The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Materials Science and Engineering Institute for NanoBioTechnology and Program in Molecular Biophysics Johns Hopkins University Baltimore United States

Institute of Animal Physiology and Genetics of the CAS Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Před aktualizací

doi: 10.1101/2022.01.06.475273 PubMed

Před aktualizací

doi: 10.7554/eLife.88144.1 PubMed

Před aktualizací

doi: 10.7554/eLife.88144.2 PubMed

Před aktualizací

doi: 10.7554/eLife.88144.3 PubMed

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