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FLASH GENE

Symbol

FGFR3

contributors: mct/pgu - updated : 29-03-2017

HGNC name	fibroblast growth factor receptor 3
HGNC id	3690

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ACH achondroplasia BSCGS2 Beare-Stevenson cutis gyrata syndrome 3 CATSHL camptodactyly, tall stature and hearing loss syndrome CRS10 craniosynostosis, syndromatic 10 CRS5B craniosynostosis, syndromatic 5B CRS8 craniosynostosis, syndromatic 8 CRSCNS craniosynostosis, non syndromatic FENS FGFR3 epidermal nevus syndrome HCH hypochondroplasia LADD2 lacrimoauriculodentodigital syndrome 2 SADDAN severe achondroplasia with developmental delay and acanthosis nigricans TNTP1 thanatophoric dysplasia, type 1 TNTP2 thanatophoric dysplasia, type 2
Location	4p16.3      Physical location : 1.795.038 - 1.810.599
Synonym name	tyrosine kinase JTK4
	hydroxyaryl-protein kinase
	CD333 antigen
Synonym symbol(s)	CEK2, JTK4, CD333, HSFGFR3EX
EC.number	2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	15.56 kb     18 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	cytosine-phosphate-guanine/HTF
	Binding site   transcription factor
text structure	binding sites for sp1, AP2, Krox24, IgHC4 and ZESTE
	SHOX strongly activate the extended FGFR3 promoter)

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - D4S115 - D4S168 - D4S113 - FGFR3 ,[D4S99 - D4S98 ] - D4S114 - D4S166 - WHSC2 - D4S43 - cen
Text	see D4S10

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed variant 6 - - - isoform 6 - - epithelial cells 1995 7495869 also called FGFR3b activated by FGF1, FGF3 does not cooperate with the FGFR3c isoform in endochondral bone development variant 7 - - 370 isoform 7 - 125 mesenchymal cells 2011 21894939 also called FGFR3c activated by FGF1, FGF4, FGF5, FGF6, FGF8 main transducer of the balance between cell proliferation and differentiation during normal chondrocyte development FGF1 and FGF2 elicit a similar FGFR3c response at low, but not at high, concentrations BGN binds to FGFR3c and FGF1 (PMID: 25260943) NM_000142 17 splicing 4304 NP_000133 87.7 806 in the inner retina, in fibroblastic cells 1995 7495869 also called variant 1, isoform 1 or isoform IIIc 3 Ig-like domains missing exon 8 using exon 9 alternative splicing choice between IIIb and IIIc exons of the is not strictly tissue-specific: epithelial cells show exclusively IIIb transcripts while fibroblastic cells show a mixture of IIIb and IIIc transcripts NM_022965 15 - 3968 NP_075254 75 694 maybe secreted 2009 18923003 variant 2 two Ig-like domains variant 5 - - 390 isoform 5 86 782 undifferenciated chondrocytes 2001 11134040 also called FGFR3-DAB lacking the acid-box domain variant 4 - splicing - isoform 4 - - tumour and tumour cell lines 2003 14520460 also called FGFR3 IIIS soluble regulate FGF and FGFR trafficking and function, possibly contributing to the development of a malignant phenotype NM_001163213 - - 4310 - 808 in epithelial cells and fibroblastic cells 1995 7495869 isoform IIIb alternative splicing choice between IIIb and IIIc exons of the is not strictly tissue-specific: epithelial cells show exclusively IIIb transcripts while fibroblastic cells show a mixture of IIIb and IIIc transcripts

EXPRESSION

Type

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 Cardiovascular heart       lowly Digestive intestine large intestine     lowly Homo sapiens   intestine small intestine jejunum     Homo sapiens Nervous brain         Reproductive male system testis       Homo sapiens Adult Skeleton axial skull       Urinary bladder           kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective cartilage       Epithelial absorptive excretory digestive epithelium (mucosa)     Homo sapiens Muscular striatum cardiac   highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol   chondrocyte Digestive enterocyte Homo sapiens Digestive Paneth Homo sapiens Muscular myocyte Homo sapiens Reproductive spermatogonia Homo sapiens Adult

