FGF1 (fibroblast growth factor 1 (acidic))

2013-08-01   Seiji Mori , Yoshikazu Takada 




Atlas Image
Figure1. FGF1 gene spans 105,89 kb on chromosome 5 in the region of q31.3 on the minus strand. It consists of 3 coding exons and 4 untranslated exons. The transcription is regulated by four distinct promoters. These are separated in the different 5 untranslated exons, designated 1A, 1B, 1C and 1D.


The FGF1 gene is located chromosome 5 from 141971743 to 142077617 (105893 bp) on the minus strand.


The FGF1 gene has 12 splice variants shown in Ensembl database. Nine of transcripts are protein-coding isoforms and 3 of those have no protein product. The FGF1 gene transcript is basically composed of 4 exons and second to fourth exons are protein-coding. The transcription is regulated by at least 4 distinct promoters in different upstream untranslated exons, designated 1A, 1B, 1C, and 1D. These are alternatively spliced to the first protein-coding exon (Chiu et al., 2001). The promoter 1A derived transcript dominantly expresses in the kidney (Myers et al., 1993), 1B in the brain and retina (Myers et al., 1993; Myers et al., 1995), and 1C and 1D in vascular smooth muscle cells and fibroblasts (Chotani et al., 2000).


Atlas Image
Figure 2. Schematic representation of the human FGF1 isoforms.


FGFs control multiple biological processes such as proliferation, survival, migration and differentiation of a variety of cell types (Lanner and Rossant, 2010; Guillemot and Zimmer, 2011). The human and mouse FGF family consists of 22 members that are expressed in almost all tissues. Among the FGF family, FGF1 and FGF2 are prototypic FGF and have been extensively characterized. They were originally isolated from the brain and pituitary as mitogens for fibroblast cells in vitro (Gospodarowicz, 1975; Itoh and Ornitz, 2011).
FGF1 contains characteristic β-trefoil structure, since FGF1 contains 12 antiparallel β strands which assemble into a pattern with threefold internal symmetry (Zhu et al., 1991, Brych et al., 2001). Key residues responsible for Interaction between FGF1 and heparin or its receptor are characterized by crystal structure (Pellegrini et al., 2000; Mohammadi et al., 2005a; Mohammadi et al., 2005b).
FGF1 is unique among FGFs because of its ability to bind and activate all known FGFRs, FGF1 is considered to be the universal FGFR ligand (Zhang et al., 2006). Comparison of the crystal structures of FGF1-FGFR1c, FGF1-FGFR2c, and FGF1-FGFR3c complexes has provided key insights into the unique FGFR binding promiscuity of FGF1 (Olsen et al., 2004).
Atlas Image
Figure 3. Domaine structure of FGF1. FGF1 contains a nuclear localization signal (NLS) at N-terminal region and heparin binding site is located C-terminal.


Although first isolated from brain and pituitary on the basis of their ability to induce fibroblasts proliferation, FGF1 is widely expressed in developing and adult tissues (Gospodarowicz, 1974; Gospodarowicz, 1975; Gospodarowicz et al., 1978; Itoh and Ornitz, 2004). Immunohistochemical staining has shown that colorectal and gastric tissues, both normal and tumor, express FGF1, and the immunoreactivity is mainly cytoplasmic (el-Hariry et al., 1997). Various amounts of FGF1 are detected in hepatocellular carcinoma, whereas it cannot be detected in normal (Chow et al., 1998). FGF1 mRNA is detected in several types of breast epithelial cell lines such as normal (NMEC), transformed (HBL-100) (Renaud et al., 1996) and cancer cell lines MCF7, BT-20, MDA-MB-231 (Penault-Llorca et al., 1995; Renaud et al., 1996), while BT474, T47D and ZR75.1 do not express FGF1 mRNAs (Penault-Llorca et al., 1995).
Atlas Image
Figure 4. Crystal structure of FGF1. Ternary structures are depicted by its crystal structure and representative residues for the binding to its receptor (blue) and heparin (red) are shown.


FGF1 lacks the classical signal sequence, since it employs non-classical pathway to be secreted. FGF1-S100A13-SYT complex formation is required for passing through the cell membrane (Mouta Carreira et al., 1998; Tarantini et al., 1998; Landriscina et al., 2001). Secreted extracellular FGF1 can be internalized following its binding to cell surface receptors by the clathrin-mediated pathway (Wiedlocha and Sørensen, 2004). FGF1 induces FGF receptor translocation from the cell membrane to the nucleus upon interaction with its receptor during the G1 phase of the fibroblast cell cycle (Prudovsky et al., 1994). FGF1 could be enters the nucleus by its putative nuclear localization sequence (NLS) (Imamura et al., 1990; Rodriguez-Enfedaque et al., 2009). Other groups suggest that nuclear translocation of FGF1 is controled not only by NLS, but also an additional sequence which prevents endogenously expressed FGF1 from NLS dependent translocation to the nucleus, and also FGF1 could move to the nucleus by free diffusion because a molecular weight of FGF1 is only 16500 (Zhan et al., 1992; Cao et al., 1993).


