IkappaB kinase is an essential component of the Tpl2 signaling pathway.
IkappaB kinase (IKK), a key regulator of immune and inflammatory responses, is known as an effector kinase mediating activation of the transcription factor NF-kappaB. Whether IKK also participates in other signaling events is not known. Here we show that IKK serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK. Inhibition of IKKbeta in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha. Using IKK-deficient murine fibroblasts, we further demonstrate that IKKbeta, but not IKKalpha, is required for Tpl2 activation. Moreover, this novel function of IKKbeta appears to involve phosphorylation and degradation of the Tpl2 inhibitor NF-kappaB1/p105. These findings suggest that IKKbeta exerts its immune-regulatory functions by targeting different downstream signaling pathways.
Waterfield
Michael
M
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033, USA. sxs70@psu.edu
Jin
Wei
W
Reiley
William
W
Zhang
Minying
M
Sun
Shao-Cong
SC
D000818:Animals; D004789:Enzyme Activation; D020672:I-kappa B Proteins / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases