Abstract
SLP-76 (SH2 domain leukocyte protein of 76 kDa) is a recently identified substrate of the TCR-stimulated protein tyrosine kinases that functions in the signal transduction cascade linking the TCR with IL-2 gene expression. In this report, we demonstrate that engagement of the TCR results in tyrosine phosphorylation of SLP-76 in its amino-terminal acidic region. Two tyrosines (Y113 and Y128) fall within an identical five amino-acid motif and are shown to be phosphorylated upon TCR ligation. Although mutation of either Y113 and Y128 has a minimal effect on SLP-76 function, mutation of both residues decreases significantly the ability of SLP-76 to promote T cell activation. A third tyrosine within the amino-terminal region (Y145) appears to be the most important for optimal SLP-76 function, as altering it alone to phenylalanine has a potent impact on SLP-76 augmentation of NFAT promoter activity.
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.
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Review
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Leukemic
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Humans
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Interleukin-2 / biosynthesis
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Interleukin-2 / genetics
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Leukemia-Lymphoma, Adult T-Cell / pathology
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Molecular Sequence Data
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NFATC Transcription Factors
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Neoplasm Proteins / physiology
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Nuclear Proteins*
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Phosphoproteins / chemistry*
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Phosphoproteins / pharmacology
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Phosphorylation
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Promoter Regions, Genetic*
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Protein Processing, Post-Translational*
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Protein-Tyrosine Kinases / metabolism*
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Receptors, Antigen, T-Cell / physiology*
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Signal Transduction / physiology*
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Structure-Activity Relationship
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Transcription Factors / metabolism*
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Tumor Cells, Cultured
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Tyrosine / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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DNA-Binding Proteins
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Interleukin-2
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NFATC Transcription Factors
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Neoplasm Proteins
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Nuclear Proteins
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Phosphoproteins
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Receptors, Antigen, T-Cell
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SLP-76 signal Transducing adaptor proteins
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Transcription Factors
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Tyrosine
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Protein-Tyrosine Kinases