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.
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GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-Y CHEMICAL GENE-N GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-N GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N
T-cell receptor kinase Hsp90 kinase nuclear hormone receptors Hsp90 protein kinases 90-kDa heat shock protein Hsp90 interleukin (IL)-2 geldanamycin IL-2 receptor molecular chaperone Lck Raf-1 kinases extracellular signal regulated kinase (ERK)-2 kinase T-cell receptor nuclear factor of activated T-cells NF-AT benzoquinonoid ansamycin Hsp90 kinase geldanamycin geldanamycin geldanamycin Geldanamycin geldanamycin geldanamycin lysophosphatide acyltransferase