FGF1 is a mitogen for numerous different cell types in vitro. FGF1 has been implicated in a range of physiological processes, including development, morphogenesis, wound healing and angiogenesis (Beenken and Mohammadi, 2009). However, FGF1/FGF2 double-knockout mice do not exhibit any of the phenotypic abnormalities. This results suggest that the developmental and physiological roles of FGF1 are highly restricted, even though its functions remain unclear (Miller et al., 2000).
FGF1 binds to integrin ανβ3 (Mori et al., 2008), and the integrin-binding site of FGF1 overlapps with the heparin-binding site (but not identical). The FGF1 mutant that does not bind to ανβ3 (R50E) is dominant-negative (antagonistic), while it still binds to FGFR1 and heparin (Yamaji et al., 2010). FGF1 induces integin-FGF1-FGFR ternary complex, but R50E does not (Yamaji et al., 2010). R50E suppresses angiogenesis and tumorigenesis (Mori et al., 2013).


Length of FGFs is in the range of 150 to 300 amino acids. The conserved core 120-amino acid have been shown a 30-60% identity (Itoh and Ornitz, 2004; Itoh and Ornitz, 2007).

Implicated in

Entity name
Gastrointestinal tumor
FGF1 is overexpressed in 42% of colorectal adenomas, 76% of colorectal cancers, and 54% of gastric cancers as compared to the normal mucosal tissues. These results imply that overexpression of FGF1 often arises in a human colorectal and gastric cancers. FGF1 may play a role in the progression of these tumours (el-Hariry et al., 1997). Cancer-associated fibroblasts expressing fibroblast activation protein (FAP) is implicated in the invasive behavior of colorectal cancer. FAP enhances fibroblast cells to produce FGF1 and activates FGFR3 of colon cancer cells in vitro resulted in the increased cell migration and invasion (Henriksson et al., 2011).
Entity name
Breast cancer
The majority of breast cancer, including cancer adjacent cells expresses active FGF1 protein (Smith et al., 1994); however, mRNA of FGF1 is expressed higher level in benign neoplastic and hyperplastic tissue than in malignant tissue (Anandappa et al., 1994). Another group demonstrates that the extent and intensity of immunoreactivity of FGF1 in cancer cells is much greater than those of cells from fibroadenoma or mastopathy (Yoshimura et al., 1998). FGF1 is detected in epithelial cells of breast fibroadenomas, and FGFR4 is expressed both in epithelial cells and stromal fibroblasts. These suggest a paracrine/autocrine regulation of epithelial and stromal cells of fibroadenomas through an FGF1-FGFR4 interaction (La Rosa et al., 2001).
Entity name
Nerve injury
FGF1 is one of neuronotrophic factor and enhances nerve regeneration process (Walter et al., 1993). FGF1 increases the branching number of myelinated axons that regenerate damaged neurons and FGF1 also induces the axon elongation of primary sensory and motor neurons through the nerve guide in animals (Cordeiro et al., 1989). Protein expression profiles throughout 28 days of peripheral nerve regeneration reveals that FGF1 increases throughout the experimental period in the both proximal and distal nerve segments (Bryan et al., 2012).
Entity name
Cardiac ischemia
Level of FGF1 in pericardial fluid is associated with severe myocardial ischemia. FGF1 is released from the myocardial tissue into pericardial result from the myocardial ischemia (Iwakura et al., 2000). FGF1 may contribute to the functional preservation for the myocardium damage. In fact, treatment with FGF1 by extravascular delivery system increases coronary flow in the artificially constricted territory (Lopez et al., 1998), and also systemic bolus of FGF1 immediately after myocardial ischemia reduces apoptosis in animal model (Cuevas et al., 1997).


