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FLASH GENE

Symbol

FGFR2

contributors: mct - updated : 26-03-2019

HGNC name	fibroblast growth factor receptor 2 (bacteria-expressed kinase, keratinocyte growth factor receptor, craniofacial dysostosis 1, Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome)
HGNC id	3689

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ACS1 acrocephalosyndactyly type 1 ANBXL1 Antley-Bixler syndrome 1 BBDS Bent bone dysplasia CRS11 craniosynostosis, syndromatic 11 CRS5A craniosynostosis, syndromatic 5A CRS6 craniosynostosis, syndromatic 6 CRS7B craniosynostosis, syndromatic 7B CRS7C craniosynostosis, syndromatic 7C LADD1 lacrimo-auriculo-dento-digital syndrome 1
Location	10q26.13      Physical location : 123.237.844 - 123.357.972
Synonym name	tyrosyl-protein kinase
	keratinocyte growth factor receptor
	CD332 antigen
	FGF receptor
	bacteria-expressed kinase
	hydroxyaryl-protein kinase
	protein tyrosine kinase, receptor like 14
Synonym symbol(s)	BEK, KSAM, JWS, CEK3, CFD1, ECT1, KGFR, TK14, BFR1, CD332, BFR-1, TK25, FLJ98662
EC.number	2.7.10.1

DNA

TYPE	anonymous DNA segment
STRUCTURE	120.13 kb     18 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	alternative promoter
text structure	2 mutually exclusive exons, K-SAM and BEK
	the choice of exon IIIc in mesenchymal cells involves activation of this exon and repression of exon IIIb through intronic splicing silencers flanking FGFR2 exon IIIb

MAPPING

cloned

Y

linked

Y

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	alternative splicing of FGFR2 pre-mRNA results in the mutually exclusive use of exons IIIb and IIIc, which leads to critically important differences in receptor function

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000141 18 splicing 4654 NP_000132 92 821 . in various epithelia, in spermatogonia, in inner retina . expressed in mesenchymal cells, and during epithelial-mesenchymal transition (EMT), is expressed in colorectal, pancreatic, bladder, cervical, and prostate cancers 2018 28930565 also called BEK and K-sam or variant 1, IIIc isoform three Ig domains, including the IIIc-type encoded by exon 9, and the C1-type carboxyl terminus encoded by exon 20 required for differentiation of the simple embryonic limb ectoderm into thre complex apical ectodermal ridge epithelium interaction with FGF10 for palate development with FGFR1 in kidney mesenchyme, are critical for normal early renal development NM_022970 18 - 4657 NP_075259 92 822 . expressed mainly on epithelial cells, mesenchymal, spermatogonia . abundantly present in the normal pituitary gland with contrasting down-regulation in neoplastic pituitary cells . is mainly expressed in normal epithelial cells, as well as in oral mucosal, esophageal, gastric, colorectal, pancreatic, pulmonary, breast, endometrial, cervical, and prostate cancers 2018 28930565 also called variant 2 or K-sam-IIH1, IIIb, and BFR-1, FGFR2b, KGFR three Ig domains, including the IIIb type encoded by exon 8, and the C1-type carboxyl terminus encoded by exon 20 required for normal function of the osteoblast lineage during both intramembrane and endochondral osteogenesis an increase in FGFR2c binding to multiple FGFs results in craniosynostosis, whereas binding of mutant FGFR2c to FGF10 results in severe limb pathology involved in skin homeostasis and cancer development target of MAGEA3 FGF10/FGFR2b signaling is essential for cardiac fibroblast development and growth of the myocardium its expression represents a key event regulating keratinocyte early differentiation during the switch from undifferentiated to differentiating cells FGFR2b-induced phagocytosis and autophagy involve converging autophagosomal and phagosomal compartments FGFR2b signalling would control the number of melanosomes in keratinocytes, determining skin pigmentation         - - - 1992 1582255 NM_001144913 17 splicing 2781 NP_001138385 - 769 - 2018 29068468 also called variant 3, FGFR2c lacking exons 8-10, soluble form FGFR2 maintains a niche-dependent population of self-renewing highly potent non-adherent mesenchymal progenitors through FGFR2c ectopic expression of FGFR2c in normal human keratinocytes induces epithelial-mesenchymal transition and leads to invasiveness and anchorage-independent growth NM_001144914 15 splicing 3821 NP_001138386 - 709 - 1992 1582255 also called variant 4 truncated, lack IgIII domain NM_001144915 17 splicing 3708 NP_001138387 - 707 - 1992 1582255 also called variant 5 3 Ig like domains NM_001144916 15 splicing 4103 NP_001138388 - 706 - 1992 1582255 also called variant 6 NM_001144917 16 splicing 4306 NP_001138389 - 705 - 1992 1582255 also called variant 7 NM_001144919 17 splicing 3011 NP_001138391 - 680 - 1992 1582255 also called variant 9 unique carboxy terminus NM_001144918 16 - 4303 NP_001138390 - 704 - 1992 1582255 also called variant 8 lack exon 3-4 NM_023029 16 - 3890 NP_075418 - 732 - 1992 1582255 NM_001320654 17 - 4038 NP_001307583 - 593 - 1992 1582255 NM_001320658 18 - 4648 NP_001307587 - 819 - 1992 1582255

