title: NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity.
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-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.
authors.affiliation: Division of Immune Cell Biology, National Institute for Medical Research, London NW7 1AA, United Kingdom.
authors.forename: S
authors.initials: S
authors.lastname: Beinke
authors.forename: J
authors.initials: J
authors.lastname: Deka
authors.forename: V
authors.initials: V
authors.lastname: Lang
authors.forename: M P
authors.initials: MP
authors.lastname: Belich
authors.forename: P A
authors.initials: PA
authors.lastname: Walker
authors.forename: S
authors.initials: S
authors.lastname: Howell
authors.forename: S J
authors.initials: SJ
authors.lastname: Smerdon
authors.forename: S J
authors.initials: SJ
authors.lastname: Gamblin
authors.forename: S C
authors.initials: SC
authors.lastname: Ley
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D004795:Enzyme Stability; D048369:MAP Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D010446:Peptide Fragments; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases