FGFsFGFRs

FGFs and FGFRs refer to the fibroblast growth factor ligands and their tyrosine kinase receptors, a signaling system essential for development, tissue maintenance, and repair. In humans, FGFR1–FGFR4 are the main signaling receptors, with FGFRL1 (often called FGFR5) lacking a functional kinase domain and acting, in part, as a decoy. The FGF family contains multiple ligands (at least 22 known) that bind to FGFRs with varying affinity, producing tissue- and context-dependent effects.

Most FGFs require heparan sulfate proteoglycans to stabilize the ligand–receptor encounter and promote receptor dimerization and autophosphorylation. A subset of FGFs—often referred to as endocrine FGFs, including FGF19, FGF21, and FGF23—depend on the cofactor beta-Klotho (KLB) or other Klotho family members to engage FGFRs and elicit signaling, enabling systemic actions such as metabolic regulation.

Upon ligand binding, FGFRs dimerize and activate their intracellular tyrosine kinase domains, triggering downstream signaling pathways such as RAS–MAPK, PI3K–AKT, PLCγ, and sometimes STAT. These cascades regulate cell proliferation, differentiation, survival, migration, and angiogenesis. The spatial and temporal patterning of FGF–FGFR signaling is shaped by receptor isoforms, alternative splicing (notably FGFR1–FGFR3 producing IIIb and IIIc variants), ligand availability, and cofactor expression.

Dysregulation of FGF–FGFR signaling is implicated in development and disease. Activating FGFR mutations or gene amplifications and FGFR gene fusions are linked to various cancers and skeletal disorders. In craniosynostosis and achondroplasia, specific FGFR mutations underlie abnormal bone growth. Therapeutic strategies include FGFR tyrosine kinase inhibitors, ligand traps, and monoclonal antibodies, though clinical use requires managing potential on-target toxicities and resistance mechanisms.