Abstract
CD3, CD2, and CD28 are functionally distinct receptors on T lymphocytes. Engagement of any of these receptors induces the rapid tyrosine phosphorylation of a shared group of intracellular signaling proteins, including Vav, Cbl, p85 phosphoinositide 3-kinase, and the Src family kinases Lck and Fyn. Ligation of CD3 also induces the tyrosine phosphorylation of HS1, a 75-kDa hematopoietic cell-specific intracellular signaling protein of unknown function. We have examined changes in HS1 phosphorylation after differential stimulation of CD3, CD2, and CD28 to elucidate its role in T cells and to further delineate the signaling pathways recruited by these receptors. Unlike ligation of CD3, stimulation with anti-CD28 mAb or CHO cells expressing the CD28 ligands CD80 or CD86 did not lead to tyrosine phosphorylation of HS1 in Jurkat T cells. Additionally, no tyrosine phosphorylation of HS1 was induced by mitogenic pairs of anti-CD2 mAbs capable of activating the transcription factor NFAT (nuclear factor of activated T cells). Costimulation through CD28 and/or CD2 did not modulate the CD3-dependent phosphorylation of HS1. In vivo studies indicated that CD3-induced HSI phosphorylation was dependent upon both the Src family tyrosine kinase Lck and the tyrosine phosphatase CD45, did not require MEK1 kinase activity, and was regulated by protein kinase C activation. Thus, although CD3, CD28, and CD2 activate many of the same signaling molecules, they differed in their capacity to induce the tyrosine phosphorylation of HSI. Furthermore, activation-dependent tyrosine phosphorylation of HS1 was not required for NFAT transcriptional activation.
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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Animals
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Antibodies, Monoclonal / pharmacology
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Blood Proteins / metabolism*
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CD2 Antigens / physiology*
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CD28 Antigens / physiology*
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CD3 Complex / physiology*
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CHO Cells
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Cell Cycle Proteins*
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Cricetinae
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Cricetulus
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DNA-Binding Proteins / physiology*
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Enzyme Activation
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Humans
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Jurkat Cells
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Leukocyte Common Antigens / physiology
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Lymphocyte Activation*
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases*
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NFATC Transcription Factors
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Nuclear Proteins*
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Phosphorylation
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Protein Kinase C / metabolism
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Protein Processing, Post-Translational*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-vav
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Signal Transduction / physiology*
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T-Lymphocytes / immunology*
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription Factors / physiology*
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Transcription, Genetic
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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Blood Proteins
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CD2 Antigens
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CD28 Antigens
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CD3 Complex
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Cell Cycle Proteins
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DNA-Binding Proteins
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HCLS1 protein, human
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NFATC Transcription Factors
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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Transcription Factors
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VAV1 protein, human
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Protein-Tyrosine Kinases
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Protein Serine-Threonine Kinases
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Protein Kinase C
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Leukocyte Common Antigens
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Tetradecanoylphorbol Acetate