Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway.
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.
Lee
F S
FS
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Hagler
J
J
Chen
Z J
ZJ
Maniatis
T
T
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004790:Enzyme Induction; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases; D008970:Molecular Weight; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human