Fibroblast growth factor 23–Fibroblast growth factor receptor 1 complex (FGF23–FGFR1 complex)

The Fibroblast growth factor 23–Fibroblast growth factor receptor 1 (FGF23–FGFR1) complex is a ternary signaling assembly essential for maintaining systemic phosphate homeostasis and vitamin D metabolism (UniProt Q9GZV9, P11362). The complex is formed when the bone-derived hormone FGF23 binds to the FGFR1c isoform in the presence of the transmembrane protein alpha-Klotho, which acts as an essential co-receptor to increase the affinity of FGF23 for the receptor (PMID: 17086192). Once assembled, the complex activates the MAPK/ERK signaling pathway in the renal proximal tubules, leading to the downregulation of sodium-phosphate cotransporters and the suppression of active vitamin D synthesis (PMID: 29343898). Pathological overproduction of FGF23 leads to excessive signaling through this complex, resulting in phosphate wasting diseases such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) (NIH/GARD). Conversely, deficient signaling or FGF23 resistance can lead to hyperphosphatemic familial tumoral calcinosis (PubMed: 16415873). Therapeutic targeting of this complex is clinically validated by Burosumab, a monoclonal antibody that binds to FGF23 and prevents its interaction with the FGFR1-Klotho complex, thereby restoring normal phosphate levels (FDA Label: Crysvita). Additionally, pan-FGFR inhibitors used in oncology, such as Erdafitinib, can inadvertently disrupt this complex, leading to hyperphosphatemia as a common side effect (PubChem CID: 67165467). Understanding the structural and functional nuances of this complex is vital for developing treatments for mineral bone disorders and managing the toxicities of FGFR-targeted cancer therapies.

Other names

FGF23-FGFR1c-Klotho complexFGF23-FGFR1 signaling complexFGF23-FGFR-Klotho ternary complex

Neutralization of the FGF23 ligand to prevent assembly of the signaling complex or ATP-competitive inhibition of the FGFR1 tyrosine kinase domain to block downstream signal transduction.