Fibroblast Growth Factors (FGFs) are signaling proteins that play fundamental roles in biological processes. These proteins act as molecular messengers, orchestrating growth, proliferation, differentiation, and survival. FGFs are crucial for tissue development and maintenance, ensuring physiological function. Their broad involvement makes them subjects of extensive research, from embryonic development to disease mechanisms.
The FGF Family and Their Mechanisms
FGFs are a diverse group of proteins, with 22 members. These proteins are structurally related, sharing a conserved core. FGFs primarily act by binding to and activating specific Fibroblast Growth Factor Receptors (FGFRs), transmembrane receptor tyrosine kinases. There are four main FGFRs (FGFR1-4) in humans, each binding to different FGF ligands with varying affinities.
The interaction between an FGF ligand and its FGFR leads to receptor dimerization, initiating transphosphorylation. This phosphorylation activates the FGFR’s intracellular kinase domain, which activates downstream signaling pathways. Pathways include Ras-MAPK, PI3K-Akt, and PLCĪ³. These cascades ultimately regulate gene expression and cellular functions like proliferation, differentiation, migration, and survival.
Heparan sulfate proteoglycans (HSPGs) serve as co-receptors that modulate FGF-FGFR binding and signaling. HSPGs are essential for forming a stable ternary complex involving FGF, FGFR, and HSPG, facilitating receptor dimerization and activation. Sulfation patterns of heparan sulfate chains influence FGF-FGFR interaction specificity and strength, fine-tuning signaling outcomes.
Roles in Body Development and Maintenance
FGFs are crucial throughout embryonic development, regulating development. They contribute to patterning embryonic axes, inducing cell lineages, and coordinating morphogenetic movements. For example, FGF8 is crucial for brain development; FGF10 is important for limb and lung formation. FGF signaling also contributes to organ development, including the central nervous system, supporting neural stem cell proliferation and neurogenesis.
Beyond development, FGFs are involved in adult tissue repair and regeneration. They stimulate wound healing, promoting cell proliferation, migration, and angiogenesis. FGF2 (basic FGF) stimulates epithelial and mesenchymal cell proliferation during wound healing and tissue remodeling. These proteins also contribute to muscle and bone regeneration, highlighting their broad role in tissue integrity and function.
FGFs also have significant roles in metabolic regulation. Specific FGFs (FGF19, FGF21, FGF23) function as endocrine factors, circulating to distant organs. For instance, FGF21 is involved in glucose and lipid metabolism, influencing insulin sensitivity and fat use. FGF23 is a key regulator of phosphate and vitamin D homeostasis, controlling levels in blood and bone. These endocrine FGFs demonstrate this family’s systemic metabolic control.
FGFs in Health and Disease
Dysregulation of FGF and FGFR signaling pathways can cause health conditions. Imbalances like activating mutations or overexpression cause disorders. Developmental disorders often arise from FGFR mutations; for example, mutations in FGFR1, FGFR2, and FGFR3 can cause craniosynostosis; certain FGFR mutations also contribute to forms of dwarfism.
Metabolic diseases are also linked to FGF dysregulation. Altered levels or function of endocrine FGFs (FGF21, FGF23) contribute to diabetes, obesity, and chronic kidney disease. For example, FGF21 dysregulation can impair glucose and lipid metabolism, while FGF23 signaling issues can lead to abnormal phosphate levels, impacting bone and kidney function.
The FGF/FGFR pathway is implicated in cancer due to its roles in cell growth, survival, and angiogenesis. Genetic alterations in FGFR genes lead to overactive signaling, driving tumor growth and progression. This aberrant signaling promotes uncontrolled cell proliferation, enhances tumor angiogenesis, and contributes to anti-cancer therapy resistance. Many solid tumors (e.g., breast, lung, gastric cancers) show such dysregulation, making FGF/FGFR a focus in oncology.
Targeting FGFs for Therapeutic Benefit
FGFs’ involvement in diseases has led to therapeutic strategies to modulate their activity. One approach involves small molecule inhibitors that target FGFRs, blocking FGFR signaling. These inhibitors can be designed to be selective for specific FGFRs, reducing off-target effects. Examples include drugs approved for certain cancers, like pemigatinib and erdafitinib, targeting FGFR alterations in cholangiocarcinoma and urothelial carcinoma.
Monoclonal antibodies block FGF ligands or directly inhibit FGFR activity. These antibodies offer a targeted way to interrupt FGF signaling, particularly in cancers where FGFs or FGFRs are overactive. For FGF deficiencies, recombinant FGFs or FGF analogs can be administered to replace or augment natural FGF function. This approach is explored for tissue repair, like chronic wound healing, where FGF2 stimulates regeneration.
Significant progress has been made, but challenges remain in developing highly specific therapies that avoid affecting FGFs’ normal roles. Research focuses on refining these therapies, exploring combination strategies, and identifying biomarkers to select patients for FGF-targeted treatments, maximizing efficacy and minimizing side effects.