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FLASH GENE

Symbol

FGFR1

contributors: mct - updated : 28-02-2017

HGNC name	fibroblast growth factor receptor 1
HGNC id	3688

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CRS7A craniosynostosis, syndromatic 7 ECCL encephalocraniocutaneous lipomatosis HRTFDS Hartsfield syndrome KAL2 Kallmann syndrome 2 NIHH normosmic idiopathic hypogonadotropic hypogonadism OGD osteoglophonic dysplasia SCLLS stem-cell leukemia/lymphoma syndrome
Location	8p11.22      Physical location : 38.268.656 - 38.326.352
Synonym name	FMS-like tyrosine kinase 2
	basic fibroblast growth factor receptor 1
	heparin-binding growth factor receptor
	hydroxyaryl-protein kinase
	fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, Pfeiffer syndrome)
Synonym symbol(s)	FGFRA, FLT2, CEK, FLG, BFGFR, C-FGR, CD331, H2, H3, H4, H5, KAL2, N-SAM
EC.number	2.7.1.112, 2.7.10.1

DNA

TYPE	functioning gene
SPECIAL FEATURE	head to head
STRUCTURE	57.70 kb     18 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site
text structure	three potential Sp factor binding sites located at 49 bp, 68 bp, and 100 bp upstream from the 3 prime end of the promoter segment
	two non-consensus E2F binding sequences at positions + 4 to + 22 and + 25 to + 43 critical for E2F-1-mediated transactivation of FGFR 1 promoter

MAPPING

cloned

Y

linked

N

status

provisional

Map

see CEBPD

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001174064 19 - 5963 NP_001167535 - 812 - 1991 1650441 NM_001174063 18 - 5895 NP_001167534 - 820 - 1991 1650441 NM_023110 18 - 5917 NP_075598 91.9 822 - 1991 1650441 using exon 9 NM_015850 18 splicing 5911 NP_056934 - 820 - 1991 1650441 two missing AAs Arg-Met NM_023105 17 splicing 5650 NP_075593 - 733 - 1991 1650441 lacking the first Ig domain (exon 3) NM_023106 17 splicing 5644 NP_075594 - 730 - 1991 1650441 lacking exon 3 Arg-Met NM_001174065 18 - 5215 NP_001167536 - 820 - 1991 1650441 NM_001174066 17 - 4954 NP_001167537 - 733 - 1991 1650441 NM_001174067 19 - 5375 NP_001167538 - 853 - 1991 1650441

EXPRESSION

Type	ubiquitous

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       highly Nervous ganglia sensory ganglia dorsal root   highly Homo sapiens Adult Reproductive female system ovary     highly Respiratory respiratory tract trachea     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone       Muscular striatum cardiac     Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Cardiovascular endothelial cell Muscular myocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	endothelial stem/progenitor cells

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a signal peptide
	three Ig-like C2 type extracellular domains
	an acid box and heparin binding region between the first and second Ig loops
	a single membrane-spanning segment
	an intracellular split tyrosine-kinase domain at the C-terminus, and a C-terminal fragment of FGFR1, generated by receptor activation-dependent cleavage, which traffics to the nucleus and regulates the expression of target genes

mono polymer

homomer , dimer

HOMOLOGY

interspecies

homolog to murine Fgfr1

intraspecies

homolog to fibroblast growth factor receptor 1(flg/fms related gene)

Homologene

FAMILY

fibroblast growth factor receptor family

CATEGORY

enzyme , receptor membrane tyrosine kinase

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	full-length FGFR1 (120 kD) is in the plasma membrane/organelle fraction and a truncated FGFR1 fragment (55–60 kD) in the nuclear fraction; localized to the nucleus specifically in breast cancer cells that invaded into the stroma, and this invasion was impaired significantly by blocking FGFR signaling

basic FUNCTION	receptor tyrosine kinase, class IV, fibroblast growth factor receptor 1 (receptor for acidic FgF) involved in limb induction
	playing a role in the modulation of bone elongation
	mediate two independent signaling pathways in retinal pigment epithelial cells
	regulates proliferation, differentiation, and maintenance of normal myocardium
	playing a role in rhabdomyosarcoma tumorigenesis and a possible association with the deregulation of proliferation and differentiation of skeletal myoblasts in rhabdomyosarcoma
	negatively regulates endothelial cell function by altering the balance of modulatory cytokines
	with FGFR2 in kidney mesenchyme, are critical for normal early renal development
	FGFR1, FGFR2, FGFR3, differentially control the normal generation of oligodendrocyte progenitor (OLP) from the embryonic ventral forebrain
	internalization of FGFR1 controls axon growth and morphology of adult sensory neurons via selective activation of intracellular signaling pathways
	clathrin-mediated endocytosis is required for efficient internalization and downregulation of FGFR1
	initiates MAPK signaling, whereas SDC4-dependent FGFR1 macropinocytosis modulates the kinetics of MAPK activation
	adipose FGFR1 regulates lipid metabolism through direct effect on adipose tissue and indirect effects on liver under starvation conditions that cause hepatic stress
	crucial for breast cancer cell proliferation and tumor growth and angiogenesis
	play an important role in many signalling cascades

