Source:http://linkedlifedata.com/resource/pubmed/id/16849316
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
36
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pubmed:dateCreated |
2006-9-4
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pubmed:abstractText |
The p38alpha MAPK participates in a variety of biological processes. Activation of p38alpha is mediated by phosphorylation on specific regulatory tyrosine and threonine sites, and the three dual kinases, MAPK kinase 3 (MKK3), MKK4, and MKK6, are known to be the upstream activators of p38alpha. In addition to activation by upstream kinases, p38alpha can autoactivate when interacting with transforming growth factor-beta-activated protein kinase 1-binding protein 1 (TAB1). Here we used MKK3 and MKK6 double knock-out (MKK3/6 DKO) and MKK4/7 DKO mouse embryonic fibroblast (MEF) cells to examine activation mechanisms of p38alpha. We confirmed that the MKK3/6 pathway is a primary mechanism for p38alpha phosphorylation in MEF cells, and we also showed the presence of other p38alpha activation pathways. We show that TAB1-mediated p38alpha phosphorylation in MEF cells did not need MKK3/4/6, and it accounted for a small portion of the total p38alpha phosphorylation that was induced by hyperosmolarity and anisomycin. We observed that a portion of peroxynitrite-induced phospho-p38alpha is associated with an approximately 85-kDa disulfide complex in wild-type MEF cells. Peroxynitrite-induced phosphorylation of p38alpha in the approximately 85-kDa complex is independent from MKK3/6 because only phospho-p38alpha not associated with the disulfide complex was diminished in MKK3/6 DKO cells. In addition, our data suggest interference among different pathways because TAB1 had an inhibitory effect on p38alpha phosphorylation in the peroxynitrite-induced approximately 85-kDa complex. Mutagenesis analysis of the cysteines in p38alpha revealed that no disulfide bond forms between p38alpha and other proteins in the approximately 85-kDa complex, suggesting it is a p38alpha binding partner(s) that forms disulfide bonds, which enable it to bind to p38alpha. Therefore, multiple mechanisms of p38alpha activation exist that can influence each other, be simultaneously activated by a given stimulus, and/or be selectively used by different stimuli in a cell type-specific manner.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Disulfides,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 4,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 6,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 7,
http://linkedlifedata.com/resource/pubmed/chemical/Peroxynitrous Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/SB 203580,
http://linkedlifedata.com/resource/pubmed/chemical/TAB1 protein, MAPKKK activator...,
http://linkedlifedata.com/resource/pubmed/chemical/p38 Mitogen-Activated Protein...
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
8
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pubmed:volume |
281
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
26225-34
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16849316-Animals,
pubmed-meshheading:16849316-Cells, Cultured,
pubmed-meshheading:16849316-Disulfides,
pubmed-meshheading:16849316-Enzyme Activation,
pubmed-meshheading:16849316-Fibroblasts,
pubmed-meshheading:16849316-Imidazoles,
pubmed-meshheading:16849316-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:16849316-Isoenzymes,
pubmed-meshheading:16849316-MAP Kinase Kinase 3,
pubmed-meshheading:16849316-MAP Kinase Kinase 4,
pubmed-meshheading:16849316-MAP Kinase Kinase 6,
pubmed-meshheading:16849316-MAP Kinase Kinase 7,
pubmed-meshheading:16849316-MAP Kinase Signaling System,
pubmed-meshheading:16849316-Mice,
pubmed-meshheading:16849316-Mice, Knockout,
pubmed-meshheading:16849316-Mutagenesis, Site-Directed,
pubmed-meshheading:16849316-Peroxynitrous Acid,
pubmed-meshheading:16849316-Phosphorylation,
pubmed-meshheading:16849316-Pyridines,
pubmed-meshheading:16849316-RNA Interference,
pubmed-meshheading:16849316-p38 Mitogen-Activated Protein Kinases
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pubmed:year |
2006
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pubmed:articleTitle |
Multiple activation mechanisms of p38alpha mitogen-activated protein kinase.
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pubmed:affiliation |
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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