Tyrosines 113, 128, and 145 of SLP-76 are required for optimal augmentation of NFAT promoter activity.
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.
Fang
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Graduate Program in Immunology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
Motto
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Ross
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Koretzky
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D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins / Q000502:physiology; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D014157:Transcription Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases