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. 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. FGF-1 3The abbreviations used are: FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; Hsp90, heat shock protein 90; TPCK, l-1-tosylamido-2-phenylethyl chloromethyl ketone; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; PI, phosphatidylinositol; PBS, phosphate-buffered saline. 3The abbreviations used are: FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; Hsp90, heat shock protein 90; TPCK, l-1-tosylamido-2-phenylethyl chloromethyl ketone; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; PI, phosphatidylinositol; PBS, phosphate-buffered saline. and FGF-2 bind to and activate FGFRs on the surface of target cells. Several downstream signaling cascades such as the Ras/MAPK, phospholipase C-γ/PKC, and PI 3-kinase/Akt pathways are then initiated (1Schlessinger J. Cell. 2000; 103: 211-225Abstract Full Text Full Text PDF PubMed Scopus (3500) Google Scholar). FGF signaling is important in several cellular processes such as proliferation, angiogenesis, migration, survival, and differentiation (2Mason I.J. Cell. 1994; 78: 547-552Abstract Full Text PDF PubMed Scopus (525) Google Scholar, 3Wiedl/ocha A. Sorensen V. Curr. Top. Microbiol. Immunol. 2004; 286: 45-79PubMed Google Scholar). In addition, FGF-1 and FGF-2 have the peculiar ability to translocate through the endosomal membrane into the cytosol and then be transported into the nucleus (4Olsnes S. Klingenberg O. Wiedl/ocha A. Physiol. Rev. 2003; 83: 163-182Crossref PubMed Scopus (97) Google Scholar). Several laboratories have presented data indicating that the nuclear targeting is involved in the proliferation of cells. Thus, elimination of the N-terminal nuclear localization signal of FGF-1 resulted in considerably reduced mitogenic activity even if binding and activation of the receptors was not much changed (5Imamura T. Engleka K. Zhan X. Tokita Y. Forough R. Roeder D. Jackson A. Maier J.A. Hla T. Maciag T. Science. 1990; 249: 1567-1570Crossref PubMed Scopus (324) Google Scholar). When FGF-1 was introduced into the cytosol as a fusion protein with diphtheria toxin, it stimulated DNA synthesis in cells lacking FGFRs arguing for an intracellular role of the growth factor (6Wiedl/ocha A. Falnes P.O. Madshus I.H. Sandvig K. Olsnes S. Cell. 1994; 76: 1039-1051Abstract Full Text PDF PubMed Scopus (218) Google Scholar). Similarly, nuclear FGF-2 has been shown to activate rDNA transcription and to be associated with cell proliferation (7Bouche G. Gas N. Prats H. Baldin V. Tauber J.P. Teissie J. Amalric F. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 6770-6774Crossref PubMed Scopus (390) Google Scholar, 8Bailly K. Soulet F. Leroy D. Amalric F. Bouche G. FASEB J. 2000; 14: 333-344Crossref PubMed Scopus (69) Google Scholar). Nuclear FGF-2 has also been proposed to be involved in the survival of carcinoma cells important for lung metastasis (9Thomas-Mudge R.J. Okada-Ban M. Vandenbroucke F. Vincent-Salomon A. Girault J.M. Thiery J.P. Jouanneau J. Oncogene. 2004; 23: 4771-4779Crossref PubMed Scopus (31) Google Scholar). We recently found that after endocytosis by the specific FGFRs, FGF-1 and -2 translocate from endosomes into the cytosol (10Mal/ecki J. Wiedl/ocha A. Wesche J. Olsnes S. EMBO J. 2002; 21: 4480-4490Crossref PubMed Scopus (57) Google Scholar, 11Mal/ecki J. Wesche J. Skjerpen C.S. Wiedl/ocha A. Olsnes S. Mol. Biol. Cell. 2004; 15: 801-814Crossref PubMed Google Scholar). The positive inside membrane potential was found to be crucial for translocation across the endosomal membrane. Furthermore, we have shown that FGF-1 is then transported further from the cytosol to the nucleus by the concerted action of two nuclear localization signals (12Wesche J. Mal/ecki J. Wiedl/ocha A. Ehsani M. Marcinkowska E. Nilsen T. Olsnes S. Biochemistry. 