FGF Family Signaling Pathways

Overview of Fibroblast Growth Factor (FGF) Family Signaling Pathways

The mammalian Fibroblast Growth Factor (FGF) superfamily consists of eighteen secreted proteins (FGF-1 – FGF-10 and FGF-16 – FGF-23) and four intracellular FGFs (FGF-11 – FGF-14), known as FGF homologous factors. The secreted FGFs belong to one of six subfamilies (FGF-1, FGF-4, FGF-7, FGF-8, FGF-9, and FGF-19) based on sequence homology, biological functions, and evolutionary relationships, while the intracellular FGFs make up the FGF-11 subfamily. Secreted FGFs are typically sequestered by heparan sulfate proteoglycans (HSPGs) that are tethered to the cell surface and/or associated with the extracellular matrix, causing their effects to be localized to nearby cells. Only the FGF-19 subfamily, including FGF-21, FGF-23, and FGF-19 in humans or the mouse FGF-19 equivalent, FGF-15, acts in an endocrine manner. Although these FGFs are also dependent on HSPGs for signaling, they bind to heparin/heparan sulfate (HS) with very low affinity compared to the other FGFs, allowing them to more freely circulate. Unlike the canonical, secreted FGFs, intracellular FGFs (iFGFs) are nonsignaling proteins that interact with the cytosolic carboxy-terminal tail of voltage-gated sodium (NaV) channels. This group of FGFs have been shown to regulate neuronal and myocardial excitability by modulating both the current density and gating properties of Na_V channels.

Secreted FGFs bind to one of four transmembrane receptors with intracellular tyrosine kinase domains (FGF R1, FGF R2, FGF R3, and FGF R4) in a 2:2:2 HSPG-FGF-FGF receptor ratio. Ligand binding specificity is determined by the differential expression patterns of the FGFs, FGF receptors, and glycosaminoglycan structures, different receptor binding capacities, the requirement for specific co-factors such as the Klotho family proteins, and alternative splicing of the FGF receptors that results in two different versions of the extracellular Ig-like domain III (b or c). Following HSPG-ligand-binding to the FGF receptor, the receptor homodimerizes, leading to activation of the cytoplasmic intracellular kinase domain of the receptor, and recruitment and docking of adaptor proteins such as FRS2, GRB2, Shb, and Shc. These adaptor proteins subsequently activate multiple downstream signaling pathways including the Ras-MAPK pathway, the Jak-STAT pathway, the PI 3-Kinase-Akt pathway, the PLC gamma pathway, and the p38 and JNK MAPK pathways. Through these signaling pathways, FGFs promote fundamental cellular processes such as survival, proliferation, differentiation, and motility. Secreted FGFs have been shown to be involved in a wide range of biological processes during normal physiological development including cell differentiation in the early embryo, pattern formation, branching morphogenesis, limb development, and organogenesis, including heart and brain development. Additionally, they contribute to the maintenance of tissue homeostasis, repair, and metabolism in adult organisms. Gain or loss of function mutations in FGFs are associated with a variety of developmental defects and pathological conditions including cancer.

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