Ligand bias underlies differential signaling of multiple FGFs via FGFR1

0585091 - ÚŽFG 2025 RIV GB eng J - Journal Article
Karl, K. - Del Piccolo, N. - Light, T. - Roy, T. - Deduja, P. - Ursachi, V. - Fafílek, Bohumil - Krejčí, Pavel - Hristova, K.
Ligand bias underlies differential signaling of multiple FGFs via FGFR1.
eLife. Roč. 12, Apr 3 (2024), č. článku RP88144. ISSN 2050-084X. E-ISSN 2050-084X
Institutional support: RVO:67985904
Keywords : FGF ligands * embryonic development
OECD category: Developmental biology
Impact factor: 7.7, year: 2022
Method of publishing: Open access
https://elifesciences.org/articles/88144

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. Forster 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.
Permanent Link: https://hdl.handle.net/11104/0352906