2005; 44: 6071-6081Crossref PubMed Scopus (35) Google Scholar). In the nucleus FGF-1 is phosphorylated by PKCδ and then rapidly exported to the cytosol by a leptomycin B-sensitive protein, probably exportin-1, and subsequently degraded (13Wiedl/ocha A. Nilsen T. Wesche J. Sorensen V. Mal/ecki J. Marcinkowska E. Olsnes S. Mol. Biol. Cell. 2005; 16: 794-810Crossref PubMed Google Scholar). We have previously shown that the translocation of FGF-1 is prevented by PI 3-kinase inhibitors suggesting that it is regulated by signaling events (14Klingenberg O. Wiedl/ocha A. Citores L. Olsnes S. J. Biol. Chem. 2000; 275: 11972-11980Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Another class of proteins that are endocytosed and translocated from endosomes are certain protein toxins. They have targets in the cytosol and need to translocate an enzymatic moiety into the host cells. Several of them, e.g. anthrax and diphtheria toxin, utilize the low pH in endosomes to trigger translocation (15Wesche J. Elliott J.L. Falnes P.O. Olsnes S. Collier R.J. Biochemistry. 1998; 37: 15737-15746Crossref PubMed Scopus (171) Google Scholar, 16Sandvig K. Olsnes S. J. Cell Biol. 1980; 87: 828-832Crossref PubMed Scopus (282) Google Scholar). Interestingly, it was recently found that efficient translocation of diphtheria toxin catalytic domain requires the cytosolic chaperone Hsp90 (17Ratts R. Zeng H. Berg E.A. Blue C. McComb M.E. Costello C.E. vanderSpek J.C. Murphy J.R. J. Cell Biol. 2003; 160: 1139-1150Crossref PubMed Scopus (160) Google Scholar). Hsp90 has also been shown to be essential for the translocation of Clostridium botulinum C2 toxin and iota-like toxins (18Haug G. Leemhuis J. Tiemann D. Meyer D.K. Aktories K. Barth H. J. Biol. Chem. 2003; 278: 32266-32274Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 19Haug G. Aktories K. Barth H. Infect. Immun. 2004; 72: 3066-3068Crossref PubMed Scopus (56) Google Scholar). In light of the recent findings that certain toxins depend on Hsp90 for efficient translocation from endosomes to cytosol, we decided to investigate whether transport of FGF-1 and FGF-2 is also dependent on this chaperone. We here demonstrate that Hsp90 inhibitors completely block the translocation of the growth factors from endosomes to the cytosol. Materials, Media, and Buffers—[35S]Methionine (1000 Ci/mmol), [33P]phosphate (3000 Ci/mmol) were obtained from Amersham Biosciences. Geldanamycin was obtained from Calbiochem, and radicicol was from Sigma. Recombinant FGF-1 was prepared as described previously (20Wesche J. Wiedl/ocha A. Falnes P.O. Choe S. Olsnes S. Biochemistry. 2000; 39: 15091-15100Crossref PubMed Scopus (25) Google Scholar). The following buffers were used: HEPES medium, bicarbonate- and serum-free Eagle's minimal essential medium buffered with HEPES to pH 7.4; dialysis buffer, 140 mm NaCl, 20 mm HEPES, and 2 mm CaCl2, adjusted to pH 7.0 with NaOH; lysis buffer, 0.1 m NaCl, 20 mm NaH2PO4, 10 mm EDTA, 1% Triton X-100, 1 mm phenylmethylsulfonyl fluoride, and 1 mm N-ethylmaleimide, pH 7.4; PBS, 140 mm NaCl and 10 mm NaH2PO4, pH 7.4. Cell Cultures—NIH/3T3 and HUVE cells were propagated as earlier described (6Wiedl/ocha A. Falnes P.O. Madshus I.H. Sandvig K. Olsnes S. Cell. 1994; 76: 1039-1051Abstract Full Text PDF PubMed Scopus (218) Google Scholar). Cells were seeded into tissue culture plates the day preceding the experiments. In Vitro Transcription and Translation—Plasmid DNA was linearized downstream of the encoding gene and transcribed with T3 RNA polymerase as described (21McGill S. Stenmark H. Sandvig K. Olsnes S. EMBO J. 1989; 8: 2843-2848Crossref PubMed Scopus (29) Google Scholar). The mRNA was precipitated with ethanol and dissolved in H2O containing 10 mm dithiothreitol and 0.1 unit/μl RNasin. The translation was performed