Fibroblast growth factor receptor 1-4 (FGFR1-4) (FGFR1-4)

The Fibroblast Growth Factor Receptor (FGFR) family comprises four closely related receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4) that are essential for various physiological processes, including embryonic development, tissue repair, and angiogenesis (UniProt P11362, P21802, P22607, P22455). These receptors consist of an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular split tyrosine kinase domain. Binding of fibroblast growth factors (FGFs) induces receptor dimerization and phosphorylation of the kinase domains, which subsequently activates downstream signaling cascades such as the MAPK, PI3K/AKT, and PLCγ pathways (PMID: 26070591). Aberrant FGFR signaling, often caused by gene amplifications, point mutations, or chromosomal fusions, is implicated in the pathogenesis of numerous cancers, including bladder, lung, and breast cancers, as well as cholangiocarcinoma (PMID: 31067375). Therapeutic strategies primarily focus on small-molecule inhibitors that target the ATP-binding pocket of the kinase domains to block signaling. While effective, these inhibitors are often associated with specific side effects like hyperphosphatemia, caused by the inhibition of FGFR1 in the kidneys, and retinal toxicities (FDA: Balversa, Pemazyre).

Other names

FGFR1FGFR2FGFR3FGFR4CD331CD332CD333CD334Tyrosine-protein kinase receptorBasic fibroblast growth factor receptor 1Keratinocyte growth factor receptorFGFR1-4 kinase domains

ATP-competitive inhibition of the intracellular tyrosine kinase domains of FGFR1, FGFR2, FGFR3, and FGFR4, preventing receptor autophosphorylation and downstream signaling through the MAPK, PI3K/AKT, and PLCγ pathways (PMID: 31067375).