Fibroblast growth factor receptor 1-4 with heparan sulfate proteoglycan co-receptor (FGFR1-4/HSPG)

The Fibroblast growth factor receptor 1-4 (FGFR1-4) with heparan sulfate proteoglycan (HSPG) co-receptor complex is a fundamental signaling unit on the cell surface that regulates diverse physiological processes. This complex consists of one of the four high-affinity receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, or FGFR4) and HSPGs, such as syndecans or glypicans, which serve as essential co-receptors by stabilizing the binding of fibroblast growth factor (FGF) ligands and facilitating receptor dimerization [3, 5, 6]. Upon activation, the complex triggers intracellular signaling cascades, including the MAPK/ERK, PI3K/AKT, and PLCγ pathways, which are critical for cell growth, survival, and angiogenesis [6, 14]. Dysregulation of this signaling axis through gene amplification, activating mutations, or chromosomal fusions is a major driver in various cancers, including urothelial, lung, breast, and gastric carcinomas [5, 12, 15]. Therapeutic targeting of this complex primarily involves small-molecule tyrosine kinase inhibitors (TKIs) that block the ATP-binding site of the FGFR intracellular domain to prevent downstream signaling [14]. Monitoring of this target often involves assessing genetic alterations in the receptors and tracking pharmacodynamic markers like serum phosphate levels, which are affected by the inhibition of FGF23-mediated signaling [11, 17].

Other names

FGFR-HSPG complexFibroblast growth factor receptor complexHeparan sulfate-dependent FGFR signaling complexFGFR1-4/HSGAG complexFGF-FGFR-HSPG ternary complex

Drugs targeting this complex are primarily small-molecule tyrosine kinase inhibitors (TKIs) that competitively bind to the ATP-binding pocket of the FGFR intracellular domain [3, 14]. This binding prevents receptor autophosphorylation and the subsequent activation of downstream signaling cascades such as the MAPK/ERK, PI3K/AKT, and PLCγ pathways [6, 12]. Some experimental strategies also aim to disrupt the extracellular ternary complex formation between the FGF ligand, the FGFR, and the HSPG co-receptor [4, 7].