The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation.
The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. Geldanamycin also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation.
Schnaider
T
T
Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
Somogyi
J
J
Csermely
P
P
Szamel
M
M
D000217:Acyltransferases / Q000378:metabolism; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation / Q000187:drug effects*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D016853:Muromonab-CD3 / Q000494:pharmacology; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009687:Nuclear Proteins; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D016853:Muromonab-CD3; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011809:Quinones; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D015759:Ionomycin; D000217:Acyltransferases; C065553:arachidonoyl coenzyme A lysophosphatide acyltransferase; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D013755:Tetradecanoylphorbol Acetate; C001277:geldanamycin