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth palate     highly Endocrine neuroendocrine pituitary     highly Homo sapiens   parathyroid       highly Hearing/Equilibrium ear       highly Skeleton axial skull face maxilla     axial skull face mandible   Visual eye retina       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Epithelial barrier lining retinal pigment epithelium (RPE)     Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Reproductive spermatogonia Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

Text	in gonads, in the coelomic domain of XX and XY gonads and in testis cords

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a signal peptide, three Ig-like domains
	an acidic region between the first and second Ig loops
	a single membrane-spanning segment
	an intracellular split tyrosine-kinase domain
	three immunoglobulin C2 type domains
	a ligand (FGF)-binding D2 domain

HOMOLOGY

interspecies	homolog to rattus Fgfr2 (97.19 pc)
	homolog to murine Fgfr2 (96.95 pc)

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family
	fibroblast growth factor receptor subfamily

CATEGORY

enzyme , signaling growth factor , receptor

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic,vesicle
	intracellular,nucleus,nucleoplasm

basic FUNCTION	receptor tyrosine kinase class IV, keratinocyte growth factor receptor, involved in vertebral development
	important regulator of bone formation and osteoblast activity, playing an important role in regulation of RUNX2 function and bone formation
	mediate two independent signaling pathways in retinal pigment epithelial cells
	playing distinct roles in proliferation and Sertoli cell differentiation during testis development
	FGFR2 signalling may be potentially a regulator of the NMD (nonsense-mediated decay) pathway
	FGFR1, FGFR2, fGFR3, differentially control the normal generation of oligodendrocyte progenitor (OLP) from the embryonic ventral forebrain
	maintains a critical balance between the proliferation and differentiation of osteoprogenitor cell
	maintains a critical balance between the proliferation and differentiation of osteoprogenitor cells
	essential in sustaining the breast TIC(tumor-initiating cells) pool through promotion of self-renewal and maintenance of bipotent TICs
	involved in the development of frontal brain regions and its impairment in cognitive and social behaviors
	FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining PAX6 levels in corneal epithelium via ERK-independent pathways during embryonic development
	region-specific requirements for FGFR2 signaling in the developing caudal Wolffian duct (WD) epithelia
	FGFR2 regulates epithelial maturation and cell cycle progression in the urethral endoderm and in the surface ectoderm
	FGFR2 mediated FGF signaling may play an important role in palate initiation
	role for FGFR2 in development of the middle ear skeletal tissues, suggesting potential causes for conductive hearing loss in LADD syndrome
	role of a TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in lung organogenesis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

