| First Author | Beinke S | Year | 2003 |
| Journal | Mol Cell Biol | Volume | 23 |
| Issue | 14 | Pages | 4739-52 |
| PubMed ID | 12832462 | Mgi Jnum | J:306773 |
| Mgi Id | MGI:6708637 | Doi | 10.1128/MCB.23.14.4739-4752.2003 |
| Citation | Beinke S, et al. (2003) NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. Mol Cell Biol 23(14):4739-52 |
| abstractText | 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. |
