Fig. 5

Hypothetical model of the N-glycosylation-dependent cellular trafficking of FGFR1. A. After co-translational synthesis in the ER, the wild type FGFR1 is N-glycosylated at several positions. The N227 site precludes FGFR1 transport to the nuclear envelope, while N-glycosylation sites in the D2 and D3 domain promote FGFR1 transport via the ER/Golgi/secretory vesicles to the plasma membrane, where the receptor becomes available for FGFs’ stimulation. During the transport to the cell surface, N-glycosylation of FGFR1 ensures low level of FGFR1 autoactivation in the intracellular compartments in the absence of FGFs. B. Signal peptide (SP)-driven co-translational ER targeting of the N-glycosylation-deficient FGFR1 (FGFR1.GF) results in the initial accumulation of FGFR1.GF in the ER, where it binds several protein folding and quality control factors, such as BiP or protein disulfide isomerase A4. In the absence of N-glycans, the extracellular region of FGFR1.GF undergoes unfolding and aggregation, initiating ligand-independent FGFR1.GF autoactivation. Alternatively, the absence of N-glycans in the properly folded extracellular region of FGFR1.GF facilitates FGFR1.GF dimerization and activation in the absence of FGFs. In both scenarios, intracellular FGFR1 displays a high degree of autoactivation. Lateral diffusion of the ER-trapped FGFR1.GF within the ER-membrane, which is continuous with the nuclear envelope, results in the transport of FGFR1.GF to the nuclear envelope. Importins and NPC are likely involved in this step. FGFR1.GF is retained in the nuclear envelope presumably by participating in complexes with a precise set of nuclear proteins. Importantly, FGFR1.GF localized to the nuclear envelope is highly kinase active, indicating the presence of a novel nuclear FGFR1 signaling cascade