Reference - Detail
| RRC ID | 67104 |
|---|---|
| Author | Jun JE, Kulhanek KR, Chen H, Chakraborty A, Roose JP. |
| Title | Alternative ZAP70-p38 signals prime a classical p38 pathway through LAT and SOS to support regulatory T cell differentiation. |
| Journal | Sci Signal |
| Abstract |
T cell receptor (TCR) stimulation activates diverse kinase pathways, which include the mitogen-activated protein kinases (MAPKs) ERK and p38, the phosphoinositide 3-kinases (PI3Ks), and the kinase mTOR. Although TCR stimulation activates the p38 pathway through a "classical" MAPK cascade that is mediated by the adaptor protein LAT, it also stimulates an "alternative" pathway in which p38 is activated by the kinase ZAP70. Here, we used dual-parameter, phosphoflow cytometry and in silico computation to investigate how both classical and alternative p38 pathways contribute to T cell activation. We found that basal ZAP70 activation in resting T cell lines reduced the threshold ("primed") TCR-stimulated activation of the classical p38 pathway. Classical p38 signals were reduced after T cell-specific deletion of the guanine nucleotide exchange factors Sos1 and Sos2, which are essential LAT signalosome components. As a consequence of Sos1/2 deficiency, production of the cytokine IL-2 was impaired, differentiation into regulatory T cells was reduced, and the autoimmune disease EAE was exacerbated in mice. These data suggest that the classical and alternative p38 activation pathways exist to generate immune balance. |
| Volume | 12(591) |
| Published | 2019-7-23 |
| DOI | 10.1126/scisignal.aao0736 |
| PII | 12/591/eaao0736 |
| PMID | 31337738 |
| PMC | PMC7340343 |
| MeSH | Animals Cell Differentiation Chickens Encephalomyelitis, Autoimmune, Experimental / metabolism Enzyme Activation Female Flow Cytometry Humans Interleukin-2 / metabolism Jurkat Cells Kinetics Leukocytes, Mononuclear / metabolism Mice Mice, Knockout Protein Binding Receptors, Antigen, T-Cell / metabolism SOS1 Protein / metabolism Son of Sevenless Proteins / metabolism Stochastic Processes T-Lymphocytes / cytology* Th1 Cells / cytology Th2 Cells / cytology ZAP-70 Protein-Tyrosine Kinase / metabolism* p38 Mitogen-Activated Protein Kinases / metabolism* |
| IF | 6.467 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 5 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | Sos1^(-)/Sos2^(-)DT40(RCB1868) |