The autoinhibitory function of D1 domain of FGFR1 goes beyond the inhibition of ligand binding.

Fibroblast growth factors (FGFs) and their plasma membrane-localized receptors (FGFRs) transduce signals that regulate developmental processes and metabolism. In numerous cancer types genetic aberrations of FGFR1 lead to its uncontrolled activation. To circumvent the unrestrained signal transduction, several intramolecular inhibitory mechanisms within FGFR1 have evolved. In vitro experiments with receptor truncation have demonstrated that the N-terminal D1 domain of FGFR1 negatively regulates ligand binding to the receptor. Here, we show that D1-specific monovalent antibody fragments can activate FGFR1 and its downstream signaling cascades in the absence of ligand. These data suggest that the D1 domain of FGFR1 may play autoinhibitory role not only by controlling ligand binding, but also by regulating the overall conformation of FGFR1, keeping it in a state that disfavors autoactivation in the absence of its cognate growth factor.