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

ossification

text	bone development and maintenance

PATHWAY

metabolism

signaling

FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction

a component	forms a multi-protein complex with MTOR in vascular smooth muscle cells
	GRB14 was recruited to FGFR1 into a trimeric complex containing also phospholipase C gamma (PLCG1)
	homodimerization of FGFR1 appear to be a fundamental mechanism for the agonist activity of all FGF ligands at least in the case of the MAPK signaling

INTERACTION

DNA

RNA

small molecule

protein	specific interaction between phosphorylated Y463 in FGFR1 with the CRKL SH2 domain
	link between FGFR1 and the cell adhesion molecule neurofascin
	interacting with FLRT1 (critical role of FLRT1 phosphorylation in the interdependent regulation of FLRT1 function and FGF receptor signalling)
	NEDD4 is an E3 ubiquitin ligase regulating endocytosis and signalling of FGFR1
	FGFR1 is a substrate for the serine protease GZMB, and endogenous GZMB can play a promigratory role, at least in part through cleaving FGFR1
	LRIT3 is a regulator of the FGFR1
	FGF21 effects on chondrocyte function are specific and depend on the normal activity of the FGFR1 and MAPK3
	by binding FGFR1 and/or FGFR3, FGF21 prevents GH-mediated stimulation of chondrocyte proliferation and differentiation
	correlation between PAR1 and FGFR1 suggests an association of the two receptors with a more aggressive breast cancer phenotype and, consequently, a potential role during tumor progression
	PARK7 stimulates the differentiation of human mesenchymal stem cells to osteoblasts and induces angiogenesis in endothelial cells through activation of FGFR1 signalling
	stimulates bone regeneration by inducing osteogenesis and angiogenesis via regulating FGFR1 signaling
	RPS6KA3 is a potential FGFR1 interaction partner
	DNM2 dependent endocytosis of FGFR1 is required for angiogenesis in response to FGF2 and the non-classical FGF ligand, FGF21
	ESYT2 and ESYT3, but not ESYT1, selectively interact with activated FGFR1
	MAP3K4 acts as a critical node to integrate FGF20-FGFR1 signaling responses to specifically influence hair cells (HCs) development

cell & other

REGULATION

activated by

homodimerization in the presence of both the FGF agonist ligand and heparan sulfate glycosaminoglycan

Other	regulated by the pRB/E2F pathway
	its expression itself is regulated by FGF8 and FGF signaling, which may be of importance in breast tumors expressing FGFs at a high level

ASSOCIATED DISORDERS

corresponding disease(s)

CRS7A , SCLLS , OGD , KAL2 , NIHH , HRTFDS , ECCL

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       with FOP in t(6;8)(q27;p11),with CEP1 in t(8;9)(p11;q33), with ZNF198 in t(8;13)(p11;q12) tumoral somatic mutation       aberrant alternative splicing in glioblastoma (exon skipping) tumoral fusion       with BCR in t(8;22) (p11;q11) tumoral   amplification     during the progression of in situ to invasive breast carcinoma tumoral       gain of function in the 8p11 myeloproliferative syndrome tumoral fusion       with TIF1 in t(7;8)(q34;p11)in myeloproliferative syndrome tumoral fusion       with TNS3 in t(7;8) (p12.3;p11.2)in Kallmann syndrome with cleft lip and cleft palate tumoral fusion       to CPSF6, in t(8;12)(p11;q15) and the 8p11 myeloproliferative syndrome constitutional     --other   dysfunction (expression) of the FGFR1, SOS1 and RAF1 genes is involved in the development of unilateral or bilateral cryptorchidism tumoral     --over   in renal cell carcinoma tumoral fusion       NTRK2 is a new gene fusion target in pilocytic astrocytoma (fusion with QKI, FGFR1) tumoral fusion       to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively in glioblastoma tumoral fusion       fusion FGFR1/TPR in 8p11 myeloproliferative syndrome tumoral fusion       ZMYM2-FGFR1 fusion in myeloproliferative syndrome tumoral   amplification     in squamous lung carcinomas

Susceptibility

Variant & Polymorphism SNP	SNP g.8592931G-->C was found to have a significant negative correlation with the cephalic index for all populations

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS