Alternative titles; symbols
HGNC Approved Gene Symbol: FGF2
Cytogenetic location: 4q28.1 Genomic coordinates (GRCh38) : 4:122,826,682-122,898,236 (from NCBI)
Fibroblast growth factor-2 (FGF2) is a wide-spectrum mitogenic, angiogenic, and neurotrophic factor that is expressed at low levels in many tissues and cell types and reaches high concentrations in brain and pituitary. FGF2 has been implicated in a multitude of physiologic and pathologic processes, including limb development, angiogenesis, wound healing, and tumor growth (summary by Ortega et al., 1998).
Abraham et al. (1986) isolated a clone encoding FGFB from a bovine pituitary cDNA library. Southern blot analysis and genomic cloning of the human gene indicated that basic FGF is encoded by a single gene split by at least 2 introns of size greater than 15 kb (Abraham et al., 1986). Kurokawa et al. (1987) isolated a cDNA for basic FGF. The 4-kb cDNA had a coding sequence, 5-prime and 3-prime untranslated regions, and a poly(A) chain.
Using RT-PCR, Krejci et al. (2007) detected expression of several FGF genes in femoral growth plate cartilage from 20- to 28-week gestation fetuses; however, only FGF1 (131220), FGF2, FGF17 (603725), and FGF19 (603891) proteins were expressed at detectable levels. Immunohistochemical analysis showed that FGF17 and FGF19 were uniformly expressed throughout the growth plate. In contrast, FGF1 was expressed only in the proliferative and hypertrophic zones, and FGF2 was expressed only in the proliferative and resting zones.
Mergia et al. (1986) used a bovine basic FGF cDNA as a hybridization probe in Southern blot analysis of DNAs isolated from a panel of mouse-human cell hybrids. They concluded that FGFB is on chromosome 4, which carries other growth factors: EGF (131530) and TCGF (IL2; 147680). Lafage-Pochitaloff et al. (1990) mapped the FGFB gene to 4q26-q27 by in situ hybridization. By in situ hybridization to human metaphase and prometaphase chromosomes, Fukushima et al. (1990) concluded that the FGFB gene maps to 4q25. Using in situ chromosomal hybridization, Mattei et al. (1992) demonstrated that the corresponding gene in the mouse is on chromosome 3.
Eckenstein (1994) reviewed the role of fibroblast growth factors in the central nervous system. He calculated that there are 500 biologic units of FGF2 per gram of cerebral cortex, in contrast to 1 biologic unit per gram of nerve growth factor (162030).
Doniach (1995) reviewed the evidence that basic FGF can influence anteroposterior neural pattern and may be a 'posteriorizing' inducer. Gritti et al. (1996) used basic fibroblast growth factor to isolate multipotential stem cells from the adult mouse striatum that were able to proliferate and differentiate into astrocytes, oligodendrocytes, and neurons. For a review of the role of this gene in limb development, see Johnson and Tabin (1997).
Jung et al. (1999) studied the initiation of mammalian liver development from endoderm by fibroblast growth factors. Close proximity of cardiac mesoderm, which expresses FGF1, FGF2, and FGF8 (600483), causes the foregut endoderm to develop into the liver. Treatment of isolated foregut endoderm from mouse embryos with FGF1 or FGF2, but not FGF8, was sufficient to replace cardiac mesoderm as an inducer of the liver gene expression program, the latter being the first step of hepatogenesis. The hepatogenic response was restricted to endoderm tissue, which selectively coexpresses FGF receptors -1 (136350) and -4 (134935). Different FGF signals appear to initiate distinct phases of liver development during mammalian organogenesis.
Kawaguchi et al. (2001) studied the effect of a single local application of recombinant human FGF2 on fracture healing in nonhuman primates. Although 4 of 10 animals treated with the vehicle alone remained in a nonunion state even after 10 weeks, bone union was complete at 6 weeks in all 10 animals treated with FGF2. Significant differences in bone mineral content and density at the fracture site between the vehicle and FGF2 groups were seen at 6 weeks and thereafter. FGF2 also increased the mechanical property of the fracture site. The authors concluded that FGF2 accelerates fracture healing and prevents nonunion in primates, and therefore proposed it as a potent bone anabolic agent for clinical use.
Cao et al. (2003) reported that a combination of 2 angiogenic factors, platelet-derived growth factor-BB (PDGF-BB; see 190040) and FGF2, synergistically induces vascular networks, which remain stable for more than a year even after depletion of angiogenic factors. In both rat and rabbit ischemic hindlimb models, PDGF-BB and FGF2 together markedly stimulated collateral arteriogenesis after ligation of the femoral artery, with a significant increase in vascularization and improvement in paw blood flow. A possible mechanism of angiogenic synergism between PDGF-BB and FGF2 involves upregulation of the expression of PDGF receptor-alpha (PDGFRA; 173490) and PDGF receptor-beta (PDGFRB; 173410) by FGF2 in newly formed blood vessels. Cao et al. (2003) showed that single angiogenic factors, including FGF2, VEGF (192240), and PDGF-BB, were unable to establish stable vascular networks. In contrast, a combination of PDGF-BB and FGF2, but not PDGF-BB and VEGF or VEGF and FGF2, synergistically induced angiogenesis and long-lasting functional vessels. While each of the angiogenic factors FGF2, VEGF, and PDGF-BB is able to stimulate angiogenesis in the short term, none of these factors alone is able to maintain these newly formed vessels.
Development of the endocrine pancreas includes a series of early events wherein precursor cells cluster to form cell aggregates that subsequently differentiate into islets of Langerhans. Hardikar et al. (2003) showed that a human pancreatic cell line differentiated into hormone-producing islet-like cell aggregates after exposure to a defined serum-free medium. These cells provided evidence that FGF2 is a paracrine chemoattractant during clustering of these cells. Hardikar et al. (2003) concluded that FGF2, acting as a paracrine chemoattractant, stimulates clustering of precursor cells, an early step leading to islet-like cell aggregate formation.
Alavi et al. (2003) showed FGFB and VEGF differentially activate Raf1 (164760), resulting in protection from distinct pathways of apoptosis in human endothelial cells and chick embryo vasculature. FGFB activated Raf1 via p21-activated protein kinase-1 (PAK1; 602590) phosphorylation of serines 338 and 339, resulting in Raf1 mitochondrial translocation and endothelial cell protection from the intrinsic pathway of apoptosis, independent of the mitogen-activated protein kinase kinase-1 (MEK1; 176872). In contrast, VEGF activated Raf1 via Src kinase (CSK; 124095), leading to phosphorylation of tyrosines 340 and 341 and MEK1-dependent protection from extrinsic-mediated apoptosis. Alavi et al. (2003) concluded that RAF1 may be a pivotal regulator of endothelial cell survival during angiogenesis.
Kim et al. (2003) found that human FGF2 induced osteopontin (SPP1; 166490) expression and cranial suture closure in mouse calvaria organ cultures. In mouse cells, FGF2 indirectly induced osteopontin expression by upregulating expression of Fos (164810)- and Jun (165160)-related genes encoding activator protein-1 (AP1) subunits, and AP1 induced osteopontin expression via an AP1 response element in the osteopontin promoter. Blocking the ERK pathway (see 601795) suppressed FGF2-stimulated AP1 and osteopontin expression and retarded FGF2-accelerated cranial suture closure.
In rodent cortical progenitor cells that differentiate into astrocytes, Song and Ghosh (2004) found that FGF2 regulates the ability of ciliary neurotrophic factor (CNTF; 118945) to induce expression of glial fibrillary acidic protein (GFAP; 137780), an astrocyte-specific gene. FGF2 facilitates access of the signal transducer and activator of transcription (STAT)/CRE-binding protein (CBP) complex to the GFAP promoter by inducing lys4 methylation and suppressing lys9 methylation of histone H3 at the STAT binding site. Thus, astrocyte differentiation involves a switch in chromatin state at a specific site, representing epigenetic regulation.
Chang et al. (2004) demonstrated that there is a dose-dependent response of FGF2 for lymphangiogenesis, and that lymphangiogenesis can occur in the absence of preexisting or developing vascular bed, i.e., in the absence of angiogenesis, in the mouse cornea.
Krejci et al. (2007) showed that FGF1, FGF2, and FGF17, but not FGF19, elicited potent activation of an ERK reporter gene in primary cultures of human fetal chondrocytes. FGF1, FGF2, and FGF17, but not FGF19, also inhibited proliferation of FGFR3 (134934)-expressing rat chondrosarcoma chondrocytes.
Lievens et al. (2016) reported that mouse Zdhhc3 (617150) catalyzed S-palmitoylation of the transmembrane isoforms of Ncam1 (116930), Ncam140 and Ncam180. Using site-directed mutagenesis and inhibitor studies, they showed that Fgf2 induced phosphorylation of Zdhhc3 on tyr18 via the tyrosine kinase activity of its receptor, Fgfr1. Src (190090) directly phosphorylated Zdhhc3 on tyr295 and tyr297. The 2 kinases had opposite effects on Zdhhc3 activity, with Fgfr1-dependent phosphorylation enhancing Zdhhc3 activity, and Src-dependent phosphorylation inhibiting Zdhhc3 activity. Autopalmitoylation, an intermediate reaction state in palmitate transfer to target proteins, was enhanced by absence of all 5 tyrosines in Zdhhc3 and was abolished with the dominant-negative cys157-to-ser (C157S) mutation at the active site of Zdhhc3. Overexpression of tyrosine-mutant Zdhhc3 in cultured rat hippocampal neurons increased the number of neurites and tended to increase neurite length. Lievens et al. (2016) concluded that FGF2-FGFR1 signaling facilitates ZDHHC3 tyrosine phosphorylation and triggers NCAM1 palmitoylation for neurite extension, whereas SRC-mediated ZDHHC3 phosphorylation inhibits NCAM1 palmitoylation and neurite extension.
