). Ligand-dependent FGFR2 dimerization releases FGFR2 from autoinhibition due to autophosphorylation of a key tyrosine residue within the activation loop of kinase domain. FRS2 (FRS2A) and FRS3 (FRS2B) are tyrosine phosphorylated by FGFR2 to recruit GRB2 and PTPN11 for the activation of SOS - RAS - RAF- MAP3K - MAP2K - MAPK and GAB1 - PI3K - AKT signaling cascades. Phospholipase C-gamma (PLCgamma) is recruited to FGFR2 through its interaction with phosphotyrosine residues on the C-terminal tail of activated FGFR2, which results in the catalysis of phosphatidylinositol diphosphate (PIP2) to diacylglycerol (DAG) and inositol triphosphate (IP3). DAG activates protein kinase C (PKC) signaling cascade, while IP3 induces Ca2+ release from endoplasmic reticulum for the following activation of Calmodulin-Calcineurin-NFAT signaling cascade. FGFR2 transduces FGF signals to the MAPK and PI3K-AKT signaling cascades through FRS2 or FGF3, and to the PKC and NFAT signaling cascades through PLCgamma.

Homology

FGFR2b and FGFR2c are almost identical except the latter half of the third Ig-like domain as mentioned above. Among receptor-type tyrosine kinases, FGFR2 isoforms are more homologous to FGFR1 isoforms.

Mutations

Note

Germinal missense mutations of FGFR2 gene occur in congenital skeletal disorders. Intronic single nucleotide polymorphisms (SNPs) of FGFR2 gene are associated with increased cancer risk. Somatic missense mutations or gene amplification of FGFR2 occur in several types of cancer.
Atlas Image
Germinal and somatic point mutations of FGFR2.

Germinal

Germinal missense mutations of FGFR2 gene occur in congenital skeletal disorders, such as Crouzon syndrome, Jackson-Weiss syndrome, Apert syndrome, Pfeiffer syndrome, and Beare-Stevenson syndrome, which are featured by short-limbed bone dysplasia (craniosynostosis), and syndrome-specific abnormalities, such as Crouzonoid facies, bone syndactyly, limb abnormalities, and cutis gyrata. FGFR2 missense mutations around the third Ig-like domain result in altered ligand-receptor specificity to create the autocrine signaling loop. FGFR2 missense mutations within the tyrosine kinase domain lead to ligand independent activation of FGFR2. Germinal FGFR2 missense mutations cause congenital skeletal disorders due to aberrant FGFR2 signaling activation.
In addition, SNPs within intron 2 of FGFR2 gene are associated with increased risk of breast cancer, partly due to transcriptional upregulation of FGFR2.

Somatic

Somatic missense mutations or gene amplification of FGFR2 occur in uterus cancer (endometrial cancer), lung cancer, breast cancer, gastric cancer, and ovarian cancer. Genetic alterations of FGFR2 lead to aberrant activation of FGFR2 signaling cascades due to the creation of autocrine signaling loop or the release of FGFR2 from autoinhibition.

Implicated in

Entity name
Cancer
Disease
Somatic missense mutations or gene amplification of FGFR2 occur in endometrial cancer, lung cancer, breast cancer, gastric cancer, and ovarian cancer as mentioned above. In addition, class switch from FGFR2b to FGFR2c occurs during malignant progression of prostate cancer and bladder cancer. Somatic mutations and class switch of FGFR2 isoforms induce aberrant FGFR2 signaling activation in tumor cells.
Prognosis
FGFR2 gene amplification accompanied by FGFR2 overexpression in breast cancer and gastric cancer is associated with poor prognosis. Class switch from FGFR2b to FGFR2c is associated with more malignant phenotype in prostate cancer and bladder cancer.
Atlas Image
Mechanisms of oncogenic FGFR2 signaling activation.
Entity name
Congenital skeletal disorder
Disease
Germinal mutations of FGFR2 gene occur in Crouzon syndrome, Jackson-Weiss syndrome, Apert syndrome, Pfeiffer syndrome, and Beare-Stevenson syndrome. FGFR2 missense mutations cause congenital skeletal disorders due to aberrant FGFR2 signaling activation as mentioned above.

