NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase.
NF-kappaB family of transcription factors plays a pivotal role in regulation of immune and inflammatory responses. NF-kappaB is known to function by binding to the kappaB enhancer and directly activating target gene transcription. Here we demonstrate another function of NF-kappaB, in which the nfkappab1 gene product p105 regulates MAP kinase signaling triggered by the bacterial component lipopolysaccharide. p105 exerts this signaling function by controlling the stability and function of an upstream kinase, Tpl2. In macrophages, Tpl2 forms a stable and inactive complex with p105, and activation of Tpl2 involves its dissociation from p105 and subsequent degradation. Thus, p105 functions as a physiological partner and inhibitor of Tpl2, which provides an example of how a transcription factor component regulates upstream signaling events.
Waterfield
Michael R
MR
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
Zhang
Minying
M
Norman
Lourdes P
LP
Sun
Shao Cong
SC
D000818:Animals; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C489843:Map3k8 protein, mouse