Glycosylation of FGF/FGFR: An underrated sweet code regulating cellular signaling programs

Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute plasma-membrane localized signaling hubs that transmit signals from the extracellular environment to the cell interior, governing pivotal cellular processes like motility, metabolism, differentiation, division and death. FGF/FGFR signaling is critical for human body development and homeostasis; dysregulation of FGF/FGFR units is observed in numerous developmental diseases and in about 10% of human cancers. Glycosylation is a highly abundant posttranslational modification that is critical for physiological and pathological functions of the cell. Glycosylation is also very common within FGF/FGFR signaling hubs. Vast majority of FGFs (15 out of 22 members) are N-glycosylated and few FGFs are O-glycosylated. Glycosylation is even more abundant within FGFRs; all FGFRs are heavily N-glycosylated in numerous positions within their extracellular domains. A growing number of studies points on the multiple roles of glycosylation in fine-tuning FGF/FGFR signaling. Glycosylation modifies secretion of FGFs, determines their stability and affects interaction with FGFRs and co-receptors. Glycosylation of FGFRs determines their intracellular sorting, constitutes autoinhibitory mechanism within FGFRs and adjusts FGF and co-receptor recognition. Sugar chains attached to FGFs and FGFRs constitute also a form of code that is differentially decrypted by extracellular lectins, galectins, which transform FGF/FGFR signaling at multiple levels. This review focuses on the identified functions of glycosylation within FGFs and FGFRs and discusses their relevance for the cell physiology in health and disease.