Abstract
CTLA-4 is a negative regulator of T cell responses. Sequence analysis of this molecule reveals the presence of two cytoplasmic tyrosine residues at positions 165 and 182 that are potential Src homology (SH)-2 domain binding sites. The role of phosphorylation of these residues in CTLA-4-mediated signaling is unknown. Here, we show that sole TCR ligation induces zeta-associated protein (ZAP)-70-dependent tyrosine phosphorylation of CTLA-4 that is important for cell surface retention of this molecule. However, CTLA-4 tyrosine phosphorylation is not required for down-regulation of T cell activation following CD3-CTLA-4 coengagement. Specifically, inhibition of extracellular signal-regulated kinase (ERK) activation and of IL-2 production by CTLA-4-mediated signaling occurs in T cells expressing mutant CTLA-4 molecules lacking the cytoplasmic tyrosine residues, and in lck-deficient or ZAP-70-deficient T cells. Therefore, CTLA-4 function involves interplay between two different levels of regulation: phosphotyrosine-dependent cell surface retention and phosphotyrosine-independent association with signaling molecules.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abatacept
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Antigens, CD
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Antigens, Differentiation / biosynthesis
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Antigens, Differentiation / genetics
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Antigens, Differentiation / metabolism*
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Antigens, Differentiation / physiology*
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CD3 Complex / immunology
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CD3 Complex / metabolism
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CTLA-4 Antigen
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cytoplasm / immunology
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Cytoplasm / metabolism
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Enzyme Activation / immunology
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Humans
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Immunoconjugates*
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Immunosuppressive Agents / metabolism*
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Jurkat Cells
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Ligands
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutagenesis, Site-Directed
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Phosphorylation
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Protein-Tyrosine Kinases / physiology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Tyrosine / metabolism*
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Antigens, CD
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Antigens, Differentiation
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CD3 Complex
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CTLA-4 Antigen
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CTLA4 protein, human
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Immunoconjugates
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Immunosuppressive Agents
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Interleukin-2
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Ligands
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Tyrosine
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Abatacept
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Protein-Tyrosine Kinases
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases