IkappaB kinase alpha (IKKalpha) regulation of IKKbeta kinase activity.
Two related kinases, IkappaB kinase alpha (IKKalpha) and IKKbeta, phosphorylate the IkappaB proteins, leading to their degradation and the subsequent activation of gene expression by NF-kappaB. IKKbeta has a much higher level of kinase activity for the IkappaB proteins than does IKKalpha and is more critical than IKKalpha in modulating tumor necrosis factor alpha activation of the NF-kappaB pathway. These results indicate an important role for IKKbeta in activating the NF-kappaB pathway but leave open the question of the role of IKKalpha in regulating this pathway. In the current study, we demonstrate that IKKalpha directly phosphorylates IKKbeta. Moreover, IKKalpha either directly or indirectly enhances IKKbeta kinase activity for IkappaBalpha. Finally, transfection studies to analyze NF-kappaB-directed gene expression suggest that IKKalpha is upstream of IKKbeta in activating the NF-kappaB pathway. These results indicate that IKKalpha, in addition to its previously described ability to phosphorylate IkappaBalpha, can increase the ability of IKKbeta to phosphorylate IkappaBalpha.
Yamamoto
Y
Y
Division of Hematology-Oncology, Department of Medicine, Harold Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8594, USA.
Yin
M J
MJ
Gaynor
R B
RB
D004789:Enzyme Activation; D051550:I-kappa B Kinase; D007527:Isoenzymes / Q000378:metabolism; D008970:Molecular Weight; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007527:Isoenzymes; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase