The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway
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–associa...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2016
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| Online Access: | http://hdl.handle.net/1721.1/101165 https://orcid.org/0000-0002-7487-8858 https://orcid.org/0000-0003-1268-9602 |
| _version_ | 1826197796470915072 |
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| author | 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 |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science 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 |
| author_sort | Sjolin-Goodfellow, Hanna |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:53:17Z |
| format | Article |
| id | mit-1721.1/101165 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:53:17Z |
| publishDate | 2016 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1011652022-09-27T15:47:14Z The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway 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 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 Frushicheva, Maria P. Chakraborty, Arup K. 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. National Institutes of Health (U.S.) (Grant P01 AI91580) National Institutes of Health (U.S.) (Grant R01 AI083636) Cancer Research Institute (New York, N.Y.) (Irvington Fellowship) 2016-02-11T03:50:52Z 2016-02-11T03:50:52Z 2015-05 2014-06 Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/101165 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. https://orcid.org/0000-0002-7487-8858 https://orcid.org/0000-0003-1268-9602 en_US http://dx.doi.org/10.1126/scisignal.2005596 Science Signaling Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | 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 The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway |
| title | The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway |
| title_full | The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway |
| title_fullStr | The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway |
| title_full_unstemmed | The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway |
| title_short | The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway |
| title_sort | catalytic activity of the kinase zap 70 mediates basal signaling and negative feedback of the t cell receptor pathway |
| url | http://hdl.handle.net/1721.1/101165 https://orcid.org/0000-0002-7487-8858 https://orcid.org/0000-0003-1268-9602 |
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