Mechanism of p38 MAP kinase activation in vivo

被引:407
作者
Brancho, D
Tanaka, N
Jaeschke, A
Ventura, JJ
Kelkar, N
Tanaka, Y
Kyuuma, M
Takeshita, T
Flavell, RA
Davis, RJ [1 ]
机构
[1] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA
[2] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA
[3] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[4] Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA
[5] Tohoku Univ, Sch Med, Dept Microbiol, Sendai, Miyagi 9808575, Japan
[6] Shinshu Univ, Sch Med, Dept Microbiol, Matsumoto, Nagano 3908621, Japan
关键词
MAP kinase; p38; JNK; MKK3; MKK4; MKK6;
D O I
10.1101/gad.1107303
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 MKK6 are 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.
引用
收藏
页码:1969 / 1978
页数:10
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