Different FGFS Stimulate FGFR1 in Different Ways

Abstract

Fibroblast Growth Factor Receptor 1 (FGFR1) is a Receptor Tyrosine Kinase (RTK) that is important for cell proliferation, survival, and motility. It is critical for embryonic skeletal development, and genetic mutations in FGFR1 can result in abnormalities such as Osteoglophonic dysplasia and Pfeiffer Syndrome. FGFR1 is found in the mesoderm of the developing limb bud, while its cognate ligands are expressed in the limb bud ectoderm. It is believed that the ligands can diffuse through the mesoderm to activate the protein. Knockouts in mouse embryos of three specific ligands, Fibroblast Growth Factor (FGF) 4, FGF 8, and FGF 9, alone and combined, all result in distinctive skeletal phenotypes. How FGFR1 can recognize and respond to each unique ligand is currently unclear. The current model postulates that the three ligands are functionally the same, but each ligand has a unique spatial and temporal expression. We have found, however, that the current paradigm is not correct. In fact, each ligand stimulates distinctly different downstream signaling pathways. We proved this by using fluorescence and western blotting to quantitatively study FGFR1 association and FGFR1 signaling in response to the three ligands. The new knowledge about FGF-FGFR interactions, gained here, can change how RTK signaling is viewed and can greatly affect future drug development endeavors.