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

ABSTRACT: 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.

SUBMITTER: Giardino Torchia ML 

PROVIDER: S-EPMC5834678 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP-70<sup>T293</sup> and destabilization of the signalosome.

Giardino Torchia Maria Letizia ML   Dutta Debjani D   Mittelstadt Paul R PR   Guha June J   Gaida Matthias M MM   Fish Kamonwan K   Barr Valarie A VA   Akpan Itoro O IO   Samelson Lawrence E LE   Tagad Harichandra D HD   Debnath Subrata S   Miller Jenkins Lisa M LM   Appella Ettore E   Ashwell Jonathan D JD  

Proceedings of the National Academy of Sciences of the United States of America 20180212 9

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-70<sup>T293A</sup>) had enhanced TCR proximal signaling and increased effector responses. Lack of ZAP-70<sup>T293  ...[more]

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