Abstract
Mice homozygous for a single tyrosine mutation in LAT (linker for activation of T cells) exhibited an early block in T cell maturation but later developed a polyclonal lymphoproliferative disorder and signs of autoimmune disease. T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma1 (PLC-gamma1) and of nuclear factor of activated T cells, calcium influx, interleukin-2 production, and cell death were reduced or abrogated in T cells from LAT mutant mice. In contrast, TCR-induced Erk activation was intact. These results identify a critical role for integrated PLC-gamma1 and Ras-Erk signaling through LAT in T cell development and homeostasis.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Antibodies, Antinuclear / blood
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Autoimmune Diseases / immunology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / physiology
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CD5 Antigens / analysis
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Calcium / metabolism
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Calcium Signaling
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Carrier Proteins / genetics*
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Carrier Proteins / physiology*
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Cell Division
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Interleukin-2 / biosynthesis
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Isoenzymes / metabolism*
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Lymphocyte Activation
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Lymphoproliferative Disorders / etiology*
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Lymphoproliferative Disorders / immunology
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Lymphoproliferative Disorders / pathology
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MAP Kinase Signaling System
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Membrane Proteins*
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases / metabolism
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Phenotype
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Phospholipase C gamma
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Phosphoproteins / genetics*
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Phosphoproteins / physiology*
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Phosphorylation
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Point Mutation*
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / physiology
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T-Lymphocytes / immunology*
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T-Lymphocytes / physiology
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / pathology
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Transcription Factors / metabolism
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Type C Phospholipases / metabolism*
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ras Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Antinuclear
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CD5 Antigens
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Carrier Proteins
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Interleukin-2
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Isoenzymes
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Lat protein, mouse
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Membrane Proteins
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Phosphoproteins
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Receptors, Antigen, T-Cell
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Transcription Factors
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Mitogen-Activated Protein Kinases
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Type C Phospholipases
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Phospholipase C gamma
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ras Proteins
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Calcium