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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases

Jesus M Salvador1, Paul R Mittelstadt, Tad Guszczynski

  • 1Gene Response Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Nature Immunology
|March 1, 2005
PubMed

Insights

T cells use a novel pathway for immune signaling, where p38 mitogen-activated protein kinases (MAPKs) are activated by phosphorylation at Tyr323, a key step in T cell receptor (TCR) signaling.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Mitogen-activated protein kinases (MAPKs) are crucial for immune responses.
  • MAPKs are typically activated by phosphorylation of a Thr-X-Tyr motif by upstream kinases.
  • The T cell receptor (TCR) pathway is central to adaptive immunity.

Purpose of the Study:

  • To elucidate the specific mechanism of p38 MAPK activation in T cells upon TCR stimulation.
  • To identify the key molecules and phosphorylation events involved in this alternative activation pathway.

Main Methods:

  • Investigated p38 MAPK phosphorylation sites (Tyr323, Thr180, Tyr182) in T cells stimulated via TCR.
  • Utilized genetic manipulation, including Zap70 and LAT-deficient T cells.
  • Employed kinase inhibitors to block p38 activity.

Main Results:

  • TCR stimulation activates p38 via phosphorylation at Tyr323, followed by autophosphorylation at Thr180 and Tyr182.
  • This pathway requires the tyrosine kinase Zap70 but not the adaptor protein LAT.
  • TCR activation of p38 is diminished in cells lacking Tyr323, and p38 activity is essential for its dual phosphorylation in T cells.

Conclusions:

  • Phosphorylation of Tyr323, dependent on Lck and mediated by Zap70, is a critical mechanism for TCR-induced p38 activation in T cells.
  • This represents an alternative pathway distinct from the canonical MAPK activation motif.
  • Understanding this pathway offers insights into T cell immune regulation.

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