Abstract
Both NF-kappaB and c-Jun are activated by cytokines such as TNF-alpha and by stresses such as UV irradiation. A key step in the activation of NF-kappaB is the phosphorylation of its inhibitor, IkappaB alpha, by a ubiquitination-inducible multiprotein kinase complex (IkappaB alpha kinase). A central kinase in the c-Jun activation pathway is mitogen-activated protein kinase/ERK kinase kinase-1 (MEKK1). Here, we show that MEKK1 induces the site-specific phosphorylation of IkappaB alpha in vivo and, most strikingly, can directly activate the IkappaB alpha kinase complex in vitro. Thus, MEKK1 is a critical component of both the c-Jun and NF-kappaB stress response pathways. Since the IkappaB alpha kinase complex can be independently activated by ubiquitination or MEKK1-dependent phosphorylation, it may be an integrator of multiple signal transduction pathways leading to the activation of NF-kappaB.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Line
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DNA-Binding Proteins / metabolism
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Enzyme Activation
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Enzyme Induction
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HeLa Cells
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Humans
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I-kappa B Kinase
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I-kappa B Proteins*
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1*
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Mitogen-Activated Protein Kinases*
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Molecular Weight
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / metabolism*
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Transfection
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Tumor Necrosis Factor-alpha / metabolism
Substances
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DNA-Binding Proteins
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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MAP3K1 protein, human