NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity

Mol Cell Biol. 2003 Jul;23(14):4739-52. doi: 10.1128/MCB.23.14.4739-4752.2003.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Peptide Fragments
  • Protein Precursors
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases