The fibroblast growth factors are a family of cell signaling proteins that are involved in a wide variety of processes, most notably as crucial elements for normal development. Any irregularities in their function lead to a range of developmental defects. These growth factors generally act as systemic or locally circulating, extracellular signaling molecules that activate cell surface receptors, but a defining property of FGFs is that they bind to heparin and heparan sulfate thus some of them are found to be sequestered in the extracellular matrix of tissues that contain heparan sulfate proteoglycans and they are released locally upon injury or tissue remodeling.
Members of EGF Family
In humans, 22 members of the FGF family have been identified, all of which are structurally related signaling molecules:
Table 1. FGF family related products
|FGF Receptor||FGFR1||FGFR1a||FGFRL1 / FGFR5|
|Golgi glycoprotein 1 / GLG1|
|FGF Regulators||Alpha 2-macroglobulin / A2M||Alpha 2-macroglobulin-like 1 / A2ML1||CNPY2|
|FRS2||Klotho / KL||Klotho beta / KLB|
|LRIT3||Pentraxin 3 / PTX 3 / TSG-14||SHISA4|
FGF1, also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the FGF1 gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycosylated 17-18 kDa protein. Fibroblast growth factor protein was first purified in 1975, but soon afterwards others using different conditions isolated acidic FGF, Heparin-binding growth factor-1, and Endothelial cell growth factor-1. Gene sequencing revealed that this group was actually the same growth factor and that FGF1 was a member of a family of FGF proteins.
Figure 1. FGF1 protein
FGF2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the FGF2 gene. It is synthesized primarily as a 155 amino acid polypeptide, resulting in an 18 kDa protein. In normal tissue, bFGF is present in basement membranes and in the subendothelial extracellular matrix of blood vessels. It stays membrane-bound as long as there is no signal peptide.
INT-2 proto-oncogene protein also known as FGF-3 is a protein that in humans is encoded by the FGF3 gene. FGF-3 is a member of the fibroblast growth factor family. FGF3 binds to Fibroblast Growth Factor Receptor 3 (FGFR3) to serve as a negative regulator of bone growth during ossification. Effectively, FGF-3 inhibits proliferation of chondrocytes within growth plate.
During embryonic development, the 21-kD protein FGF4 functions as a signaling molecule that is involved in many important processes. Studies using Fgf4 gene knockout mice showed developmental defects in embryos both in vivo and in vitro, revealing that FGF4 facilitates the survival and growth of the inner cell mass during the post implantation phase of development by acting as an autocrine or paracrine ligand.
FGF5 is a 268 amino acid, 29.1 kDa protein, which also naturally occurs as a 123 amino acid isoform splice variant (FGF5s). FGF5 is produced in the outer root sheath of the hair follicle as well as perifollicular macrophages, with maximum expression occurring in the late anagen phase of the hair cycle. The alternatively spliced isoform FGF5s, has been identified as an antagonist of FGF5 in a number of studies.
This protein is a potent epithelial cell-specific growth factor, whose mitogenic activity is predominantly exhibited in keratinocytes but not in fibroblasts and endothelial cells. Studies of mouse and rat homologs of this gene implicated roles in morphogenesis of epithelium, reepithelialization of wounds, hair development and early lung organogenesis.
Fgf8 is important and necessary for setting up and maintaining the midbrain/hindbrain border (or mesencephalon/met-encephalon border) which plays the vital role of “organizer” in development, like the Spemann “organizer” of the gastrulating embryo. FGF8 is expressed in the region where Otx2 and Gbx2 cross inhibit each other and is maintained expression by this interaction. Once expressed, the FGF8 induces other transcription factors to form cross-regulatory loops between cells, thus the border is established.
Figure 2. FGF8 protein
FGF9 has also been shown to play a vital role in male sex development. FGF9’s role in sex determination begins with its expression in the bi-potent gonads for both females and males. The absence of FGF9 causes an individual, even an individual with X and Y chromosomes, to develop into a female, as it is needed to carry out important masculinizing developmental functions such as the multiplication of sertoli cells and creation of the testis cords.
Figure 3. FGF9 protein
Fibroblast growth factor 10 is a paracrine signaling molecule seen first in the limb bud and organogenesis development. FGF10 starts the developing of limbs and it is involved in the branching of morphogenesis in multiple organs such as the lungs, skin, ear and salivary glands. During the limb development Tbx4/Tbx5 stimulates the production of FGF10 in the lateral plate mesoderm where it will create an epithelial-mesenchymal FGF signal with FGF8.
Members FGF11, FGF12, FGF13, and FGF14, also known as FGF homologous factors 1-4 (FHF1-FHF4), have been shown to have distinct functions compared to the FGFs. Although these factors possess remarkably similar sequence homology, they do not bind FGFRs and are involved in intracellular processes unrelated to the FGFs. This group is also known as "iFGF".
Members of the FGF19 subfamily (FGF15, FGF19, FGF21, and FGF23) bind less tightly to heparan sulfates, and so they can act in an endocrine fashion on far-away tissues, such as intestine, liver, kidney, adipose, and bone. For example: FGF15 and FGF19 (FGF15/19) are produced by intestinal cells but act on FGFR4-expressing liver cells to downregulate the key gene (CYP7A1) in the bile acid synthesis pathway. FGF23 is produced by bone but acts on FGFR1-expressing kidney cells to regulate the synthesis of vitamin D and phosphate homeostasis.
FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. FGFs are important players in wound healing. FGF1 and FGF2 stimulate angiogenesis and the proliferation of fibroblasts that give rise to granulation tissue, which fills up a wound space/cavity early in the wound-healing process. FGF7 and FGF10 (also known as Keratinocyte Growth Factors KGF and KGF2, respectively) stimulate the repair of injured skin and mucosal tissues by stimulating the proliferation, migration and differentiation of epithelial cells, and they have direct chemotactic effects on tissue remodeling. During the development of the central nervous system, FGFs play important roles in neural stem cell proliferation, neurogenesis, axon growth, and differentiation. FGF signaling is important in promoting surface area growth of the developing cerebral cortex by reducing neuronal differentiation and hence permitting the self-renewal of cortical progenitor cells. FGF signaling pathway has also been demonstrated to drive hindgut identity during gastrointestinal development, and the up regulation of the FGF4 in pluripotent stem cell has been used to direct their differentiation for the generation of intestinal Organoids and tissues in vitro.
Role in disease
FGF1 is multifunctional with many reported effects. For one example, in mice with diet-induced diabetes that is an experimental equivalent of type 2 diabetes in humans, a single injection of the FGF1 protein is enough to restore blood sugar levels to a healthy range for > 2 days. FGF2 has been shown in preliminary animal studies to protect the heart from injury associated with a heart attack, reducing tissue death and promoting improved function after reperfusion. FGF5 has been identified as a potentially important factor in androgenetic alopecia. In 2017, a large genome wide association study of men with early onset androgenetic alopecia identified polymorphisms in FGF5 as having a strong association with male pattern hair loss. Blocking FGF5 in the human scalp extends the hair cycle, resulting in less hair fall, faster hair growth rate and increased hair growth. In lung development, FGF9 is expressed in the mesothelium and pulmonary epithelium, where its purpose is to retain lung mesenchymal proliferation. Inactivation of FGF9 results in diminished epithelial branching. By the end of gestation, the lungs that are developed cannot sustain life and will result in a prenatal death.