The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway
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Chakraborty_The catalytic activity.pdf
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Author(s)
Sjolin-Goodfellow, Hanna
Frushicheva, Maria P.
Ji, Qinqin
Cheng, Debra A.
Kadlecek, Theresa A.
Cantor, Aaron J.
Kuriyan, John
Salomon, Arthur R.
Weiss, Arthur
Chakraborty, Arup K
Date Issued
May 2015
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Sjolin-Goodfellow, H., M. P. Frushicheva, Q. Ji, D. A. Cheng, T. A. Kadlecek, A. J. Cantor, J. Kuriyan, A. K. Chakraborty, A. R. Salomon, and A. Weiss. “The Catalytic Activity of the Kinase ZAP-70 Mediates Basal Signaling and Negative Feedback of the T Cell Receptor Pathway.” Science Signaling 8, no. 377 (May 19, 2015): ra49–ra49.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Physics
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DOI of Published Version
https://doi.org/10.1126/scisignal.2005596
