Molecular determinants that mediate selective activation of p38 MAP kinase isoforms
UMass Chan AffiliationsHoward Hughes Medical Institute, Program in Molecular Medicine
Graduate School of Biomedical Sciences
KeywordsAmino Acid Motifs; Amino Acid Sequence; Amino Acid Substitution; Animals; COS Cells; Calcium-Calmodulin-Dependent Protein; Kinases; Enzyme Activation; Isoenzymes; MAP Kinase Kinase 3; MAP Kinase Kinase 6; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; *Mitogen-Activated Protein Kinases; Molecular Sequence Data; Phosphorylation; Phosphothreonine; Phosphotyrosine; Protein Binding; Protein-Tyrosine Kinases; Recombinant Fusion Proteins; Sequence Alignment; Sequence Deletion; Substrate Specificity; Transfection; p38 Mitogen-Activated Protein Kinases
Medicine and Health Sciences
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AbstractThe 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.
SourceEMBO J. 2000 Mar 15;19(6):1301-11. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/33678
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.
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.
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