NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176.
Activation of the transcription factor NF-kappaB by inflammatory cytokines involves the successive action of NF-kappaB-inducing kinase (NIK) and two IkappaB kinases, IKK-alpha and IKK-beta. Here we show that NIK preferentially phosphorylates IKK-alpha over IKK-beta, leading to the activation of IKK-alpha kinase activity. This phosphorylation of IKK-alpha occurs specifically on Ser-176 in the activation loop between kinase subdomains VII and VIII. A mutant form of IKK-alpha containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-kappaB activation. Conversely, a mutant form of IKK-alpha containing glutamic acid at residue 176 is constitutively active. Thus, the phosphorylation of IKK-alpha on Ser-176 by NIK may be required for cytokine-mediated NF-kappaB activation.
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Tularik, Inc., Two Corporate Drive, South San Francisco, CA 94080, USA.
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D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D000097782:NF-kappaB-Inducing Kinase; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human