Fibroblast Growth Factor Superfamily

FGF Ligands

The Fibroblast Growth Factor (FGF) superfamily consists of 22 proteins in mice and humans. Of these, 18 are secreted proteins and 4 are intracellular FGFs, known as FGF homologous factors. The secreted FGFs are divided into six subfamilies based on sequence homology and phylogeny. These include the FGF-1, FGF-4, FGF-7, FGF-8, FGF-9, and FGF-19 subfamilies. FGF-1 and FGF-2 belong to the FGF-1 subfamily, FGF-4, FGF-5, and FGF-6 belong to the FGF-4 subfamily, FGF-3, FGF-7, FGF-10, and FGF-22 belong to the FGF-7 subfamily, FGF-8, FGF-17, and FGF-18 belong to the FGF-8 subfamily, FGF-9, FGF-16, and FGF-20 belong to the FGF-9 subfamily, and FGF-19, FGF-21, and FGF-23 belong to the FGF-19 subfamily. With the exception of the FGF-19 subfamily, secreted FGFs have moderate to high affinity for heparan sulfate proteoglycans (HSPGs) that are tethered to the cell membrane or associated with the extracellular matrix and as a result, they mediate paracrine signaling. In contrast, members of the FGF-19 subfamily bind to HSPGs with significantly lower affinity, allowing them to pass through the extracellular matrix, enter the circulation, and mediate endocrine signaling. The intracellular FGFs include FGF-11, FGF-12, FGF-13, and FGF-14. In contrast to the secreted FGFs, the intracellular FGFs are non-signaling proteins that are associated with the cytosolic C-terminal tail of voltage-gated sodium channels and regulate myocardial and neuronal excitability.

FGF Receptors

There are four FGF signaling receptors, FGFR1, FGFR2, FGFR3, and FGFR4, and one decoy receptor, FGFR5, which can bind to FGFs but lacks an intracellular signaling domain. FGFR1, FGFR2, FGFR3, and FGFR4 are single-pass transmembrane proteins with 3 extracellular Ig-like domains, an 8-residue acidic box between the first and second Ig-like domain, and a split intracellular tyrosine kinase domain. The second and third Ig-like domains in the FGF receptor mediate FGF binding. Alternative splicing of FGFR1, FGFR2, and FGFR3 can generate two different isoforms of these receptors (b and c isoforms) that differ in their third extracellular Ig-like domain and as a result, have different ligand binding profiles. In addition to FGF receptors, FGF signaling also requires the presence of a co-receptor. HSPGs act as a co-receptor for the paracrine signaling FGFs, while Klotho family proteins function as co-receptors for the endocrine signaling FGFs. In the case of the paracrine signaling FGFs, crystal studies have indicated that HSPGs promote the formation of 2:2:2 HSPG-FGF-FGF receptor complexes.

FGF Signaling

FGF signaling is regulated by the binding specificities of different FGF ligands and their receptors. Ligand binding to the FGF receptor triggers a conformational change in the receptor, resulting in receptor dimerization, activation of its intracellular tyrosine kinase domain, and receptor phosphorylation. Phosphorylated tyrosine residues in the FGF receptor then serve as docking sites for SH2 domain-containing proteins, such as FRS2, GRB2, Shb, Shc, Src, and PLC-gamma, which trigger multiple downstream signaling pathways. These include the Ras-MAPK pathway, the PI 3-K-Akt pathway, the PLC-gamma-PKC pathway, and the Jak-STAT pathway. Activation of these signaling pathways leads to the expression of specific target genes that mediate the biological effects associated with different FGFs. FGF signaling is complicated by the fact that most FGFs can bind to multiple FGF receptors with different affinities. As a result, a single FGF or the presence of multiple FGFs may have synergistic or differential effects depending on the concentration of each and the cellular context.

Biological Effects of FGFs

FGF signaling is essential for both embryonic development and for the maintenance of tissue homeostasis in adult organisms. FGFs promote a broad range of cellular processes including proliferation, survival, differentiation, and migration. During development, secreted FGFs regulate germ layer formation, pattern formation, cellular differentiation, branching morphogenesis, limb formation, and organogenesis, including brain, lung, heart, skeletal system, urinary system, and lymphatic system development. In adult organisms, FGF signaling is involved in tissue repair, regeneration, metabolism, and inflammation. Gain or loss of function mutations in FGFs are associated with a variety of developmental defects and and pathological conditions including genetic skeletal diseases, chronic kidney disease, cardiovascular diseases, lung diseases, metabolic diseases, degenerative diseases, and cancer.