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FLASH GENE

Symbol

FGF1

contributors: mct/pgu - updated : 12-04-2016

HGNC name	fibroblast growth factor 1 (acidic)
HGNC id	3665

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	105.89 kb     5 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	transcription is directed by at least three distinct promoters that are conserved across mammals

MAPPING

cloned

Y

linked

Y

status

confirmed

Map	cen - D5S490 - D5S500 - CD14 - D5S658 - FGF1 - PCDHA@ - PCDHB@ - PCDHG@ - APBB3 - HBEGF - D5S2374 - PFDN1 - D5S2119 - D5S2010 - DIAPH1 - TAF7 - D5S1979 - D5S352 - D5S147 - D5S178 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000800 4 - 3755 NP_000791 - 155 - 1992 1372643 proprotein isoform 1 NM_001144935 4 - 3781 NP_001138407 - 155 - 1992 1372643 proprotein isoform 1 NM_001144934 5 - 3875 NP_001138406 - 155 - 1992 1372643 proprotein isoform 1 NM_033136 3 - 4050 NP_149127 - 60 - 1992 1372643 isoform 2 NM_001144892 4 - 3669 NP_001138364 - 155 - 1992 1372643 proprotein isoform 1 NM_033137 2 - 3516 NP_149128 - 59 - 1992 1372643 isoform 3 NM_001257206 4 - 4069 NP_001244135 - 154 - 1992 1372643 NM_001257205 4 - 4072 NP_001244134 - 155 - 1992 1372643 NM_001257211 4 - 3810 NP_001244140 - 154 - 1992 1372643 NM_001257208 4 - 3813 NP_001244137 - 155 - 1992 1372643 NM_001257207 5 - 3815 NP_001244136 - 155 - 1992 1372643 NM_001257209 4 - 3828 NP_001244138 - 155 - 1992 1372643 NM_001257210 4 - 3811 NP_001244139 - 155 - 1992 1372643 NM_001257212 4 - 3679 NP_001244141 - 154 - 1992 1372643

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 Nervous brain       highly Homo sapiens Respiratory respiratory tract trachea     highly Urinary kidney       highly Homo sapiens Visual eye

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose white     Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Nervous astrocyte Homo sapiens not specific adipocyte Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal nuclear localization signal (NLS) implicated in the stimulation of DNA synthesis
	two nuclear localization signals required for transport from the cytosol to the nucleus of externally added FGF-1 translocated into cells
	a second putative NLS (NLS2), near the C-terminus,(a bipartite NLS consisting of two clusters of lysines separated by a spacer of 10 amino acids)
	a IL1B-like domain
	implication of FGF1 C-terminal domain on its intracellular activities

HOMOLOGY

interspecies	homolog to murine Fgf1 (95.5pc)
	homolog to rattus Fgf1 (95.5pc)

Homologene

FAMILY	heparin-binding growth factors family
	fibroblast growth factor (FGF) family

CATEGORY

protooncogene , signaling growth factor

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,nucleolus
text	phosphorylation occurs normally in the nucleus, and both NLS1 and NLS2 are important for efficient transport to the nucleus
	under stress, FGF1 and S100A13 colocalize at the plasma membrane
	upon stress, FGF1 is transported to the plasma membrane where it localizes prior to transmembrane translocation

