The FGF system is the most complex of all receptor tyrosine kinase signaling networks with 18 FGF ligands and four FGFRs that deliver morphogenic signals to pattern most embryonic structures. Even when a single FGFR is expressed in the tissue, different FGFs can trigger dramatically different biological responses via this receptor. Here we show both quantitative and qualitative differences in the signaling of one of the FGF receptors, FGFR1c, in response to different FGFs. We provide an overview of the recent discovery that FGFs engage in biased signaling via FGFR1c. We discuss the concept of ligand bias, which represents qualitative differences in signaling as it is a measure of differential ligand preferences for different downstream responses. We show how FGF ligand bias manifests in functional data in cultured chondrocyte cells. We argue that FGF-ligand bias contributes substantially to FGF-driven developmental processes, along with known differences in FGF expression levels, FGF-FGFR binding coefficients and differences in FGF stability in vivo.

Department of Biology Faculty of Medicine Masaryk University Brno 62500 Czech Republic; International Clinical Research Center St Anne's University Hospital Brno 65691 Czech Republic

Department of Biology Faculty of Medicine Masaryk University Brno 62500 Czech Republic; International Clinical Research Center St Anne's University Hospital Brno 65691 Czech Republic; Institute of Animal Physiology and Genetics of the CAS Brno 60200 Czech Republic

Department of Materials Science and Engineering and Institute for NanoBioTechnology Johns Hopkins University Baltimore MD 21218 USA

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