Pubmed IDLast YearTitleAuthors
75114061994Comparative expression of fibroblast growth factor mRNAs in benign and malignant breast disease.Anandappa SY et al
192473062009The FGF family: biology, pathophysiology and therapy.Beenken A et al
223252512012Spatiotemporal expression profiling of proteins in rat sciatic nerve regeneration using reverse phase protein arrays.Bryan DJ et al
117149272001Structure and stability effects of mutations designed to increase the primary sequence symmetry within the core region of a beta-trefoil.Brych SR et al
76806601993Characterization of the nuclear translocation of acidic fibroblast growth factor.Cao Y et al
116423612001Multiple controlling mechanisms of FGF1 gene expression through multiple tissue-specific promoters.Chiu IM et al
108494272000The small GTPases Ras, Rac, and Cdc42 transcriptionally regulate expression of human fibroblast growth factor 1.Chotani MA et al
97904631998Expression of fibroblast growth factor-1 and fibroblast growth factor-2 in normal liver and hepatocellular carcinoma.Chow NH et al
27271481989Acidic fibroblast growth factor enhances peripheral nerve regeneration in vivo.Cordeiro PG et al
93851151997Fibroblast growth factor-1 prevents myocardial apoptosis triggered by ischemia reperfusion injury.Cuevas P et al
6496001978Purification of the fibroblast growth factor activity from bovine brain.Gospodarowicz D et al
218678762011From cradle to grave: the multiple roles of fibroblast growth factors in neural development.Guillemot F et al
213563882011Colorectal cancer cells activate adjacent fibroblasts resulting in FGF1/FGFR3 signaling and increased invasion.Henriksson ML et al
16992741990Recovery of mitogenic activity of a growth factor mutant with a nuclear translocation sequence.Imamura T et al
209401692011Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease.Itoh N et al
112894982000Myocardial ischemia enhances the expression of acidic fibroblast growth factor in human pericardial fluid.Iwakura A et al
112717862001Expression of acidic fibroblast growth factor (aFGF) and fibroblast growth factor receptor 4 (FGFR4) in breast fibroadenomas.La Rosa S et al
114328802001Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress.Landriscina M et al
208766562010The role of FGF/Erk signaling in pluripotent cells.Lanner F et al
95302061998Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia.Lopez JJ et al
106886722000Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice.Miller DL et al
158630292005Structural basis for fibroblast growth factor receptor activation.Mohammadi M et al
234691072013A dominant-negative FGF1 mutant (the R50E mutant) suppresses tumorigenesis and angiogenesis.Mori S et al
184413242008Direct binding of integrin alphavbeta3 to FGF1 plays a role in FGF1 signaling.Mori S et al
97128361998S100A13 is involved in the regulation of fibroblast growth factor-1 and p40 synaptotagmin-1 release in vitro.Mouta Carreira C et al
75444531995Different fibroblast growth factor 1 (FGF-1) transcripts in neural tissues, glioblastomas and kidney carcinoma cell lines.Myers RL et al
76789251993Gene structure and differential expression of acidic fibroblast growth factor mRNA: identification and distribution of four different transcripts.Myers RL et al
147326922004Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity.Olsen SK et al
110691862000Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin.Pellegrini L et al
77059431995Expression of FGF and FGF receptor genes in human breast cancer.Penault-Llorca F et al
75273941994Intact and functional fibroblast growth factor (FGF) receptor-1 trafficks near the nucleus in response to FGF-1.Prudovsky I et al
86452411996Expression and regulation by serum of multiple FGF1 mRNA in normal transformed, and malignant human mammary epithelial cells.Renaud F et al
197656182009FGF1 nuclear translocation is required for both its neurotrophic activity and its p53-dependent apoptosis protection.Rodriguez-Enfedaque A et al
75171511994Acidic and basic fibroblast growth factors in human breast tissue.Smith J et al
97128341998The extravesicular domain of synaptotagmin-1 is released with the latent fibroblast growth factor-1 homodimer in response to heat shock.Tarantini F et al
76885781993Enhanced peripheral nerve regeneration by acidic fibroblast growth factor.Walter MA et al
156457102004Signaling, internalization, and intracellular activity of fibroblast growth factor.Wiedłocha A et al
204220522010A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist.Yamaji S et al
97567211998The expression and localization of fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1) in human breast cancer.Yoshimura N et al
12801371992Analysis of endogenous and exogenous nuclear translocation of fibroblast growth factor-1 in NIH 3T3 cells.Zhan X et al
165976172006Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family.Zhang X et al
17025561991Three-dimensional structures of acidic and basic fibroblast growth factors.Zhu X et al
90720011997Fibroblast growth factor 1 and fibroblast growth factor 2 immunoreactivity in gastrointestinal tumours.el-Hariry I et al

Other Information

Locus ID:

