Bias in FGFR1 signaling in response to FGF4, FGF8, and FGF9

FGFR1 signals differently in response to the FGF ligands FGF4, FGF8 and FGF9, but the mechanism behind the differential ligand recognition is poorly understood. Here, we use biophysical tools to quantify multiple aspects of FGFR1 signaling in response to the three FGFs: potency, efficacy, ligand-induced oligomerization and downregulation, and conformation of the active FGFR1 dimers. We show that FGF4, FGF8, and FGF9 are biased ligands, and that bias can explain differences in FGF8 and FGF9-mediated cellular responses. Our data suggest that ligand bias arises due to structural differences in the ligand-bound FGFR1 dimers, which impact the interactions of the FGFR1 transmembrane helices, leading to differential recruitment and activation of the downstream signaling adaptor FRS2. This study expands the mechanistic understanding of FGF signaling during development and brings the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight. ### Competing Interest Statement The authors have declared no competing interest.