FGF-1 and FGF-2 require the cytosolic chaperone Hsp90 for translocation into the cytosol and the cell nucleus.
Similarly to many protein toxins, the growth factors fibroblast growth factor 1 (FGF-1) and FGF-2 translocate from endosomes into the cytosol. It was recently found that certain toxins are dependent on cytosolic Hsp90 for efficient translocation across the endosomal membrane. We therefore investigated the requirement for Hsp90 in FGF translocation. We found that low concentrations of the specific Hsp90 inhibitors, geldanamycin and radicicol, completely blocked the translocation of FGF-1 and FGF-2 to the cytosol and the nucleus. The drugs did not interfere with the initial binding of FGF-1 to the growth factor receptors at the cell-surface or with the subsequent internalization of the growth factors into endosomes. The activation of known signaling cascades downstream of the growth factor receptors was also not affected by the drugs. The data indicate that the drugs block translocation from endosomes to the cytosol implying that Hsp90 is required for translocation of FGF-1 and FGF-2 across the endosomal membrane.
Institute for Cancer Research at the Norwegian Radium Hospital, University of Oslo, Montebello, 0310 Oslo, Norway. jorgen.wesche@labmed.uio.no
Jørgen
J
Wesche
Jedrzej
J
Małecki
Antoni
A
Wiedłocha
Camilla Skiple
CS
Skjerpen
Peter
P
Claus
Sjur
S
Olsnes
D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D011992:Endosomes / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000494:pharmacology; D007834:Lasers; D020935:MAP Kinase Signaling System; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D018613:Microscopy, Confocal; D008954:Models, Biological; D008985:Monensin / Q000494:pharmacology; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D021381:Protein Transport; D011809:Quinones / Q000494:pharmacology; D015398:Signal Transduction; D013347:Subcellular Fractions; D013997:Time Factors; D014158:Transcription, Genetic
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D011809:Quinones; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; C040929:bafilomycin A1; D006493:Heparin; D008985:Monensin; C035359:monorden; C001277:geldanamycin