Fibroblast growth factor receptor 1 isoform c–Fibroblast growth factor 23–alpha-Klotho complex (FGFR1c-FGF23-KL)

The Fibroblast growth factor receptor 1 isoform c–Fibroblast growth factor 23–alpha-Klotho complex is a specialized endocrine signaling assembly primarily located in the renal tubules and parathyroid glands (Urakawa et al., 2006). This complex is formed when the bone-derived hormone Fibroblast growth factor 23 (FGF23) binds to the c isoform of Fibroblast growth factor receptor 1 (FGFR1c) in the presence of its obligate co-receptor, alpha-Klotho, which dramatically increases the receptor's affinity for the ligand (Chen et al., 2018). Its primary biological function is the regulation of systemic phosphate and vitamin D homeostasis; activation of the complex triggers the MAPK/ERK signaling pathway, leading to increased urinary phosphate excretion and suppression of active vitamin D (1,25-dihydroxyvitamin D) synthesis (Shimada et al., 2001). Dysregulation of this signaling axis is central to several metabolic bone diseases, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), where excessive FGF23 activity causes severe phosphate wasting and rickets (Yamazaki et al., 2002). Conversely, in chronic kidney disease (CKD), elevated FGF23 levels are associated with adverse cardiovascular outcomes and mineral imbalances (Isakova et al., 2011). Therapeutic interventions include the monoclonal antibody burosumab, which neutralizes FGF23 to restore phosphate levels, and various pan-FGFR inhibitors that block the downstream signaling of the complex (FDA, 2018).

Other names

FGF23-FGFR1c-alpha-Klotho complexFGF23-FGFR1c-Klotho ternary complexFGFR1c-FGF23-Klotho signaling complexFGF23-FGFR1c-alpha-Klotho-HS quaternary complex

Monoclonal antibody-mediated neutralization of the FGF23 ligand and small-molecule inhibition of the FGFR tyrosine kinase domain to modulate downstream signaling pathways like MAPK/ERK.