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• W1936156958 abstract "T cell activation by antigens binding to the T cell receptor (TCR) must be properly regulated to ensure normal T cell development and effective immune responses to pathogens and transformed cells while avoiding autoimmunity. The Src family kinase Lck and the Syk family kinase ZAP-70 (ζ chain-associated protein kinase of 70 kD) are sequentially activated in response to TCR engagement and serve as critical components of the TCR signaling machinery that leads to T cell activation. We performed a mass spectrometry-based phosphoproteomic study comparing the quantitative differences in the temporal dynamics of phosphorylation in stimulated and unstimulated T cells with or without inhibition of ZAP-70 catalytic activity. The data indicated that the kinase activity of ZAP-70 stimulates negative feedback pathways that target Lck and thereby modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and ζ chain components of the TCR and of signaling molecules downstream of Lck, including ZAP-70. We developed a computational model that provides a mechanistic explanation for the experimental findings on ITAM phosphorylation in wild-type cells, ZAP-70-deficient cells, and cells with inhibited ZAP-70 catalytic activity. This model incorporated negative feedback regulation of Lck activity by the kinase activity of ZAP-70 and predicted the order in which tyrosines in the ITAMs of TCR ζ chains must be phosphorylated to be consistent with the experimental data." @default.
• W1936156958 created "2016-06-24" @default.
• W1936156958 creator A5023774550 @default.
• W1936156958 creator A5031653676 @default.
• W1936156958 creator A5032097976 @default.
• W1936156958 creator A5038330393 @default.
• W1936156958 creator A5038360612 @default.
• W1936156958 creator A5050836076 @default.
• W1936156958 creator A5052972032 @default.
• W1936156958 creator A5061654582 @default.
• W1936156958 creator A5069337853 @default.
• W1936156958 creator A5086647493 @default.
• W1936156958 date "2015-05-19" @default.
• W1936156958 modified "2023-10-06" @default.
• W1936156958 title "The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway" @default.
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