for 1 h at 30 °C in micrococcal nuclease treated rabbit reticulocyte lysate (Promega, Madison, WI). Radioactive proteins were prepared in lysates containing 1 μm [35S]methionine and a 25 μm concentration of the other 19 amino acids. Labeled methionine was replaced by 25 μm unlabeled methionine when nonradioactive proteins were synthesized. The amount of protein in the nonlabeled lysates was estimated as earlier described (22Stenmark H. Afanasiev B.N. Ariansen S. Olsnes S. Biochem. J. 1992; 281: 619-625Crossref PubMed Scopus (21) Google Scholar) by translating in parallel a small aliquot of the lysate in the of μm The lysates were to [35S]methionine and in the of was in as described by PubMed Scopus Google Scholar). the was for 30 in and then for 30 in 1 m pH was to the at cells on plates were with binding Eagle's medium containing mm HEPES, pH and 10 of Cells were with for 2 h at were with binding buffer, with containing 10 with m NaCl, and with HEPES Cells were in m and the was a Recombinant FGF-1 was by the J.C. Biochem. PubMed Scopus Google Scholar). The specific activity was of cells were with of geldanamycin or radicicol for h in HEPES medium The cells were then to the medium containing 1 and for 20 at The cells were then with for 10 by a in and subsequently dissolved in 0.1 m The was and as a of by cells with the drugs. in cells in tissue culture plates cells were for h in Eagle's medium with 1% at The cells were with 25 the h and then for h with FGF-1 and 20 The cells were subsequently in PBS, pH containing inhibitors μm mm fluoride, and 30 mm The cells were in mm mm NaCl, mm EDTA, 1% Triton containing a of and inhibitors, pH The and membrane were and with the of phosphorylated the with was treated with 2 for at 25 FGF-1 is to this The was by the with containing Triton and The was by and of the cells were with proteins for h at °C and with pH m NaCl in 20 mm pH The cells were then with PBS, and 20 was to the cells. at 25 the cells were on for 30 to of the cytosol to into the The medium was and the cytosolic The of the cells was with lysis and from the to and at for The was the membrane The was in lysis for 10 on the lysate was for at and the was the nuclear The were to and subsequently by and and were for h in Eagle's medium the cells were treated with 10 and 10 FGF-1 or FGF-2 for the of in buffer, and by and kinase the membrane was with the membrane was with and with was with following the cells were on tissue culture plates and with or the for 30 FGF-1 was and the cells were further for 2 The cells were then with a of were prepared with the of 7.0 of FGF-1 by Hsp90 FGF-1 is to it is transported to the nucleus it is phosphorylated by PKCδ (13Wiedl/ocha A. Nilsen T. Wesche J. Sorensen V. Mal/ecki J. Marcinkowska E. Olsnes S. Mol. Biol. Cell. 2005; 16: 794-810Crossref PubMed Google Scholar). of FGF-1 therefore be used as an to translocation of the growth factor to the nucleus of the cells. We and cells with FGF-1 for The cells were then and for phosphorylated growth in a to phosphorylated FGF-1 was When the of FGF-1 was was We then concentrations of the Hsp90 radicicol T. H. Oncogene. 1998; 16: PubMed Scopus Google Scholar, C. R. J. Chem. PubMed Scopus Google Scholar). at low concentrations of radicicol the phosphorylated indicating that Hsp90 is required for or in the to of the growth were obtained with Hsp90 geldanamycin also completely blocked at low concentrations whether the drugs with the as we performed an in cells with or radicicol or geldanamycin and treated with to activate were and the PKCδ was with an Recombinant FGF-1 was to the PKCδ in a kinase containing in the or of radicicol, or other drugs as be in FGF-1 was phosphorylated by the and PKCδ When an was was PKCδ and FGF-1 was not as of radicicol or geldanamycin did not the in of PKCδ at low blocked the