Download Gene Section FGFR2 (fibroblast growth factor receptor 2) in Oncology and Haematology

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Gene Section
Review
FGFR2 (fibroblast growth factor receptor 2)
Masaru Katoh
Genetics and Cell Biology Section, National Cancer Center, Japan (MK)
Published in Atlas Database: August 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/FGFR2ID40570ch10q26.html
DOI: 10.4267/2042/44511
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Identity
Other names: BEK; CD332; CEK3; ECT1; KGFR; Ksam; TK14; TK25
HGNC (Hugo): FGFR2
Location: 10q26.13
Local order: WDR11 - FGFR2 - ATE1 - NSMCE4A TACC2.
Note: FGFR2 was independently cloned and
characterized by several groups as a novel receptortype tyrosine kinase BEK, KGFR, K-sam, or TK14.
DNA/RNA
Note
FGFR2 gene at chromosome 10q26.13 and FGFR1
gene at chromosome 8p12 are paralogs within the
human genome.
Description
FGFR2 gene, consisting of at least 21 exons, encodes
multiple isoforms due to alternative
Structure and alternative splicing of FGFR2 gene.
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FGFR2 (fibroblast growth factor receptor 2)
Katoh M
Schematic representation of FGF signaling cascades.
Transcription
Localisation
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 ESderived 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.
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). Liganddependent 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 - RAFMAP3K - MAP2K - MAPK and GAB1 - PI3K - AKT
signaling
cascades.
Phospholipase
C-gamma
(PLCgamma) is recruited to FGFR2 through its
interaction with phosphotyrosine residues on the Cterminal 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.
Protein
Note
FGFR2 functions as transmembrane receptor for FGF
family members, such as FGF1 (aFGF), FGF2 (bFGF),
FGF3, FGF4 (Kaposi's 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.
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 Iglike 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.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(7)
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.
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FGFR2 (fibroblast growth factor receptor 2)
Katoh M
Mutations
Germinal and somatic point mutations of FGFR2.
In addition, SNPs within intron 2 of FGFR2 gene are
associated with increased risk of breast cancer, partly
due to transcriptional upregulation of FGFR2.
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.
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.
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.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(7)
Implicated in
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
479
FGFR2 (fibroblast growth factor receptor 2)
Katoh M
Mechanisms of oncogenic FGFR2 signaling activation.
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.
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Atlas Genet Cytogenet Oncol Haematol. 2009; 13(7)
This article should be referenced as such:
Katoh M. FGFR2 (fibroblast growth factor receptor 2). Atlas
Genet Cytogenet Oncol Haematol. 2009; 13(7):477-482.
482