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	kidney, lung, small intestine, brain, lowly in spleen, liver, muscle, cartilage, skull

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
	two C-terminal intracellular split tyrosine-kinase domains

conjugated

GlycoP

isoforms

Precursor

HOMOLOGY

interspecies

homolog to murine Fgfr3

Homologene

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

CATEGORY

signaling growth factor , receptor membrane

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	ectodomain cleavage is followed by intramembrane cleavage (S2) to generate a soluble intracellular domain that is released into the cytosol and can translocate to the nucleus (mechanism for the nuclear localization of FGFR3 in response to ligand activation, which may occur in both development and disease)

basic FUNCTION	receptor tyrosine kinase class IV, negative regulator of bone growth, playing an important role in the control of chondrocyte proliferation and differentiation, a process critical for normal development of the skeleton
	essential regulator of endochondral bone growth
	promotion and inhibition of chondrocyte proliferation and differentiation depending on the time during development (mouse)
	negative regulation of endochondral ossification
	involved in lysosomal degradation through c-Cbl mediated ubiquination(defective in achondroplasia)
	potential molecular targets with its ligand FGF18, for intervention in tissue engineering aimed at cartilage repair and regeneration of damaged cartilage
	requires SNAI1 during bone development and disease as the inhibition of SNAI1 abolishes its signaling even through achondroplastic- and thanatophoric-activating FGFR3 forms
	potential tumor suppressor gene in melanoma
	FGF18 and FGFR3 are involved, possibly as partners, in the control of intestinal precursor cell proliferation
	with MAPK signaling in chondrocytes promote synchondrosis closure and fusion of ossification centers (resposible of spinal canal and foramen magnum stenosis)
	activated FGFR3 implicated in cell adaptation, including Sprouty4 (SPRY4)up regulation to inhibit the receptor-mediated ERKs activation from the endoplasmic reticulum
	transcriptional regulation of FGFR3 might play a so far underestimated role in the development of short stature
	FGFR3 signaling may potentially regulate intestinal crypt stem cell numbers by regulating the differentiation of the Paneth cell phenotype
	FGFR3 signaling also modulates other effectors and/or pathways that are required to induce Paneth cell DEFA5 expression in addition to its effects on TCF4/CTNNB activity)
	FGFR1, FGFR2, FGFR3, differentially control the normal generation of oligodendrocyte progenitor (OLP) from the embryonic ventral forebrain
	is internalized by both clathrin-dependent and clathrin-independent mechanisms
	specific role for FGFR3 in the cell cycle and chondrocyte differentiation
	impaired FGFR3 signaling pathways may affect trabecular bone formation via a paracrine mechanism during growth
	is likely a negative regulator of endochondral bone growth
	receptor tyrosine kinase that control cell proliferation, differentiation, and survival
	role of FGFR3 in regulating lipid metabolism to maintain tumor growth and survival
	regulates microtubule formation and cell surface mechanical properties in the developing organ of Corti
	transduces biochemical signals via lateral dimerization in the plasma membrane, and plays an important role in human development and disease
	has a tumor suppressor-like function in chondrogenesis
	FGF receptors FGFR3, FGFR4 control alveolar elastogenesis
	FGF8 and FGFR3 may play an important role in the onset of deep zone necrosis and pathogenesis in osteochondropathy Kashin-Beck disease in adolescent children

