Abstract
Engagement of the T-cell receptor (TCR)-CD3 complex induces a rapid increase in the activities of Src-family and Syk/Zap-70-family kinases [1] [2]. These activated kinases then induce the tyrosine phosphorylation of multiple intracellular proteins, eventually leading to T-cell activation. One of the prominent substrates for these kinases is the adaptor protein Cbl [3] and recent studies suggest that Cbl negatively regulates upstream kinases such as Syk and Zap-70 [4] [5]. Cbl-b, a homologue of Cbl, is widely expressed in many tissues and cells including hematopoietic cells [6] [7]. Cbl-b undergoes rapid tyrosine phosphorylation upon stimulation of the TCR and cytokine receptors [8] [9]. The role of Cbl-b is unclear, however. Here, we show that overexpression of Cbl-b in T cells induced the constitutive activation of the transcription factor nuclear factor of activated T cells (NFAT). A loss-of-function mutation in Cbl-b disrupted the interaction between Cbl-b and Zap-70 and nearly completely abrogated the Cbl-b-mediated activation of NFAT. Unlike the proposed role of Cbl as a negative regulator, our results suggest that the Cbl homologue Cbl-b has a positive role in T-cell signaling, most likely via a direct interaction with the upstream kinase Zap-70.
Publication types
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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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Carrier Proteins / metabolism*
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DNA-Binding Proteins / metabolism*
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Humans
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Jurkat Cells
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Kinetics
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Lymphocyte Activation
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Muromonab-CD3 / pharmacology
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NFATC Transcription Factors
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Nuclear Proteins*
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Oncogene Protein v-cbl
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins c-cbl
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Receptor-CD3 Complex, Antigen, T-Cell / physiology*
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Receptors, Antigen, T-Cell / physiology
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Recombinant Proteins / metabolism
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Retroviridae Proteins, Oncogenic / metabolism*
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Signal Transduction*
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T-Lymphocytes / immunology
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T-Lymphocytes / physiology*
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Transcription Factors / metabolism*
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Transfection
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Ubiquitin-Protein Ligases*
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DNA-Binding Proteins
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Muromonab-CD3
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NFATC Transcription Factors
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Nuclear Proteins
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Oncogene Protein v-cbl
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Phosphoproteins
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Receptor-CD3 Complex, Antigen, T-Cell
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Receptors, Antigen, T-Cell
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Recombinant Proteins
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Retroviridae Proteins, Oncogenic
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Transcription Factors
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CBLB protein, human
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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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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human