A direct interaction between the adaptor protein Cbl-b and the kinase zap-70 induces a positive signal in T cells.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Carrier Proteins, DNA-Binding Proteins, Humans, Jurkat Cells, Kinetics, Lymphocyte Activation, Muromonab-CD3, NFATC Transcription Factors, Nuclear Proteins, Oncogene Protein v-cbl, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Antigen, T-Cell, Recombinant Proteins, Retroviridae Proteins, Oncogenic, Signal Transduction, T-Lymphocytes, Transcription Factors, Transfection, Ubiquitin-Protein Ligases, ZAP-70 Protein-Tyrosine Kinase
Adaptor Proteins, Signal Transducing, Carrier Proteins, DNA-Binding Proteins, Humans, Jurkat Cells, Kinetics, Lymphocyte Activation, Muromonab-CD3, NFATC Transcription Factors, Nuclear Proteins, Oncogene Protein v-cbl, Phosphoproteins, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-cbl, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Antigen, T-Cell, Recombinant Proteins, Retroviridae Proteins, Oncogenic, Signal Transduction, T-Lymphocytes, Transcription Factors, Transfection, Ubiquitin-Protein Ligases, ZAP-70 Protein-Tyrosine Kinase
Curr. Biol.
Date: Feb. 25, 1999
PubMed ID: 10074432
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