Abstract
In the absence of costimulation, T cells activated through their antigen receptor become unresponsive (anergic) and do not transcribe the gene encoding interleukin-2 (IL-2) when restimulated with antigen. Anergic alloantigen-specific human T cells contained phosphorylated Cbl that coimmunoprecipitated with Fyn. The adapter protein CrkL was associated with both phosphorylated Cbl and the guanidine nucleotide-releasing factor C3G, which catalyzes guanosine triphosphate (GTP) exchange on Rap1. Active Rap1 (GTP-bound form) was present in anergic cells. Forced expression of low amounts of Rap1-GTP in Jurkat T cells recapitulated the anergic defect and blocked T cell antigen receptor (TCR)- and CD28-mediated IL-2 gene transcription. Therefore, Rap1 functions as a negative regulator of TCR-mediated IL-2 gene transcription and may be responsible for the specific defect in IL-2 production in T cell anergy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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CD28 Antigens / immunology
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Clonal Anergy*
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GTP-Binding Proteins / metabolism*
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Gene Expression Regulation
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Guanine Nucleotide Exchange Factors
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Guanosine Triphosphate / metabolism
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Humans
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Interleukin-2 / genetics*
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Jurkat Cells
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Nuclear Proteins / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-fyn
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Receptors, Antigen, T-Cell / immunology
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Transcription, Genetic*
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Transfection
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Ubiquitin-Protein Ligases*
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rap GTP-Binding Proteins
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ras Guanine Nucleotide Exchange Factors
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ras Proteins / metabolism
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src Homology Domains
Substances
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Adaptor Proteins, Signal Transducing
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CD28 Antigens
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CRKL protein
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Guanine Nucleotide Exchange Factors
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Interleukin-2
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Nuclear Proteins
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Proteins
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Proto-Oncogene Proteins
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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ras Guanine Nucleotide Exchange Factors
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Guanosine Triphosphate
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Protein-Tyrosine Kinases
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FYN protein, human
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Proto-Oncogene Proteins c-fyn
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GTP-Binding Proteins
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rap GTP-Binding Proteins
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ras Proteins
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CBL protein, human