Article: article from journal or magazin.
NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity.
Molecular and Cellular Biology
Publication types: Journal Article
Activation of the oncogenic potential of the MEK kinase TPL-2 (Cot) requires deletion of its C terminus. This mutation also weakens the interaction of TPL-2 with NF-kappaB1 p105 in vitro, although it is unclear whether this is important for the activation of TPL-2 oncogenicity. It is demonstrated here that TPL-2 stability in vivo relies on its high-affinity, stoichiometric association with NF-kappaB1 p105. Formation of this complex occurs as a result of two distinct interactions. The TPL-2 C terminus binds to a region encompassing residues 497 to 534 of p105, whereas the TPL-2 kinase domain interacts with the p105 death domain. Binding to the p105 death domain inhibits TPL-2 MEK kinase activity in vitro, and this inhibition is significantly augmented by concomitant interaction of the TPL-2 C terminus with p105. In cotransfected cells, both interactions are required for inhibition of TPL-2 MEK kinase activity and, consequently, the catalytic activity of a C-terminally truncated oncogenic mutant of TPL-2 is not affected by p105. Thus, in addition to its role as a precursor for p50 and cytoplasmic inhibitor of NF-kappaB, p105 is a negative regulator of TPL-2. Insensitivity of C-terminally truncated TPL-2 to this regulatory mechanism is likely to contribute to its ability to transform cells.
3T3 Cells, Animals, Binding Sites, Enzyme Stability, MAP Kinase Kinase 1, MAP Kinase Kinase Kinases/genetics, MAP Kinase Kinase Kinases/metabolism, Mice, Mitogen-Activated Protein Kinase Kinases/genetics, Mitogen-Activated Protein Kinase Kinases/metabolism, NF-kappa B/genetics, NF-kappa B/metabolism, NF-kappa B p50 Subunit, Peptide Fragments/metabolism, Protein Binding, Protein Precursors/genetics, Protein Precursors/metabolism, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases/genetics, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins/genetics, Proto-Oncogene Proteins/metabolism, Recombinant Proteins/genetics, Recombinant Proteins/metabolism
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