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

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, Jonathan D. Ashwell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2174-2179
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number9
DOIs
StatePublished - Feb 27 2018

Keywords

  • Immune synapse
  • MAP kinase
  • Signal transduction
  • T cell antigen receptor

ASJC Scopus subject areas

  • General

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