Mechanism of p38 MAP kinase activation in vivo
- Deborah Brancho1,5,
- Nobuyuki Tanaka2,5,6,
- Anja Jaeschke1,5,
- Juan-Jose Ventura1,5,
- Nyaya Kelkar1,5,
- Yoshinori Tanaka3,
- Masanao Kyuuma4,
- Toshikazu Takeshita4,
- Richard A. Flavell2, and
- Roger J. Davis1,7
- 1 Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
- 2 Howard Hughes Medical Institute and Section of Immunobiology, Yale University Medical School, New Haven, Connecticut 06520, USA
- 3 Department of Microbiology, Tohoku University School of Medicine, Sendai 980-8575, Japan
- 4 Department of Microbiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Abstract
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.
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Footnotes
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Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1107303.
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↵5 These authors contributed equally to this work.
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↵6 Present address: Department of Microbiology and Immunology, Tohoku, University School of Medicine, Sendai 980-8575, Japan.
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↵7 Corresponding author. E-MAIL Roger.Davis{at}umassmed.edu; FAX (508) 856-3210.
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- Accepted June 17, 2003.
- Received April 28, 2003.
- Cold Spring Harbor Laboratory Press
