Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases.
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.
Salvador
Jesus M
JM
Gene Response Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mittelstadt
Paul R
PR
Guszczynski
Tad
T
Copeland
Terry D
TD
Yamaguchi
Hiroshi
H
Appella
Ettore
E
Fornace
Albert J
AJ
Ashwell
Jonathan D
JD
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D004789:Enzyme Activation; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D010449:Peptide Mapping; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism
D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases