FGFR

FGFR, or fibroblast growth factor receptor, refers to a family of receptor tyrosine kinases that transduce signals for fibroblast growth factors (FGFs). The four canonical members FGFR1 through FGFR4 are single-pass transmembrane proteins with an extracellular ligand-binding domain composed of three immunoglobulin-like domains, a single transmembrane helix, and an intracellular tyrosine kinase catalytic domain. A fifth related protein, FGFRL1, lacks the tyrosine kinase activity and is sometimes discussed separately. Ligand binding, aided by heparan sulfate proteoglycans, induces receptor dimerization and autophosphorylation, enabling recruitment of adaptor proteins and activation of downstream pathways including MAPK/ERK, PI3K/AKT, PLCγ, and STAT signaling. Alternative splicing of the third immunoglobulin-like domain generates FGFR isoforms (notably FGFR1-3 IIIb and IIIc), which differentially bind FGFs and have tissue-specific expression.

Physiological roles: FGFR signaling regulates cell proliferation, differentiation, angiogenesis, and organogenesis, with important functions in limb and neural development, wound healing, and metabolism.

Pathology and therapeutics: Alterations in FGFR genes—mutations, amplifications, or chromosomal fusions—contribute to oncogenesis in several cancers (e.g., FGFR1 amplification, FGFR2 fusions in cholangiocarcinoma, FGFR3 mutations in bladder cancer and myeloma, FGFR3-TACC3 fusions). FGFR inhibitors have been developed as targeted therapies, including erdafitinib, pemigatinib, futibatinib, and infigratinib, with approvals for FGFR-altered urothelial carcinoma and cholangiocarcinoma. Side effects often include hyperphosphatemia, stomatitis, and eye disorders. Diagnosis relies on molecular testing to identify FGFR alterations.