FGFRs

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that mediate cellular responses to fibroblast growth factors (FGFs). The FGFR family in humans comprises FGFR1, FGFR2, FGFR3, and FGFR4, each with a kinase domain. A related receptor-like protein, FGFRL1, lacks an intracellular kinase domain. FGFR signaling influences development, wound healing, and tissue homeostasis.

Structural features include extracellular immunoglobulin-like domains (D1, D2, D3) that determine ligand specificity, a single-pass transmembrane helix, and an intracellular tyrosine kinase domain that becomes activated upon dimerization. FGFR1-3 undergo alternative splicing of the D3 domain to yield IIIb and IIIc isoforms with distinct ligand-binding profiles. Ligand binding requires heparan sulfate proteoglycans.

Signaling: Ligand binding induces FGFR dimerization and autophosphorylation, triggering downstream pathways including RAS–MAPK, PI3K–AKT, PLCγ, and STAT. These pathways regulate cell proliferation, differentiation, survival, migration, and angiogenesis, with critical roles in embryogenesis and organ development.

Clinical significance: FGFR alterations contribute to cancer and developmental disorders. Mutations, amplifications, or rearrangements (notably FGFR2 fusions) activate signaling and drive tumor growth in urothelial carcinoma, cholangiocarcinoma, glioblastoma, and other cancers. FGFR signaling abnormalities also underlie conditions such as craniosynostosis and achondroplasia in some FGFR2/3 mutations.

Therapeutics: FGFR inhibitors, including selective and pan-FGFR agents, target aberrant FGFR signaling. Approved and investigational drugs include erdafitinib, pemigatinib, infigratinib, and futibatinib. Resistance can occur via kinase-domain mutations or activation of alternate pathways, motivating combination strategies and next-generation inhibitors.

Ligand family: FGFs constitute a large ligand family that binds FGFRs with the help of heparan sulfate to form signaling complexes; proper regulation of FGFR activity is essential to normal development and tissue homeostasis.