AuthorsBrancho, Deborah Marie
Flavell, Richard A.
Davis, Roger J.
Document TypeJournal Article
KeywordsAnimals; Cells, Cultured; Enzyme Activation; Fibroblasts; Gene Expression Regulation; *MAP Kinase Signaling System; Male; Mice; Mice, Knockout; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; effects; Mutation; Protein Isoforms; Trans-Activators; Tumor Necrosis Factor-alpha; Ultraviolet Rays; p38 Mitogen-Activated Protein Kinases
Medicine and Health Sciences
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AbstractThe 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.
SourceGenes Dev. 2003 Aug 15;17(16):1969-78. Epub 2003 Jul 31. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32703
Related ResourcesLink to article in PubMed
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A mammalian scaffold complex that selectively mediates MAP kinase activationWhitmarsh, Alan J.; Cavanagh, Julie; Tournier, Cathy; Yasuda, Jun; Davis, Roger J. (1998-09-11)The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by the exposure of cells to multiple forms of stress. A putative scaffold protein was identified that interacts with multiple components of the JNK signaling pathway, including the mixed-lineage group of MAP kinase kinase kinases (MLK), the MAP kinase kinase MKK7, and the MAP kinase JNK. This scaffold protein selectively enhanced JNK activation by the MLK signaling pathway. These data establish that a mammalian scaffold protein can mediate activation of a MAP kinase signaling pathway.
Molecular determinants that mediate selective activation of p38 MAP kinase isoformsEnslen, Herve; Brancho, Deborah Marie; Davis, Roger J. (2000-03-16)The p38 mitogen-activated protein kinase (MAPK) group is represented by four isoforms in mammals (p38alpha, p38beta2, p38gamma and p38delta). These p38 MAPK isoforms appear to mediate distinct functions in vivo due, in part, to differences in substrate phosphorylation by individual p38 MAPKs and also to selective activation by MAPK kinases (MAPKKs). Here we report the identification of two factors that contribute to the specificity of p38 MAPK activation. One mechanism of specificity is the selective formation of functional complexes between MAPKK and different p38 MAPKs. The formation of these complexes requires the presence of a MAPK docking site in the N-terminus of the MAPKK. The second mechanism that confers signaling specificity is the selective recognition of the activation loop (T-loop) of p38 MAPK isoforms. Together, these processes provide a mechanism that enables the selective activation of p38 MAPK in response to activated MAPKK.
Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6Enslen, Herve; Raingeaud, Joel; Davis, Roger J. (1998-01-27)The cellular response to treatment with proinflammatory cytokines or exposure to environmental stress is mediated, in part, by the p38 group of mitogen-activated protein (MAP) kinases. We report the molecular cloning of a novel isoform of p38 MAP kinase, p38 beta 2. This p38 MAP kinase, like p38 alpha, is inhibited by the pyridinyl imidazole drug SB203580. The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms, while MKK3 activates only p38 alpha and p38 gamma MAP kinase isoforms. The MKK3 and MKK6 signal transduction pathways are therefore coupled to distinct, but overlapping, groups of p38 MAP kinases.