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

Nat Immunol. 2005 Apr;6(4):390-5. doi: 10.1038/ni1177. Epub 2005 Feb 27.


Signaling-responsive MAP kinases (MAPKs) are key in mediating immune responses and are activated through the phosphorylation of a Thr-X-Tyr motif by upstream MAPK kinases. Here we show that T cells stimulated through the T cell receptor (TCR) used an alternative mechanism in which p38 was phosphorylated on Tyr323 and subsequently autophosphorylated residues Thr180 and Tyr182. This required the TCR-proximal tyrosine kinase Zap70 but not the adaptor protein LAT, which was required for activation of extracellular signal-regulated protein kinase MAPKs. TCR activation of p38 lacking Tyr323 was diminished, and blocking of p38 activity prevented p38 dual phosphorylation in normal T cells but not in B cells. Thus, phosphorylation of Tyr323 dependent on the tyrosine kinase Lck and mediated by Zap70 serves as an important mechanism for TCR activation of p38 in T cells.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / immunology*
  • Enzyme Activation
  • Humans
  • Immunoblotting
  • Jurkat Cells
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / immunology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • MAP Kinase Signaling System / immunology*
  • Mice
  • Peptide Mapping
  • Phosphorylation
  • Protein-Tyrosine Kinases / immunology
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, T-Cell / immunology*
  • ZAP-70 Protein-Tyrosine Kinase
  • p38 Mitogen-Activated Protein Kinases / immunology*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Receptors, Antigen, T-Cell
  • Protein-Tyrosine Kinases
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human
  • Zap70 protein, mouse
  • p38 Mitogen-Activated Protein Kinases