Identification and characterization of an IkappaB kinase.
Activation of the transcription factor NF-kappaB by tumor necrosis factor (TNF) and interleukin-1 (IL-1) requires the NF-kappaB-inducing kinase (NIK). In a yeast two-hybrid screen for NIK-interacting proteins, we have identified a protein kinase previously known as CHUK. Overexpression of CHUK activates a NF-kappaB-dependent reporter gene. A catalytically inactive mutant of CHUK is a dominant-negative inhibitor of TNF-, IL-1-, TRAF-, and NIK-induced NF-kappaB activation. CHUK associates with the NF-kappaB inhibitory protein, IkappaB-alpha, in mammalian cells. CHUK specifically phosphorylates IkappaB-alpha on both serine 32 and serine 36, modifications that are required for targeted degradation of IkappaB-alpha via the ubiquitin-proteasome pathway. This phosphorylation of IkappaB-alpha is greatly enhanced by NIK costimulation. Thus, CHUK is a NIK-activated IkappaB-alpha kinase that links TNF- and IL-1-induced kinase cascades to NF-kappaB activation.
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Tularik, Inc., South San Francisco, California 94080, USA.
Song
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Gao
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Goeddel
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Cao
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Rothe
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D003001:Cloning, Molecular; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D051841:Transcription Factor RelB; D014157:Transcription Factors; D015003:Yeasts / Q000235:genetics; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051841:Transcription Factor RelB; D014157:Transcription Factors; D000097782:NF-kappaB-Inducing Kinase; C497593:RELB protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human