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NF-κB1 p105 Negatively Regulates TPL-2 MEK Kinase Activity

机译：NF-κB1p105负调节TPL-2 MEK激酶活性

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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-κB1 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-κB1 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-κB, 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.
机译：MEK激酶TPL-2（Cot）的致癌潜力的激活需要删除其C末端。尽管尚不清楚这对于激活TPL-2致癌性是否重要，但该突变还减弱了TPL-2与NF-κB1p105的相互作用。在此证明，TPL-2在体内的稳定性取决于其与NF-κB1p105的高亲和力，化学计量的关联。这种复合物的形成是由于两种不同相互作用的结果。 TPL-2 C末端结合一个包含p105残基497至534的区域，而TPL-2激酶域与p105死亡域相互作用。与p105死亡结构域的结合在体外可抑制TPL-2 MEK激酶的活性，而TPL-2 C末端与p105的相互作用则大大增强了这种抑制作用。在共转染的细胞中，两种相互作用都是抑制TPL-2 MEK激酶活性所必需的，因此，TPL-2的C端截短的致癌突变体的催化活性不受p105的影响。因此，除了它作为p50的前体和NF-κB的胞质抑制剂的作用外，p105还是TPL-2的负调节剂。 C末端截短的TPL-2对这种调节机制的不敏感性可能有助于其转化细胞的能力。

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