Different intracellular trafficking of FGF1 endocytosed by the four homologous FGF receptors.
Many growth factors and cytokines bind to more than one receptor, but in many cases the different roles of the separate receptors in signal transduction are unclear. Intracellular sorting of ligand-receptor complexes may modulate the signalling, and we have here studied the intracellular trafficking of ligand bound to receptors for fibroblast growth factors (FGFs). For this purpose, we transfected HeLa cells with any one of the four tyrosine kinase FGF receptors (FGFR1-4). In cells expressing any one of these receptors, externally added FGF1 was localized to sorting/early endosomes after 15 minutes at 37 degrees C. After longer incubation times, FGF1 internalized in cells expressing FGFR1 was localized mainly to late endosomes/lysosomes, similarly to EGF. By contrast, FGF1 internalized in cells expressing FGFR4 followed largely the same intracellular pathway as the recycling ligand, transferrin. In cells expressing FGFR2 or FGFR3, sorting of FGF1 to lysosomes was somewhat less efficient than that observed for FGFR1. Furthermore, FGF1 was more slowly degraded in cells expressing FGFR4 than in cells expressing FGFR1-3 and in addition, internalized FGFR4 as such was more slowly degraded than the other receptors. The data indicate that after endocytosis, FGFR4 and its bound ligand are sorted mainly to the recycling compartment, whereas FGFR1-3 with ligand are sorted mainly to degradation in the lysosomes. Alignment of the amino acid sequence of the intracellular part of the four FGFRs revealed several lysines conserved in FGFR1-3 but absent in FGFR4. Lysines are potential ubiquitylation sites and could thus target a receptor to lysosomes for degradation. Indeed, we found that FGFR4 is less ubiquitylated than FGFR1, which could be the reason for the different sorting of the receptors.
Haugsten
Ellen Margrethe
EM
Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, The University of Oslo, Montebello, 0310 Oslo, Norway.
Sørensen
Vigdis
V
Brech
Andreas
A
Olsnes
Sjur
S
Wesche
Jørgen
J
D000595:Amino Acid Sequence; D000818:Animals; D004705:Endocytosis / Q000502:physiology*; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D021381:Protein Transport / Q000502:physiology; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
D025801:Ubiquitin; D016220:Fibroblast Growth Factor 1