Abstract
Fibroblast growth factor receptors (FGFRs) are integral membrane proteins that transmit signals through the plasma membrane. FGFRs signaling needs to be precisely adjusted as aberrant FGFRs function is associated with development of human cancers or severe metabolic diseases. The subcellular localization, trafficking and function of FGFRs rely on the formation of multiprotein complexes. In this study we revealed galectins, lectin family members implicated in cancer development and progression, as novel FGFR1 binding proteins. We demonstrated that galectin-1 and galectin-3 directly bind to the sugar chains of the glycosylated extracellular part of FGFR1. Although both galectins compete for the same binding sites on FGFR1, these proteins elicit different impact on FGFR1 function and cellular trafficking. Galectin-1 mimics fibroblast growth factor as it efficiently activates FGFR1 and receptor-downstream signaling pathways that result in cell proliferation and apoptotic evasion. In contrast, galectin-3 induces extensive clustering of FGFR1 on the cell surface that inhibits constitutive internalization of FGFR1. Our data point on the interplay between extracellular galectins and FGFRs in the regulation of cell fate.
Highlights
Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases (RTKs) that together with extracellular fibroblast growth factors (FGFs) transmit signals through the plasma membrane
To study whether FGF1 binding to streptavidin-binding peptide (SBP)-FGFR1 accelerates uptake of the receptor, U2OSSBP-R1 cells were pre-labeled with streptavidin-AF555 and incubated in the presence or absence of FGF1
Our data define extracellular galectin-1 and -3 as novel FGFR1 binding proteins that directly interact with the sugar chains of the receptor
Summary
Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases (RTKs) that together with extracellular fibroblast growth factors (FGFs) transmit signals through the plasma membrane. The FGFRs-FGFs signaling is important for angiogenesis, regulation of metabolism and tissue repair [1,2,3]. FGFR1 is composed of an N-terminal extracellular region built of three Ig domains: D1, D2 and D3, from which D2 and D3 are involved in FGFs binding, a single transmembrane span and an intracellular protein kinase domain. Binding of FGFs to the extracellular part of FGFR1 stimulates receptor dimerization and induces conformational changes resulting in the activation of FGFR1 and propagation of signals [2, 17, 18]. The extracellular part of FGFRs is N-glycosylated at several positions and these modifications may influence FGFRs interaction with FGFs [19, 20]
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