Fibroblast growth factor receptors (FGFRs)

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases playing crucial roles in development and adulthood. They have a canonical structure with an extracellular ligand-binding domain (three Ig-like subunits D1-D3), a transmembrane helix, and an intracellular tyrosine kinase domain. The D2-D3 domains are key for FGF binding, regulated by the acid box. The family includes FGFR1-4 (kinase active) and FGFRL1 (decoy receptor). They are activated by FGF ligands, with specificity determined by D2-D3 and alternative splicing (b and c variants). Upon activation, FGFRs dimerize and trans-phosphorylate, recruiting docking proteins like FRS2, PRKCG, and GRB2, activating downstream pathways promoting cellular differentiation, growth, proliferation, survival, and migration. SPRY proteins provide negative feedback. Dysregulation is implicated in numerous cancers (urothelial, hepatocellular, ovarian, lung, gastric) via mechanisms including overproduction, activating mutations (e.g., FGFR3 mutations in bladder cancer like S249C, Y373C, G370C, R248C), and fusions (e.g., FGFR3-TACC3 in glioma/bladder cancer). Point mutations in FGFR3 also cause achondroplasia. FGFRs are significant drug targets, with approved inhibitors like erdafitinib and others in development. Targeting subcellular sorting is another therapeutic approach. Their critical roles in development (e.g., FGFR1 essential for early development, FGFR3 for skeletal development) highlight the importance of FGFR signaling.

Other names

FGFR

Small molecule inhibitors targeting the kinase activity of FGFRs; Blocking subcellular sorting (nuclear and mitochondrial translocation) to inhibit cancer invasion.