Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine.
Protein kinases activated by dual phosphorylation on Tyr and Thr (MAP kinases) can be grouped into two major classes: ERK and JNK. The ERK group regulates multiple targets in response to growth factors via a Ras-dependent mechanism. In contrast, JNK activates the transcription factor c-Jun in response to pro-inflammatory cytokines and exposure of cells to several forms of environmental stress. Recently, a novel mammalian protein kinase (p38) that shares sequence similarity with mitogen-activated protein (MAP) kinases was identified. Here, we demonstrate that p38, like JNK, is activated by treatment of cells with pro-inflammatory cytokines and environmental stress. The mechanism of p38 activation is mediated by dual phosphorylation on Thr-180 and Tyr-182. Immunofluorescence microscopy demonstrated that p38 MAP kinase is present in both the nucleus and cytoplasm of activated cells. Together, these data establish that p38 is a member of the mammalian MAP kinase group.
Raingeaud
J
J
Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester 01605, USA.
Gupta
S
S
Rogers
J S
JS
Dickens
M
M
Han
J
J
Ulevitch
R J
RJ
Davis
R J
RJ
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008970:Molecular Weight; D009994:Osmolar Concentration; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D019000:Phosphotyrosine; D011994:Recombinant Proteins / Q000378:metabolism; D017384:Sequence Deletion; D013312:Stress, Physiological; D013347:Subcellular Fractions / Q000201:enzymology; D013379:Substrate Specificity; D013912:Threonine; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D007375:Interleukin-1; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D010769:Phosphothreonine; D019000:Phosphotyrosine; D013912:Threonine; D014443:Tyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases