Fibroblast growth factor receptor 2 IIIc (FGFR2 IIIc)

Fibroblast growth factor receptor 2 IIIc (FGFR2 IIIc) is a mesenchymal splice variant of the FGFR2 receptor tyrosine kinase, distinguished by the inclusion of the "c" exon in its third immunoglobulin-like domain. Unlike the epithelial-specific IIIb isoform, FGFR2 IIIc is primarily expressed in mesenchymal tissues and serves as a critical marker and driver of the epithelial-mesenchymal transition (EMT) in various malignancies. It binds a broad range of ligands, including FGF1, FGF2, and FGF4, which triggers the activation of downstream signaling pathways such as MAPK/ERK and PI3K/AKT to drive cell proliferation, migration, and survival. In clinical oncology, the overexpression or genetic alteration of FGFR2 IIIc is associated with increased tumor aggressiveness and poor prognosis in cancers such as gastric, colorectal, and pancreatic ductal adenocarcinoma. Therapeutic targeting of this receptor is achieved through pan-FGFR tyrosine kinase inhibitors like erdafitinib and pemigatinib, which block the intracellular kinase activity. Additionally, isoform-specific monoclonal antibodies are being developed to selectively target the IIIc variant while sparing the IIIb isoform to reduce toxicity. Beyond its role in cancer, mutations in the IIIc-encoding region are linked to skeletal disorders like Apert syndrome, emphasizing its importance in normal developmental processes.

Other names

FGFR2cBEKCD332K-sam-IFGFR2-IIIcFibroblast growth factor receptor 2 isoform IIIc

FGFR2 IIIc functions as a receptor tyrosine kinase that, upon binding to ligands such as FGF1, FGF2, or FGF4, undergoes dimerization and trans-autophosphorylation of its cytoplasmic kinase domain. This activation initiates downstream signaling through the RAS-MAPK, PI3K-AKT, and PLCγ pathways, which promote gene expression for cell growth, survival, and motility. Therapeutic agents targeting FGFR2 IIIc primarily act as small-molecule tyrosine kinase inhibitors (TKIs) that competitively bind to the ATP-binding pocket of the receptor, thereby preventing phosphorylation and subsequent signal transduction.