text	osteogenesis

PATHWAY

metabolism

signaling

sensory transduction/vision

FGFR2-RPS6KA3 signalling pathway is involved in pathophysiology of breast cancer

a component

MMP14 forms a complex with FGFR2 and ADAM9 in osteoblasts

INTERACTION

DNA

RNA

small molecule

protein	NCAM1
	receptor for FGF9 in the XY gonad
	interaction of FRS2 with wild-type receptor occurs primarily at the vesicular membrane, whereas the interaction with the P253R receptor occurs exclusively at the plasma membrane
	MMP14 is a critical negative modulator of ADAM9 activity to maintain FGFR2 signaling in calvarial osteogenesis
	upon stimulation, FGFR2 phosphorylates tyrosine residues on GRB2, promoting dissociation from the receptor and allowing full
	co-localization of NCAM1 and FGFR2 in early vertebrate development with intracellular signaling pathways present to enable a cellular response
	activation of downstream signaling, establishing a role for GRB2 as an active regulator of RTK signaling
	GRB2 is strongly implicated in controlling FGFR2 kinase activity prior to growth factor stimulation
	FGFR2 induces rapid but reversible NANOG repression within ES cells
	HOXC6 play an important role in several cellular events through the regulation of its functional biological targets such as BMP7, FGFR2, and PDGFRA
	FGFR2 serves as a scaffold for multiple components of the NFKB1 signaling complex
	GRB2 controls FGFR2 signaling by regulating receptor kinase and PTPN11 phosphatase activity in the absence of extracellular stimulation
	LDB1 in a complex with LMO4, supports mammary stem cells by directly targeting the FGFR2 promoter in basal cells to increase its expression
	key roles played, on the melanosome transfer in normal skin, by FGF7 released by dermal fibroblasts and by its receptor FGFR2 expressed and activated on the epidermal keratinocytes
	potential role for NEGR1 in regulating neurite outgrowth through the modulation of FGFR2 signaling pathway
	FGFR2 signalling correlates with maintenance of expression of a key transcription factor for basal cell self-renewal and differentiation: SOX2
	DDX6 protein acted as an RNA-binding protein for ERBB2 and FGFR2 mRNAs and positively regulated their post-transcriptional processes
	NEGR1 and FGFR2 cooperatively regulate cortical development, suggesting a role for defective NEGR1-FGFR2 complex and convergent downstream ERK and AKT signalling in autism spectrum disorders

cell & other

REGULATION

Other

regulated by HGS (regulates the FGFR2 degradative pathway, but not its juxtanuclear recycling transport) (

ASSOCIATED DISORDERS

corresponding disease(s)

ACS1 , CRS5A , CRS6 , CRS7B , CRS11 , ANBXL1 , CRS7C , BSCGS , LADD1 , BBDS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral somatic mutation       in gastric carcinoma tumoral germinal mutation       mutation P253R in early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome tumoral     --low   by hypermethylation in gastric cancer cells, contributing to tumor progression tumoral   amplification --over   in breast cancer tumoral somatic mutation       in endometrial cancer tumoral   amplification     in diffuse-type gastric cancer constitutional   deletion     of either FGF9 or FGFR2 in an XY gonad resulted in up-regulation of WNT4 and male-to-female sex reversal constitutional     --over   increased FGFR2 activation during embryonic period leads to abnormal differentiation or regression of the tail bud and, in turn, sacrococcygeal eversion, in certain patients with severe syndromic craniosynostosis tumoral     --over   in pancreatic ductal adenocarcinoma (PDAC) and correlated with advanced stage cancer tumoral fusion       KLK2-FGFR2 fusion gene in metastatic prostate cancer

Susceptibility

to hypospadias to estrogen receptor-positive breast cancer, low-risk allele

Variant & Polymorphism SNP , other	polymorphisms increasing the risk of hypospadias
	SNP increasing the risk of breast cancer

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer reproductive uterus anti-FGFR molecularly targeted therapies in patients with advanced or recurrent endometrial carcinoma cancer reproductive breast FGFR2 inhibition is a potential strategy for anti-cancer therapy by eradicating breast tumor-initiating cells cancer digestive stomach development of FGFR-targeted therapy for gastric cancers with FGFR2 amplification cancer endocrine pancreas therapeutic target for inhibition in PDAC

ANIMAL & CELL MODELS

	cleft palate occurred in nearly all mice homozygous for the Crouzon syndrome mutation C342Y in the mesenchymal splice form of Fgfr2
	a soluble truncated Fgfr2 molecule encoded by a premature termination codon-containing transcript is up-regulated and persists in tissues of an Apert mouse model
	deletion of Fgfr2 or its ligand Fgf10 results in severe hypospadias in mice, in which the entire urethral plate is open along the ventral side of the penis