Fibroblast growth factor receptor 1 IIIc isoform (FGFR1-IIIc)

Fibroblast growth factor receptor 1 (FGFR1) IIIc isoform is a transmembrane receptor tyrosine kinase that serves as a critical mediator of cellular signaling, growth, and metabolic homeostasis (UniProt P11362). It is produced through the alternative splicing of exon 9 in the third immunoglobulin-like domain, a process that confers high affinity for mesenchymal fibroblast growth factors such as FGF2 and FGF4 (PMID: 25244513). In addition to its role in embryonic development and tissue repair, FGFR1-IIIc functions as a receptor for endocrine FGFs (FGF21 and FGF23) when associated with the co-receptors alpha-Klotho or beta-Klotho, thereby regulating phosphate and glucose metabolism (PMID: 28218728). In the context of human disease, FGFR1-IIIc is frequently dysregulated in various malignancies, including squamous cell lung cancer and breast cancer, often through gene amplification or the formation of oncogenic fusions like FGFR1-TACC3 (PMID: 23172221). Pharmacological targeting of this receptor primarily involves small-molecule tyrosine kinase inhibitors (TKIs) such as erdafitinib and pemigatinib, which block the intracellular kinase activity to inhibit tumor progression (FDA). However, therapeutic use is often complicated by class-specific adverse effects, most notably hyperphosphatemia, which arises from the disruption of the FGF23-FGFR1-Klotho axis in the renal tubules (PMID: 31110039).

Other names

FGFR1cFGFR1-IIIcCD331BFGFRCEKFLGFLT2KAL2N-SAM

Competitive inhibition of the adenosine triphosphate (ATP) binding site within the intracellular tyrosine kinase domain, thereby preventing autophosphorylation and the subsequent activation of downstream signaling cascades including the MAPK/ERK, PI3K/AKT, and PLC-gamma pathways (PMID: 25244513).