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

S Beinke1, J Deka, V Lang

  • 1Division of Immune Cell Biology, National Institute for Medical Research, London NW7 1AA, United Kingdom.

Molecular and Cellular Biology
|July 2, 2003
PubMed

Insights

NF-kappaB1 p105 negatively regulates TPL-2 (Cot) kinase activity through dual interactions. Deletion of the TPL-2 C terminus disrupts this regulation, contributing to oncogenic activation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncogenesis

Background:

  • The oncogenic potential of MEK kinase TPL-2 (Cot) is activated by C-terminal deletion.
  • The interaction between TPL-2 and NF-kappaB1 p105 is weakened by this mutation, but its role in oncogenicity is unclear.

Purpose of the Study:

  • To investigate the role of NF-kappaB1 p105 in regulating TPL-2 stability and activity.
  • To elucidate the molecular mechanisms underlying the interaction between TPL-2 and NF-kappaB1 p105.

Main Methods:

  • In vitro kinase assays
  • Co-transfection experiments in cells
  • Analysis of protein-protein interactions

Main Results:

  • TPL-2 stability in vivo depends on its association with NF-kappaB1 p105.
  • Two distinct interactions mediate complex formation: TPL-2 C terminus with p105 (residues 497-534) and TPL-2 kinase domain with p105 death domain.
  • p105 binding inhibits TPL-2 MEK kinase activity, an effect augmented by the C-terminal interaction.

Conclusions:

  • NF-kappaB1 p105 acts as a negative regulator of TPL-2 kinase activity.
  • C-terminally truncated TPL-2 is insensitive to p105-mediated inhibition, likely contributing to its oncogenic transformation ability.

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