The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway
| Autor: | Arthur R. Salomon, Aaron J. Cantor, Qinqin Ji, Debra A. Cheng, John Kuriyan, Theresa A. Kadlecek, Hanna Sjolin-Goodfellow, Arup K. Chakraborty, Arthur Weiss, Maria P. Frushicheva |
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| Přispěvatelé: | Institute for Medical Engineering and 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. |
| Rok vydání: | 2015 |
| Předmět: |
Phosphopeptides
Proteomics Biochemistry Mass Spectrometry Jurkat Cells Models Immunoreceptor tyrosine-based activation motif Receptors 2.1 Biological and endogenous factors Aetiology Phosphorylation Feedback Physiological Immunity Cellular ZAP-70 Protein-Tyrosine Kinase biology ZAP70 CD28 hemic and immune systems Cell biology medicine.anatomical_structure Immunological Antigen Signal Transduction CD3 T cell Physiological 1.1 Normal biological development and functioning Receptors Antigen T-Cell chemical and pharmacologic phenomena Article Catalysis Feedback Underpinning research Clinical Research medicine Humans Inflammatory and Immune System Kinase activity Protein kinase A Molecular Biology T-cell receptor Models Immunological Immunity Cell Biology T-Cell Lymphocyte Specific Protein Tyrosine Kinase p56(lck) biology.protein Cellular Biochemistry and Cell Biology |
| Zdroj: | Science signaling, vol 8, iss 377 Sjölin-Goodfellow, H; Frushicheva, MP; Ji, Q; Cheng, DA; Kadlecek, TA; Cantor, AJ; et al.(2015). The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway. Science Signaling, 8(377), ra49. doi: 10.1126/scisignal.2005596. UCSF: Retrieved from: http://www.escholarship.org/uc/item/9rz7n24s PMC |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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