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NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity.
1Division of Immune Cell Biology, National Institute for Medical Research, London NW7 1AA, United Kingdom.
Molecular and Cellular Biology
|July 2, 2003
Summary
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.