Phosphorylation of NF-kappaB1/p105 by oncoprotein kinase Tpl2: implications for a novel mechanism of Tpl2 regulation.
The oncoprotein kinase Tpl2 plays an essential role in macrophage activation by the bacterial component lipopolysaccharide (LPS). In response to LPS stimulation, Tpl2 phosphorylates a downstream kinase, MEK1, leading to the activation of ERK signaling pathway. Recent studies demonstrate that the NF-kappaB1 precursor protein p105 functions as an inhibitor of Tpl2 and that the LPS-stimulated Tpl2 activation requires p105 degradation. However, how p105 inhibits the signaling function of Tpl2 is not completely understood. We show here that p105 does not inhibit the intrinsic kinase activity of Tpl2. When complexed with p105, Tpl2 remains catalytically active and uses p105 as a substrate. However, the p105-bound Tpl2 is unable to phosphorylate its physiological target, MEK1. These findings suggest that p105 functions as a competitive inhibitor of Tpl2 that blocks its access by MEK1.
Babu
Geetha R
GR
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033, USA.
Jin
Wei
W
Norman
Lourdes
L
Waterfield
Michael
M
Chang
Mikyoung
M
Wu
Xuefeng
X
Zhang
Minying
M
Sun
Shao-Cong
SC
D000595:Amino Acid Sequence; D000818:Animals; D001345:Autoradiography; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D020672:I-kappa B Proteins; D007527:Isoenzymes; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse