FGFs

FGF, or fibroblast growth factors, comprise a family of secreted signaling proteins that regulate development, tissue repair, angiogenesis, and metabolism. In humans, the family includes numerous members grouped into paracrine, autocrine, and endocrine subfamilies.

Paracrine FGFs (such as FGF1 and FGF2) act locally and typically require heparan sulfate proteoglycans to stabilize FGF-FGFR interactions. Endocrine FGFs (notably FGF19, FGF21, and FGF23) act on distant tissues and require co-receptors such as beta-klotho (for FGF19/21/23) or alpha-klotho (for FGF23) to activate FGFRs.

FGFRs, a family of receptor tyrosine kinases, include FGFR1–4; alternative splicing yields isoforms with different ligand affinity. Upon FGF binding, FGFR dimerizes and autophosphorylates, triggering downstream pathways such as RAS-MAPK, PI3K-AKT, and PLCγ.

Functions include development, limb and brain formation, and organogenesis; in adults, FGFs regulate angiogenesis, wound healing, and metabolism.

Clinical relevance: dysregulation of FGF signaling is linked to cancer and skeletal disorders; targeted therapies with FGFR inhibitors are used in cancers bearing FGFR alterations, with side effects such as hyperphosphatemia and mucocutaneous changes.

Endocrine FGFs also have systemic roles in metabolism: FGF19/21 influence bile acid and glucose homeostasis, while FGF23 controls phosphate and vitamin D metabolism.

All FGFs share a beta-trefoil structural motif and, for paracrine FGFs, rely on heparan sulfate to promote receptor engagement.