the did not block the the data demonstrate that the Hsp90 inhibitors not interfere with the of FGF-1 by PKCδ in Geldanamycin has been to be to certain cells and we the of the drugs in cells. we the of cells treated with the Hsp90 in of the cells was when were treated for h with of the inhibitors We also whether the of protein synthesis was changed in cells treated with the drugs. The cells were treated with concentrations of the drugs for and the ability of the cells to into was used to the of protein synthesis were at 10 was at In a 10 concentration of the inhibitors was is the concentration was We therefore that the of of FGF-1 was not to of the drugs. Hsp90 of FGF-1 and FGF-2 to the and the of FGF-1 in the we to investigate at of the transport the We therefore to FGF-1 to cells and into cytosol, and nuclear (20Wesche J. Wiedl/ocha A. Falnes P.O. Choe S. Olsnes S. Biochemistry. 2000; 39: 15091-15100Crossref PubMed Scopus (25) Google Scholar). this we used to in the membrane to cytosolic proteins into the The medium was then and the cytosolic The of the cells were with 1% Triton and by into a nuclear and a membrane We that the resulted in of proteins from the of the The membrane and were found as in the membrane The cytosolic proteins Hsp90 and were found in the cytosolic and membrane a of the proteins was found in the membrane was it is to the amount of used that of the cytosolic are concentrations of are affected as We the of the cytosolic protein and adjusted the amount of to a of that the amount of proteins found in the cytosolic is In Hsp90 and with the of and therefore be of the membrane the nuclear was found in the nuclear and of the membrane and cytosolic were found in the nuclear In the of proteins that the of the of the The localization of FGF-1 in cells with the growth factor was then the in after for FGF-1 was found in In the of geldanamycin or radicicol FGF-1 was found in the membrane 2 and a we a PI 3-kinase that the translocation of FGF-1 to the cytosol and the nucleus (14Klingenberg O. Wiedl/ocha A. Citores L. Olsnes S. J. Biol. Chem. 2000; 275: 11972-11980Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). in this FGF-1 was found in the membrane We also the translocation of FGF-2 in the of When to FGF-2 was from the cytosol, and nuclear In in the of geldanamycin the growth factor was found in the membrane and was from the cytosol and nuclear Hsp90 has in been found to proteins in the cytosol J.C. J. Cell Biol. PubMed Scopus Google Scholar). Thus, when Hsp90 is by geldanamycin or radicicol, the proteins of the chaperone have a reduced We therefore the that the of FGF-1 in the cytosol and the nucleus be to of the growth factor by in the of We therefore whether of FGF-1 be in the of a as be in the of with geldanamycin or radicicol did not in the of phosphorylated growth is therefore probably not the for the of the growth factor in the cytosol and in the nucleus. the data indicate that FGF-1 and FGF-2 are dependent on cytosolic Hsp90 to translocate to the cytosol and the nucleus. and of FGF-1 by the drugs also interfere with the binding of FGF-1 to the FGFRs on the cell-surface of cells or the subsequent endocytosis of the growth we cells with of in the of In we also geldanamycin or radicicol to whether the drugs with the in was of the drugs on the binding to the We also the binding in a by cells with in the of and then of unlabeled In parallel we geldanamycin or radicicol to whether the drugs with the in this was in the binding to the FGFRs whether the Hsp90 inhibitors were or not whether the endocytosis of FGF-1 was changed in the of the we FGF-1 with the L. Wesche J. E. Olsnes S. Mol. Biol. Cell. PubMed Scopus Google Scholar). was to cells in the or of geldanamycin or radicicol for 2 h at endosomes containing FGF-1 was then We in the of whether the inhibitors