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Open Access Publications from the University of California

The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway

  • Author(s): Sjölin-Goodfellow, H
  • Frushicheva, MP
  • Ji, Q
  • Cheng, DA
  • Kadlecek, TA
  • Cantor, AJ
  • Kuriyan, J
  • Chakraborty, AK
  • Salomon, AR
  • Weiss, A
  • et al.

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© by the American Association for the Advancement of Science. 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 (z chain-associated protein kinase of 70 kD) are sequentially activated in response to TCR engagement and serve as critical components of the TCRsignalingmachinery that leads to T cell activation.We performed amass 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 z 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 z chains must be phosphorylated to be consistent with the experimental data.

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