basic FUNCTION	heparin binding growth factor
	functioning as a modifier of endothelial cell migration and proliferation, as well as an angiogenic factor and mitogen for a variety of mesoderm- and neuroectoderm cells
	involved in organogenesis, in cardiomyocyte proliferation and angiogenesis during development
	perichondrial FGF1, FGF2, FGF6, FGF7, FGF9, FGF18, FGF21, fGF22 regulate growth plate chondrogenesis
	potent inducer of cell migration and chemotaxis
	activates spinal astrocytes, and activated astrocytes are implicated in neurodegenerative disorders such as amyotrophic lateral sclerosis
	involved in opening pannexin and connexin hemichannels
	stress-induced unconventional export of FGF1, is associated with and dependent on the formation of membrane blebs and localized cell surface exposure of phosphatidylserine
	metabolic role for FGF1 as a critical transducer of PPARG signalling that mediates the proper coupling of nutrient storage to adaptive remodelling of adipose tissue
	FGF1 and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels
	induces maturation and cell cycle exit in chondrocytes, triggers rapid accumulation of RBL1-PPP2R2A complexes coinciding with RBL1 dephosphorylation
	prolonged biological activity of FGF1 can be achieved by increasing its proteolytic resistance directly linked to improved global thermostability
	acts through cell surface tyrosine kinase receptors, but FGF1 can also act directly in the cell nucleus, as a result of nuclear import of endogenously produced, non-secreted FGF1 or by transport of extracellular FGF1 via endosomes and cytosol into the nucleus
	antidiabetes function of FGF1 may act partially through increasing beta-cell differentiation
	role of intracellular FGF1 is to protect the cell against stress conditions by providing an additional signal for cell survival, independently of receptor-activated signaling cascades
	lacking a secretion peptide signal and acting mainly in an intracellular and nuclear manner

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	PPARG-FGF1 axis is critical for maintaining metabolic homeostasis and insulin sensitization
	Heparan sulfate (HS) chains form ternary complexes with FGF1/FGFR when enzymes carry out modifications in a specific manner

INTERACTION

DNA

RNA

small molecule

protein	associated with S100A13 and p40 extracellular domain of synaptotagmin 1 (SYT1) for the release of signal peptide-less FGF1 in a temperature stress-induced pathway
	directly interacts with integrins in a dose-dependent manner (with ITGAV)
	interacting with S100A13 (released from the cells as a copper-dependent multiprotein complex that includes a small calcium-binding protein S100A13)
	induces regulated intramembrane proteolysis (RIP) of FGFR3
	both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB
	KPNA1, KPNB1 were required for nuclear import of FGF1
	LRRC59 is strictly required for nuclear import of exogenous FGF1
	nucleolin (NCL), a nuclear multifunctional protein, is an interaction partner of FGF1, and NCL-FGF1 interaction is critical for the intranuclear phosphorylation of FGF1 by PRKCD and thereby the regulation of nuclear export of FGF1
	direct interaction of CTGF and FGF1, suggesting the co-presence of these molecules in the cartilage microenvironment
	BGN binds to FGFR3c and FGF1
	in heat-shocked cells, FGF1 and the C-terminal fragment of AHNAK2 colocalized with F-actin in the vicinity of the cell membrane

cell & other

REGULATION

induced by

temperature stress-induced pathway

Phosphorylated by

PRKCD (in the nucleus, FGF1 can be phosphorylated by PRKCD, and this event induces nuclear export of FGF1)

Other	accessible to pharmacologic regulation
	down-regulated by the binding of RFX1 to its promoter region
	induced in visceral (i.e. gonadal) white adipose tissue (WAT) in response to a high-fat diet
	phosphorylation does not regulate FGF1 neurotrophic activity but inhibits its anti-apoptotic activity after TP53-dependent apoptosis induction

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function results in diet-induced insulin resistance

Susceptibility

to intracranial aneurysm to Alzheimer disease(AD) to variation of systolic Blood pressure

Variant & Polymorphism SNP	SNP at intron 4 increasing the risk of intracranial aneurysm
	promoter polymorphism (-1385 A/G) was significantly associated with AD risk
	SNP rs152524 was associated in a dose-dependent manner with systolic Blood pressure

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     mutant R50E suppressed tumor growth while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E cardiovascular atheroma   FGF1/MAPK14 inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction

ANIMAL & CELL MODELS

Fgf1 is highly induced in adipose tissue in response to high-fat diet (HFD) and mice lacking Fgf1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with HFD