were or the it is to of FGF-1 in cells the FGF Furthermore, the not in transport to the and it is therefore not to in the nucleus It that the drugs not binding and internalization of and the data to the that it is the translocation of the growth factors from endosomes to the cytosol that is Geldanamycin or FGF signaling be in the translocation of FGF-1 into the cells (14Klingenberg O. Wiedl/ocha A. Citores L. Olsnes S. J. Biol. Chem. 2000; 275: 11972-11980Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). We therefore investigated whether the Hsp90 inhibitors cell signaling from the FGF we whether the of the is by the kinase of the FGFR, was was by the of a in a to phosphorylated was after of cells by FGF-1 or activation of was whether geldanamycin and radicicol were or after with FGF-1 or was and was in the and of the The is the membrane with an to demonstrate we the activation of the PI 3-kinase to of of cells by FGF-1 or phosphorylated was 2 and The of geldanamycin and radicicol did not the activation of and In the cells were stimulated for was to a after and In this it also to be phosphorylated when the drugs were and the is small and after a The in the indicate that of were in the cell signaling events investigated are not much affected by the drugs. It therefore to be a in signaling that the block in translocation of FGF-1 and -2 into the cell when are treated with Hsp90 of of by have earlier that translocation of FGF-1 and FGF-2 to the cytosol is blocked by the inhibitors of and (10Mal/ecki J. Wiedl/ocha A. Wesche J. Olsnes S. EMBO J. 2002; 21: 4480-4490Crossref PubMed Scopus (57) Google Scholar, 11Mal/ecki J. Wesche J. Skjerpen C.S. Wiedl/ocha A. Olsnes S. Mol. Biol. Cell. 2004; 15: 801-814Crossref PubMed Google probably the potential across the membrane of intracellular is required for translocation to even in the of the translocation be when the cells are treated with the or that across in an is probably to of the membrane potential by activation of the in the membrane. Thus, the with the translocation completely blocked translocation by of FGF-1 When was the of the the translocation was Interestingly, it was to for the to efficient translocation with for a was also to FGF-1 been blocked by of the The data indicate that the block of translocation by or the growth factor in intracellular it is to of the growth factor is rapidly translocated to the cytosol, to of the membrane potential across the membrane. We used this to the required for the Hsp90 inhibitors to block the membrane translocation in the internalization The of the is in FGF-1 was to cells in the or in the of to translocation and of the growth factor in endosomes. was then to the block in translocation as FGF-1 was also found in the cytosolic and nuclear When geldanamycin or radicicol was as as 30 the translocation into the cytosol and the nucleus was completely blocked and an was FGF-1 in the cytosolic or nuclear when a PI 3-kinase FGF-1 translocation (14Klingenberg O. Wiedl/ocha A. Citores L. Olsnes S. J. Biol. Chem. 2000; 275: 11972-11980Abstract Full Text Full Text PDF PubMed Scopus (34) Google was indicate that the Hsp90 inhibitors block the membrane translocation as such and not earlier we have that Hsp90 is crucial for the translocation of FGF-1 and FGF-2 across cellular it to be the membrane translocation from endosomes into the cytosol that requires The of Hsp90 inhibitors on in the by FGF-1 to the nucleus was the initial binding of the growth factors to the FGF receptors the endocytosis of FGF-1 was affected by the Hsp90 FGF-1 and FGF-2 to be in endosomes in the of the Hsp90 It therefore that it is the translocation across the endosomal membrane that is affected when Hsp90 is We have previously shown that FGF translocation is dependent on signaling by PI 3-kinase (14Klingenberg O. Wiedl/ocha