Breakpoints

Atlas Image

Bibliography

Pubmed IDLast YearTitleAuthors
18515511991BEK and FLG, two receptors to members of the FGF family, are amplified in subsets of human breast cancers.Adnane J et al
21654841990Characterization of the receptor for keratinocyte growth factor. Evidence for multiple fibroblast growth factor receptors.Bottaro DP et al
115969612001Negative autoregulation of fibroblast growth factor receptor 2 expression characterizing cranial development in cases of Apert (P253R mutation) and Pfeiffer (C278F mutation) syndromes and suggesting a basis for differences in their cranial phenotypes.Britto JA et al
109828552000An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein.Carstens RP et al
183374502008Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis.Cha JY et al
176971262007Aberrant fibroblast growth factor receptor signaling in bladder and other cancers.Chaffer CL et al
16487041991Multiple mRNAs code for proteins related to the BEK fibroblast growth factor receptor.Champion-Arnaud P et al
178039372007A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases.Chen H et al
165024192006Twist1 dimer selection regulates cranial suture patterning and fusion.Connerney J et al
161409232005Somatic mutations of the protein kinase gene family in human lung cancer.Davies H et al
14004331992A novel form of fibroblast growth factor receptor 2. Alternative splicing of the third immunoglobulin-like domain confers ligand binding specificity.Dell KR et al
90181181997Decreased expression of keratinocyte growth factor receptor in a subset of human transitional cell bladder carcinomas.Diez de Medina SG et al
16972631990Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors.Dionne CA et al
15822551992BEK, a receptor for multiple members of the fibroblast growth factor (FGF) family, maps to human chromosome 10q25.3----q26.Dionne CA et al
185521762008Drug-sensitive FGFR2 mutations in endometrial carcinoma.Dutt A et al
175299672007Genome-wide association study identifies novel breast cancer susceptibility loci.Easton DF et al
158630302005Cellular signaling by fibroblast growth factor receptors.Eswarakumar VP et al
83556931993Control of BEK and K-SAM splice sites in alternative splicing of the fibroblast growth factor receptor 2 pre-mRNA.Gilbert E et al
115648992001CGH, cDNA and tissue microarray analyses implicate FGFR2 amplification in a small subset of breast tumors.Heiskanen M et al
21729781990Related fibroblast growth factor receptor genes exist in the human genome.Houssaint E et al
179978232007Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases.Huijts PE et al
175299732007A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.Hunter DJ et al
118568672001Fibroblast growth factor receptor 2 (FGFR2): genomic sequence and variations.Ingersoll RG et al
78741701994Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.Jabs EW et al
113258142001Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers.Jang JH et al
117818722002Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis.Kan SH et al
13135741992K-sam gene encodes secreted as well as transmembrane receptor tyrosine kinase.Katoh M et al
167731962006FGF signaling network in the gastrointestinal tract (review).Katoh M et al
186361422008Cancer genomics and genetics of FGFR2 (Review).Katoh M et al
183321032008Fibroblast growth factor receptor 2 phosphorylation on serine 779 couples to 14-3-3 and regulates cell survival and proliferation.Lonic A et al
88147011996Expression of FGFR2 BEK and K-SAM mRNA variants in normal and malignant human breast.Luqmani YA et al
95372561998Inhibition of growth of malignant rat prostate tumor cells by restoration of fibroblast growth factor receptor 2.Matsubara A et al
184620182008Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.Meyer KB et al
18460481991Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop.Miki T et al
155617802004Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells.Moffa AB et al
84535951993DNA amplification in human gastric carcinomas.Mor O et al
86630441996Receptor specificity of the fibroblast growth factor family.Ornitz DM et al
104250341999Clinical spectrum of fibroblast growth factor receptor mutations.Passos-Bueno MR et al
95855831998Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations.Paznekas WA et al
77059431995Expression of FGF and FGF receptor genes in human breast cancer.Penault-Llorca F et al
175257452007Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes.Pollock PM et al
184833262008FGFR2 is a breast cancer susceptibility gene in Jewish and Arab Israeli populations.Raskin L et al
17111901991PCR-based identification of new receptors: molecular cloning of a receptor for fibroblast growth factors.Raz V et al
79874001994Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.Reardon W et al
106024771999Tumour suppressive properties of fibroblast growth factor receptor 2-IIIb in human bladder cancer.Ricol D et al
85278951995Keratinocyte growth factor as a cytokine that mediates mesenchymal-epithelial interaction.Rubin JS et al
75285171994Characteristics of FGF-receptors expressed by stromal and epithelial cells cultured from normal and hyperplastic prostates.Story MT et al
129009002003Beare-Stevenson syndrome: Two South American patients with FGFR2 analysis.Vargas RA et al
93006561997Craniosynostosis: genes and mechanisms.Wilkie AO et al
77193441995Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.Wilkie AO et al
123574702002FGFs, their receptors, and human limb malformations: clinical and molecular correlations.Wilkie AO et al
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76877391993Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy.Yan G et al
13162751992A confined variable region confers ligand specificity on fibroblast growth factor receptors: implications for the origin of the immunoglobulin fold.Yayon A et al
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Other Information