Crystal Structure
Plotnikov et al. (1999) determined the crystal structure of FGF2 bound to a naturally occurring variant of FGF receptor-1 (FGFR1) consisting of immunoglobulin-like domains 2 (D2) and 3 (D3) at 2.8-angstrom resolution. Two FGF2:FGFR1 complexes form a 2-fold symmetric dimer. Within each complex, FGF2 interacts extensively with D2 and D3 as well as with the linker between the 2 domains. The dimer is stabilized by interactions between FGF2 and D2 of the adjoining complex and by a direct interaction between D2 of each receptor. A positively charged canyon formed by a cluster of exposed basic residues likely represents the heparin-binding site. A general model for FGF- and heparin-induced FGFR dimerization was inferred from the crystal structure.
To elucidate the structural determinants governing specificity in FGF signaling, Plotnikov et al. (2000) determined the crystal structures of FGF1 and FGF2 complexed with the ligand-binding domains (D2 and D3) of FGFR1 and FGFR2 (176943), respectively. They found that highly conserved FGF-D2 and FGF-linker interfaces define a general binding site for all FGF-FGFR complexes. Specificity is achieved through interactions between the N-terminal and central regions of FGFs and 2 loop regions in D3 that are subject to alternative splicing. These structures provide a molecular basis for FGF1 as a universal FGFR ligand and for modulation of FGF-FGFR specificity through primary sequence variations and alternative splicing.
To determine the function of FGF2 in vivo, Ortega et al. (1998) generated Fgf2 knockout mice, lacking all 3 Fgf2 isoforms, by homologous recombination in embryonic stem cells. Fgf2-null mice were viable, fertile, and phenotypically indistinguishable from homozygous Fgf2 wildtype littermates by gross examination. However, abnormalities in the cytoarchitecture of the neocortex, most pronounced in the frontal motor-sensory area, could be detected by histologic and immunohistochemical methods. A significant reduction in neuronal density was observed in most layers of the motor cortex. Cell density was normal in other regions of the brain such as the striatum and the hippocampus. In addition, the healing of excisional skin wounds was delayed in mice lacking Fgf2. The results indicated that FGF2, although not essential for embryonic development, plays a specific role in cortical neurogenesis and skin wound healing in mice, which, in spite of the apparent redundancy of FGF signaling, cannot be carried out by other FGF family members.
To investigate the role of FGF2 in bone, Montero et al. (2000) examined mice with a disruption of the Fgf2 gene. They found a significant decrease in trabecular bone volume, mineral apposition, and bone formation rates. In addition, there was a profound decreased mineralization of bone marrow stromal cultures from Fgf2-deficient mice. The results showed that FGF2 helps determine bone mass as well as bone formation.
Dono et al. (1998) generated mice deficient in FGF2 by targeted disruption. FGF2-deficient mice were viable, but displayed cerebral cortex defects at birth. Bromodeoxyuridine pulse labeling of embryos showed that proliferation of neuronal progenitors is normal, whereas a fraction of them fail to colonize their target layers in the cerebral cortex. A corresponding reduction in the parvalbumin-positive neurons was observed in adult cortical layers. Neuronal defects were not limited to the cerebral cortex, as ectopic parvalbumin-positive neurons were present in the hippocampal commissure and neuronal deficiencies were observed in the cervical spinal cord. FGF2-deficient adult mice were hypotensive. While they responded normally to angiotensin II-induced hypertension, the neural regulation of blood pressure by the baroreceptor reflex was impaired. Dono et al. (1998) concluded that their study establishes that FGF2 participates in controlling fates, migration, and differentiation of neuronal cells, whereas it is not essential for their proliferation.
Using Fgf2-deficient and wildtype cardiomyocyte precursor cells from neonatal mouse hearts, Rosenblatt-Velin et al. (2005) observed that after injection into Fgf2-deficient or wildtype neonates, homing to the heart occurred in all groups regardless of the capacity of the recipients or the injected cells to synthesize Fgf2. However, differentiation in situ was seen only if either the recipient mouse or the injected cells were able to produce Fgf2. Rosenblatt-Velin et al. (2005) concluded that cardiogenic differentiation depends on FGF2.
In rats with induced status epilepticus and hippocampal damage, Paradiso et al. (2009) found that injection of FGF2 and BDNF (113505)-containing vectors into the lesioned hippocampus resulted in increased neuronogenesis with appropriate distribution, less neuronal damage, decreased epileptogenesis, and decreased occurrence and severity of spontaneous recurrent seizures 2 to 3 weeks later. The findings indicated that supplementation of specific growth factors in lesioned areas of the brain may decrease neuronal damage and lessen epileptogenesis.
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