The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation

Tamás Schnaider, János Somogyi, P. Csermely, Marta Szamel

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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-l 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.

Original languageEnglish
Pages (from-to)52-61
Number of pages10
JournalCell Stress and Chaperones
Volume5
Issue number1
Publication statusPublished - Jan 2000

Fingerprint

T-cells
Lymphocyte Activation
Phosphotransferases
Chemical activation
T-Lymphocytes
T-Cell Antigen Receptor
raf Kinases
Rifabutin
NFATC Transcription Factors
HSP90 Heat-Shock Proteins
Protein folding
Acyltransferases
Signal transduction
Phosphorylation
Molecular Chaperones
Interleukin-2 Receptors
Mitogen-Activated Protein Kinase 1
Protein Folding
Eukaryotic Cells
Cell membranes

ASJC Scopus subject areas

  • Clinical Biochemistry

Cite this

The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. / Schnaider, Tamás; Somogyi, János; Csermely, P.; Szamel, Marta.

In: Cell Stress and Chaperones, Vol. 5, No. 1, 01.2000, p. 52-61.

Research output: Contribution to journalArticle

@article{cbb260ecf4e1437f8939f22d0cf567fd,
title = "The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation",
abstract = "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-l 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.",
author = "Tam{\'a}s Schnaider and J{\'a}nos Somogyi and P. Csermely and Marta Szamel",
year = "2000",
month = "1",
language = "English",
volume = "5",
pages = "52--61",
journal = "Cell Stress and Chaperones",
issn = "1355-8145",
publisher = "Springer Netherlands",
number = "1",

}

TY - JOUR

T1 - The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation

AU - Schnaider, Tamás

AU - Somogyi, János

AU - Csermely, P.

AU - Szamel, Marta

PY - 2000/1

Y1 - 2000/1

N2 - 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-l 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.

AB - 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-l 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.

UR - http://www.scopus.com/inward/record.url?scp=0033973837&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033973837&partnerID=8YFLogxK

M3 - Article

C2 - 10701840

AN - SCOPUS:0033973837

VL - 5

SP - 52

EP - 61

JO - Cell Stress and Chaperones

JF - Cell Stress and Chaperones

SN - 1355-8145

IS - 1

ER -