A. Citores L. Olsnes S. J. Biol. Chem. 2000; 275: 11972-11980Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Furthermore, Hsp90 is involved in the of downstream of PI 3-kinase The of Hsp90 on translocation therefore be by with the signaling from the we not much in signaling in cells treated with the Furthermore, when cells were treated with the inhibitors for a in the the translocation was We therefore that the block of translocation by Hsp90 inhibitors is to be to with signal Geldanamycin and radicicol the activity of Hsp90 for the of the chaperone J.C. J. Cell Biol. PubMed Scopus Google Scholar). Hsp90 to proteins in the and are not many other as involved in protein We have earlier that FGF-1 not to a it was not that FGF-1 a that through the membrane (20Wesche J. Wiedl/ocha A. Falnes P.O. Choe S. Olsnes S. Biochemistry. 2000; 39: 15091-15100Crossref PubMed Scopus (25) Google Scholar). Thus, Hsp90 in the to a after translocation to the cytosol. we not even of FGF-1 in the cytosol when cells were treated with the Hsp90 inhibitors, it that Hsp90 is required at a in the translocation across the membrane in the cytosol. Hsp90 be involved in the translocation of FGF across the membrane. In a membrane translocation the protein to be translocated is to the of the membrane to a Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The is then translocated across the membrane through a are involved in the translocation on the of the membrane. the of the is dependent on the chaperone is involved in the of the across the membrane J.L. R. J. Cell Biol. PubMed Scopus Google Scholar). also in the of the protein on the of the membrane Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In the chaperone a and in the and are involved Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). in FGF for translocation be by Hsp90 is involved in the of FGF-1 across the membrane. we not a binding of FGF-1 and -2 with Hsp90 in in J. A. C. S. and S. if Hsp90 as a to in we not be to a in this the with Hsp90 translocation through the membrane. Hsp90 several proteins from in the cytosol Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). We therefore whether of FGF-1 after translocation was the for the of FGF-1 in the cytosol and nucleus when the cells were treated with geldanamycin and in the of the in to geldanamycin we not FGF-1 in the cytosol or in the nucleus. is with the that it is the translocation across the membrane into the cytosol that is affected by the Hsp90 Hsp90 have an role in of the growth factor and of FGF-1 from after translocation. It is that several toxins also depend on Hsp90 for efficient translocation into the cytosol. diphtheria toxin and C. botulinum C2 toxin Hsp90 to be crucial for the translocation across the endosomal membrane (17Ratts R. Zeng H. Berg E.A. Blue C. McComb M.E. Costello C.E. vanderSpek J.C. Murphy J.R. J. Cell Biol. 2003; 160: 1139-1150Crossref PubMed Scopus (160) Google Scholar, G. Leemhuis J. Tiemann D. Meyer D.K. Aktories K. Barth H. J. Biol. Chem. 2003; 278: 32266-32274Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). binding and endocytosis did not to be affected by the drugs. In the of diphtheria toxin, Hsp90 was of a and other that was proposed to in the translocation of the toxin (17Ratts R. Zeng H. Berg E.A. Blue C. McComb M.E. Costello C.E. vanderSpek J.C. Murphy J.R. J. Cell Biol. 2003; 160: 1139-1150Crossref PubMed Scopus (160) Google Scholar). also in the of a be involved in the membrane translocation. It is that certain toxins and the FGF growth factors to utilize a Hsp90 for translocation across the endosomal membrane. The translocation is not for the translocation of toxins. the was for growth factor translocation and by toxins for efficient transport into the We are to for with

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.