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Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP-70T293 and destabilization of the signalosome

ZAP-70 is a tyrosine kinase that is essential for initiation of T cell antigen receptor (TCR) signaling. We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-...

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Bibliographic Details
Main Authors: Torchia, Maria Letizia Giardino (Author) , Gaida, Matthias (Author)
Format: Article (Journal)
Language:English
Published: February 12, 2018
In: Proceedings of the National Academy of Sciences of the United States of America
Year: 2018, Volume: 115, Issue: 9, Pages: 2174-2179
ISSN:1091-6490
DOI:10.1073/pnas.1713301115
Online Access:Verlag, Volltext: https://doi.org/10.1073/pnas.1713301115
Verlag, Volltext: https://www.pnas.org/content/115/9/2174
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Author Notes:Maria Letizia Giardino Torchia, Debjani Dutta, Paul R. Mittelstadt, June Guha, Matthias M. Gaida, Kamonwan Fish, Valarie A. Barr, Itoro O. Akpan, Lawrence E. Samelson, Harichandra D. Tagad, Subrata Debnath, Lisa M. Miller Jenkins, Ettore Appella, and Jonathan D. Ashwell
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Summary:ZAP-70 is a tyrosine kinase that is essential for initiation of T cell antigen receptor (TCR) signaling. We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. Mutant T cells expressing ZAP-70 with an alanine substitution at this residue (ZAP-70T293A) had enhanced TCR proximal signaling and increased effector responses. Lack of ZAP-70T293 phosphorylation increased association of ZAP-70 with the TCR and prolonged the existence of TCR signaling microclusters. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.
Item Description:Im Titel T293 hochgestellt
Gesehen am 12.08.2019
Physical Description:Online Resource
ISSN:1091-6490
DOI:10.1073/pnas.1713301115

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