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 chaper one 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 leg, nuclear hormone receptors, transcripti on factors, and protein kinases). Improper function of these proteins can b e induced by selective disruption of their complexes with Hsp90 using the b enzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that ge ldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor exp ression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamy cin decreases the amount and phosphorylation of Lck and Raf-l kinases and p revents activation of the extracellular signal regulated kinase (ERK)-2 kin ase. Geldanamycin also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with geldanamycin, h owever, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-ce ll stimulation. Through demonstrating the selective inhibition of kinase-re lated T-lymphocyte responses by geldanamycin, our results emphasize the sub stantial role of Hsp90-kinase complexes in T-cell activation.