Abstract
The mammalian target of rapamycin (mTOR) is an evolutionarily conserved kinase which plays a role in integrating environmental cues. mTOR signals via two complexes: TORC1, which contains the Regulatory Associated Protein of TOR (raptor), and TORC2, which contains the Rapamycin-insensitive Companion of TOR (rictor). The immunosuppressive/anti-cancer agent rapamycin inhibits TORC1 function by disrupting the mTOR-raptor interaction. In an effort to understand the downstream consequences of TORC1 activation in T cells we performed a proteomic analysis of raptor binding proteins. Using this approach we have identified Hsp90 as an activation-induced binding partner of raptor in T cells. Pharmacologic inhibition of Hsp90 leads to a decrease in raptor expression and TORC1 activity. Furthermore, full T cell activation during Hsp90 blockade leads to T cell tolerance in the form of anergy. Overall, our findings suggest that Hsp90 inhibitors might represent a novel means of promoting T cell tolerance.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Carrier Proteins / metabolism*
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Chromatography, High Pressure Liquid
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Electrophoresis, Polyacrylamide Gel
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HSP90 Heat-Shock Proteins / metabolism*
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Immunoblotting
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Immunosuppressive Agents / pharmacology
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Lymphocyte Activation / drug effects
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Mass Spectrometry
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Mice
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Protein Binding
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Protein Kinases / metabolism*
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Proteome / isolation & purification
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Proteome / metabolism
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Proteomics / methods
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Regulatory-Associated Protein of mTOR
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Signal Transduction*
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Sirolimus / pharmacology
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism*
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TOR Serine-Threonine Kinases
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Crtc1 protein, mouse
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HSP90 Heat-Shock Proteins
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Immunosuppressive Agents
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Proteome
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Regulatory-Associated Protein of mTOR
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Rptor protein, mouse
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Transcription Factors
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Protein Kinases
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Sirolimus