NCBI: 2246
MIM: 131220
HGNC: 3665
Ensembl: ENSG00000113578


dbSNP: 2246
ClinVar: 2246
TCGA: ENSG00000113578


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Regulation of actin cytoskeletonKEGGko04810
MAPK signaling pathwayKEGGhsa04010
Regulation of actin cytoskeletonKEGGhsa04810
Pathways in cancerKEGGhsa05200
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Diseases of signal transductionREACTOMER-HSA-5663202
Signaling by FGFR in diseaseREACTOMER-HSA-1226099
Signaling by FGFR1 in diseaseREACTOMER-HSA-5655302
FGFR1 mutant receptor activationREACTOMER-HSA-1839124
Signaling by activated point mutants of FGFR1REACTOMER-HSA-1839122
Signaling by FGFR2 in diseaseREACTOMER-HSA-5655253
FGFR2 mutant receptor activationREACTOMER-HSA-1839126
Activated point mutants of FGFR2REACTOMER-HSA-2033519
Signaling by FGFR3 in diseaseREACTOMER-HSA-5655332
FGFR3 mutant receptor activationREACTOMER-HSA-2033514
Signaling by activated point mutants of FGFR3REACTOMER-HSA-1839130
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
GAB1 signalosomeREACTOMER-HSA-180292
Signaling by FGFRREACTOMER-HSA-190236
Signaling by FGFR1REACTOMER-HSA-5654736
FGFR1 ligand binding and activationREACTOMER-HSA-190242
FGFR1b ligand binding and activationREACTOMER-HSA-190370
FGFR1c ligand binding and activationREACTOMER-HSA-190373
Downstream signaling of activated FGFR1REACTOMER-HSA-5654687
FRS-mediated FGFR1 signalingREACTOMER-HSA-5654693
Phospholipase C-mediated cascade: FGFR1REACTOMER-HSA-5654219
SHC-mediated cascade:FGFR1REACTOMER-HSA-5654688
PI-3K cascade:FGFR1REACTOMER-HSA-5654689
Negative regulation of FGFR1 signalingREACTOMER-HSA-5654726
Signaling by FGFR2REACTOMER-HSA-5654738
FGFR2 ligand binding and activationREACTOMER-HSA-190241
FGFR2b ligand binding and activationREACTOMER-HSA-190377
FGFR2c ligand binding and activationREACTOMER-HSA-190375
Downstream signaling of activated FGFR2REACTOMER-HSA-5654696
FRS-mediated FGFR2 signalingREACTOMER-HSA-5654700
Phospholipase C-mediated cascade; FGFR2REACTOMER-HSA-5654221
SHC-mediated cascade:FGFR2REACTOMER-HSA-5654699
PI-3K cascade:FGFR2REACTOMER-HSA-5654695
Negative regulation of FGFR2 signalingREACTOMER-HSA-5654727
Signaling by FGFR3REACTOMER-HSA-5654741
FGFR3 ligand binding and activationREACTOMER-HSA-190239
FGFR3b ligand binding and activationREACTOMER-HSA-190371
FGFR3c ligand binding and activationREACTOMER-HSA-190372
Downstream signaling of activated FGFR3REACTOMER-HSA-5654708
FRS-mediated FGFR3 signalingREACTOMER-HSA-5654706
Phospholipase C-mediated cascade; FGFR3REACTOMER-HSA-5654227
SHC-mediated cascade:FGFR3REACTOMER-HSA-5654704
PI-3K cascade:FGFR3REACTOMER-HSA-5654710
Negative regulation of FGFR3 signalingREACTOMER-HSA-5654732
Signaling by FGFR4REACTOMER-HSA-5654743
FGFR4 ligand binding and activationREACTOMER-HSA-190322
Downstream signaling of activated FGFR4REACTOMER-HSA-5654716
FRS-mediated FGFR4 signalingREACTOMER-HSA-5654712
Phospholipase C-mediated cascade; FGFR4REACTOMER-HSA-5654228
SHC-mediated cascade:FGFR4REACTOMER-HSA-5654719
PI-3K cascade:FGFR4REACTOMER-HSA-5654720
Negative regulation of FGFR4 signalingREACTOMER-HSA-5654733
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
Signaling by FGFR2 IIIa TMREACTOMER-HSA-8851708
Signaling by FGFR3 point mutants in cancerREACTOMER-HSA-8853338
RET signalingREACTOMER-HSA-8853659
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
187628122008Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer.100
215555182011The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle.60
250430582014Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer.58
158700712005Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: consequences for motor neuron survival.56
184413242008Direct binding of integrin alphavbeta3 to FGF1 plays a role in FGF1 signaling.54
175381742007Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas.51
155619392004Fibroblast growth factor 1: a key regulator of human adipogenesis.48
212397042011VEGF and FGF prime vascular tube morphogenesis and sprouting directed by hematopoietic stem cell cytokines.46
178937072008An association screen of myelin-related genes implicates the chromosome 22q11 PIK4CA gene in schizophrenia.44
184958702008Connexin hemichannel composition determines the FGF-1-induced membrane permeability and free [Ca2+]i responses.37


Seiji Mori ; Yoshikazu Takada

FGF1 (fibroblast growth factor 1 (acidic))

Atlas Genet Cytogenet Oncol Haematol. 2013-08-01

Online version: http://atlasgeneticsoncology.org/gene/40549/fgf1-(fibroblast-growth-factor-1-(acidic))