Mechanism of p38 MAP kinase activation in vivo.
The p38 mitogen-activated protein kinase (MAPK) is activated in vitro by three different protein kinases: MKK3, MKK4, and MKK6. To examine the relative roles of these protein kinases in the mechanism of p38 MAP kinase activation in vivo, we examined the effect of disruption of the murine Mkk3, Mkk4, and Mkk6 genes on the p38 MAPK signaling pathway. We show that MKK3 and MKK6are essential for tumor necrosis factor-stimulated p38 MAPK activation. In contrast, ultraviolet radiation-stimulated p38 MAPK activation was mediated by MKK3, MKK4, and MKK6. Loss of p38 MAPK activation in the mutant cells was associated with defects in growth arrest and increased tumorigenesis. These data indicate that p38 MAPK is regulated by the coordinated and selective actions of three different protein kinases in response to cytokines and exposure to environmental stress.
Brancho
Deborah
D
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Tanaka
Nobuyuki
N
Jaeschke
Anja
A
Ventura
Juan-Jose
JJ
Kelkar
Nyaya
N
Tanaka
Yoshinori
Y
Kyuuma
Masanao
M
Takeshita
Toshikazu
T
Flavell
Richard A
RA
Davis
Roger J
RJ
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D009154:Mutation; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases
D020033:Protein Isoforms; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases