Different abilities of the four FGFRs to mediate FGF-1 translocation are linked to differences in the receptor C-terminal tail.
Members of the fibroblast growth factor family bind to one or more of the four closely related membrane-spanning FGF receptors. In addition to signaling through the receptors, exogenous FGF-1 and FGF-2 are endocytosed and translocated to the cytosol and nucleus where they stimulate RNA and DNA synthesis. Here we have studied the ability of the four FGF receptors to facilitate translocation of exogenous FGF-1 to the cytosol and nucleus. FGFR1 and FGFR4 were able to mediate translocation, whereas FGFR2 and FGFR3 completely lacked this ability. By analyzing mutant FGFRs we found that the tyrosine kinase domain could be deleted from FGFR1 without abolishing translocation, whereas the C-terminal tail of the FGFRs, constituted by approximately 50 amino acids downstream of the kinase domain, plays a crucial role in FGF-1 translocation. Three amino acids residues within the C-terminal tail were found to be of particular importance for translocation. For FGFR2, the two amino acid substitutions Q774M and P800H were sufficient to enable the receptor to support FGF-1 translocation. The results demonstrate a striking diversity in function of the four FGFRs determined by their C-terminal domain.
Sørensen
Vigdis
V
The Department of Biochemistry, Institute for Cancer Research, The University of Oslo, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway. vigdis.sorensen@labmed.uio.no
Wiedlocha
Antoni
A
Haugsten
Ellen Margrethe
EM
Khnykin
Denis
D
Wesche
Jørgen
J
Olsnes
Sjur
S
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002417:Cattle; D002522:Chlorocebus aethiops; D004591:Electrophoresis, Polyacrylamide Gel; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D017386:Sequence Homology, Amino Acid
D017468:Receptors, Fibroblast Growth Factor; D016220:Fibroblast Growth Factor 1; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4