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NF-κB1 p105 Negatively Regulates TPL-2 MEK Kinase Activity.
- Source :
-
Molecular & Cellular Biology . Jul2003, Vol. 23 Issue 14, p4739. 14p. 36 Diagrams, 1 Chart, 10 Graphs. - Publication Year :
- 2003
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CARCINOGENS
*GENETIC mutation
Subjects
Details
- Language :
- English
- ISSN :
- 02707306
- Volume :
- 23
- Issue :
- 14
- Database :
- Academic Search Index
- Journal :
- Molecular & Cellular Biology
- Publication Type :
- Academic Journal
- Accession number :
- 10254492
- Full Text :
- https://doi.org/10.1128/MCB.23.14.4739-4752.2003