TY - JOUR
T1 - Intensity and duration of TCR signaling is limited by p38 phosphorylation of ZAP-70T293 and destabilization of the signalosome
AU - Torchia, Maria Letizia Giardino
AU - Dutta, Debjani
AU - Mittelstadt, Paul R.
AU - Guha, June
AU - Gaida, Matthias M.
AU - Fish, Kamonwan
AU - Barr, Valarie A.
AU - Akpan, Itoro O.
AU - Samelson, Lawrence E.
AU - Tagad, Harichandra D.
AU - Debnath, Subrata
AU - Jenkins, Lisa M.Miller
AU - Appella, Ettore
AU - Ashwell, Jonathan D.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Bei Dong for expert technical assistance and David Venson [National Cancer Institute (NCI)] for help with statistical analyses. This work was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH. M.M.G. was supported by the German Research Foundation (DFG, GA 1818/2-1).
Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/2/27
Y1 - 2018/2/27
N2 - 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.
AB - 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.
KW - Immune synapse
KW - MAP kinase
KW - Signal transduction
KW - T cell antigen receptor
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U2 - 10.1073/pnas.1713301115
DO - 10.1073/pnas.1713301115
M3 - Article
C2 - 29440413
AN - SCOPUS:85042679730
SN - 0027-8424
VL - 115
SP - 2174
EP - 2179
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -