The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation.
The CD2 co-receptor expressed on the surface of T lymphocytes is able to stimulate T cell activation, proliferation and cytokine production in the absence of direct engagement of the antigen-specific TCR. Engagement of human CD2 by mitogenic pairs of anti-CD2 mAb induces tyrosine phosphorylation of a number of intracellular proteins ... including a 120 kDa phosphoprotein that we identify as the proto-oncogene c-Cbl. Rapidly tyrosine phosphorylated following stimulation of a number of cell surface receptors, c-Cbl is an adaptor protein that has been shown to associate with a complex of intracellular signaling molecules, and to mediate both positive and negative regulatory effects. Here we show that, like TCR-CD3 stimulation, stimulation of CD2 enhanced the association of c-Cbl with both Crk(L) and the p85 subunit of phosphatidylinositol-3 kinase. Overexpression of wild-type c-Cbl protein inhibited both CD2and CD3-induced NF-AT transcriptional activity, suggesting that CD2 signaling is also negatively regulated by c-Cbl. The inhibitory effect of c-Cbl depended upon its N-terminal phosphotyrosine-binding domain, the domain that has been shown to be required for inhibition of the Syk/ZAP-70 family kinases. In Syk(-) Jurkat T cells stably expressing wild-type ZAP-70, CD2 stimulation induced only a minimal increase in ZAP-70 tyrosine phosphorylation. Nevertheless, ZAP-70 kinase was required for CD2-mediated NF-AT transcriptional activity. Thus, CD2-mediated NF-AT transcriptional activity appears to depend upon ZAP-70/Syk kinases and to be negatively regulated by c-Cbl.
Mesh Terms:
Amino Acid Sequence, Antibodies, Monoclonal, Antigens, CD2, DNA-Binding Proteins, Humans, Jurkat Cells, Lymphocyte Activation, Molecular Sequence Data, NFATC Transcription Factors, Nuclear Proteins, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Signal Transduction, T-Lymphocytes, Transcription Factors, Tyrosine, Ubiquitin-Protein Ligases, ZAP-70 Protein-Tyrosine Kinase, Zinc Fingers
Amino Acid Sequence, Antibodies, Monoclonal, Antigens, CD2, DNA-Binding Proteins, Humans, Jurkat Cells, Lymphocyte Activation, Molecular Sequence Data, NFATC Transcription Factors, Nuclear Proteins, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Signal Transduction, T-Lymphocytes, Transcription Factors, Tyrosine, Ubiquitin-Protein Ligases, ZAP-70 Protein-Tyrosine Kinase, Zinc Fingers
Int. Immunol.
Date: Jan. 01, 2001
PubMed ID: 11133830
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