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

development

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	IHH (negative regulator of IHH)
	STAT protein, PTHLH
	ligand FGF18
	interacting with RPS6KA3 (association is critical for FGFR3-dependent tyrosine phosphorylation at Y529 and Y707 of RPS6KA3 as well as its subsequent activation and RPS6KA3 is important for FGFR3-induced hematopoietic transformation)
	FGFR3 is a novel transcriptional target of SHOX
	ligands for FGFR3, FGF1, FGF2, and FGF9
	associates with Hsp90 and CDC37
	direct target of canonical Wnt signaling (Reinhold 2007)
	GLG1 is involved in FGF18 signalling via FGFR3C
	FGF1 induces regulated intramembrane proteolysis (RIP) of FGFR3
	by binding FGFR1 and/or FGFR3, FGF21 prevents GH-mediated stimulation of chondrocyte proliferation and differentiation
	FGFR3 signaling promotes the cleavage and activation of the master transcriptional regulator of lipogenesis, SREBF1, that in turn regulates the expression of SCD
	FGF23 binding to FGFR3 was enhanced in the presence of KL
	FGFR3 facilitates BMPR1A to degradation through SMURF1-mediated ubiquitination pathway
	in addition to modulating FGFR3 phosphorylation, PTPN1 and PTPN2 constrain the kinase domain by fostering an inactive-state

cell & other

REGULATION

activated by

oligomerization induced by ligand binding, followed by autophosphorylation at multiple tyrosine residues that are believed to provide docking sites for signaling factors through their respective Src homology 2 (SH2) phosphotyrosine binding domains

Other	regulated by HSP90 that is an important regulator of FGFR3 function
	FGFR3 activation in chondrocytes mimics the activation of major oncogenes signaling via the ERK pathway

ASSOCIATED DISORDERS

corresponding disease(s)

ACH , CRS10 , CRS5B , CRSCNS , CRS8 , FENS , SADDAN , TNTP1 , TNTP2 , HCH , BSCGS2 , LADD2 , CATSHL

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   LOH     in transitional cell carcinomas tumoral somatic mutation       in superficial urothelial cell carcinoma (UCC), in bladder carcinomas (superficial or low-grade) constitutional somatic mutation     gain of function somatic activating mutations in acanthosis nigricans and seborrheic keratosis tumoral     --other   dysregulated in multiple myeloma with t(4;14)(p16.3;q32) constitutional somatic mutation       mosaicism of activating mutation in skin causing epidermal nevi constitutional germinal mutation       intracellular mutations induce tyrosine phosphorylation in the Golgi, defective glycosylation and could disrupt bone development tumoral germinal mutation       in seborrheic keratosis and urothelial carcinomas tumoral fusion       TEL-FGFR3, in t(4;12)(p16;p13) with acute myeloid leukemia constitutional somatic mutation       somatic activating fibroblast growth factor 3 (FGFR3) mutations in skin can cause seborrheic keratoses tumoral       gain of function mutation activating in spermatocytic seminomas, paternal age-effect mutations activating a common 'selfish' pathway supporting proliferation in the testis constitutional germinal mutation     gain of function gain-of-function mutations, would have a stronger effect on the upper arm and leg, since FGFR3 is not targeted by SHOX in that part of the limbs and therefore expressed at higher levels than in the mesomelic segments tumoral fusion       with BAIAP2L1, in bladder carcinoma 3) tumoral fusion       to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively in glioblastoma constitutional         -

Susceptibility

to urinary bladder cancer (UBC) to short stature

Variant & Polymorphism SNP	rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors
	p.M528I mutation in FGFR3 segregates with short stature

Candidate gene
Marker	nuclear translocation of FGFR3 is frequent and carries clinicopathologic as well as prognostic significances in pancreatic cancer
Therapy target
	System Type Disorder Pubmed cancer hemopathy   therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies (for multiple myeloma associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants) osteoarticular bone   HSP90 inhibitors may be useful for treating FGFR3-mediated diseases osteoarticular bone osteochondroplasia development of tyrosine kinase inhibitors for the treatment of FGFR3-related chondrodysplasias osteoarticular bone   inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia

ANIMAL & CELL MODELS

	chondrocyte-specific activation of Fgfr3 in mice induced premature synchondrosis closure and enhanced osteoblast differentiation around synchondroses
	FGFR-3-/- mice show a marked deficit in a number of Paneth cell markers and a significant reduction in the number of lysozyme-positive Paneth cell