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

Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2174-2179. doi: 10.1073/pnas.1713301115. Epub 2018 Feb 12.


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.

Keywords: MAP kinase; T cell antigen receptor; immune synapse; signal transduction.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Gene Expression Regulation
  • Genes, T-Cell Receptor / physiology*
  • Humans
  • Jurkat Cells
  • Phosphorylation
  • Signal Transduction
  • ZAP-70 Protein-Tyrosine Kinase / genetics
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • p38 Mitogen-Activated Protein Kinases