Locus ID:

NCBI: 2263
MIM: 176943
HGNC: 3689
Ensembl: ENSG00000066468

Variants:

dbSNP: 2263
ClinVar: 2263
TCGA: ENSG00000066468
COSMIC: FGFR2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000066468ENST00000336553H7BXU9
ENSG00000066468ENST00000346997P21802
ENSG00000066468ENST00000351936A0A0A0MR25
ENSG00000066468ENST00000356226P21802
ENSG00000066468ENST00000357555P21802
ENSG00000066468ENST00000358487P21802
ENSG00000066468ENST00000359354P21802
ENSG00000066468ENST00000360144P21802
ENSG00000066468ENST00000360144A0A141AXF1
ENSG00000066468ENST00000369056P21802
ENSG00000066468ENST00000369058P21802
ENSG00000066468ENST00000369059E7EVR7
ENSG00000066468ENST00000369060P21802
ENSG00000066468ENST00000369061P21802
ENSG00000066468ENST00000429361H7C265
ENSG00000066468ENST00000457416P21802
ENSG00000066468ENST00000478859S4R381
ENSG00000066468ENST00000604236S4R3B2
ENSG00000066468ENST00000611527A0A087X2D1
ENSG00000066468ENST00000613048D2CGD1
ENSG00000066468ENST00000613324A0A087WY21
ENSG00000066468ENST00000636922A0A1B0GWF4
ENSG00000066468ENST00000638709A0A1W2PQT9

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Regulation of actin cytoskeletonKEGGko04810
Prostate cancerKEGGko05215
MAPK signaling pathwayKEGGhsa04010
Regulation of actin cytoskeletonKEGGhsa04810
Pathways in cancerKEGGhsa05200
Prostate cancerKEGGhsa05215
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Central carbon metabolism in cancerKEGGhsa05230
Central carbon metabolism in cancerKEGGko05230
DiseaseREACTOMER-HSA-1643685
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by FGFR in diseaseREACTOMER-HSA-1226099
Signaling by FGFR2 in diseaseREACTOMER-HSA-5655253
FGFR2 mutant receptor activationREACTOMER-HSA-1839126
Activated point mutants of FGFR2REACTOMER-HSA-2033519
Signaling by FGFR2 amplification mutantsREACTOMER-HSA-2023837
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by FGFRREACTOMER-HSA-190236
Signaling by FGFR2REACTOMER-HSA-5654738
FGFR2 ligand binding and activationREACTOMER-HSA-190241
FGFR2b ligand binding and activationREACTOMER-HSA-190377
FGFR2c ligand binding and activationREACTOMER-HSA-190375
Downstream signaling of activated FGFR2REACTOMER-HSA-5654696
FRS-mediated FGFR2 signalingREACTOMER-HSA-5654700
Phospholipase C-mediated cascade; FGFR2REACTOMER-HSA-5654221
SHC-mediated cascade:FGFR2REACTOMER-HSA-5654699
PI-3K cascade:FGFR2REACTOMER-HSA-5654695
Negative regulation of FGFR2 signalingREACTOMER-HSA-5654727
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
Signaling by FGFR2 IIIa TMREACTOMER-HSA-8851708
Signaling by FGFR2 fusionsREACTOMER-HSA-8853333
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164924492brivanibChemicalPathwayassociated20124951
PA166182720erdafitinibChemicalLabelAnnotationassociated
PA26880CRKGenePathwayassociated20124951
PA28115FGF2GenePathwayassociated20124951
PA33304PIK3C2AGenePathwayassociated20124951
PA33305PIK3C2BGenePathwayassociated20124951

References

Pubmed IDYearTitleCitations
175299732007A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.739
175299732007A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.739
159313892005Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer.297
192859432009ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing.234
202373442010Performance of common genetic variants in breast-cancer risk models.191
184372042008Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.167
184620182008Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.126
175257452007Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes.100
183557722008Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.99
183557722008Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.99

Citation

Masaru Katoh

FGFR2 (fibroblast growth factor receptor 2)

Atlas Genet Cytogenet Oncol Haematol. 2008-08-01

Online version: http://atlasgeneticsoncology.org/gene/40570/fgfr2