title: IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases.
abstract: The MEK-1/2 kinase TPL-2 is critical for Toll-like receptor activation of the ERK-1/2 MAP kinase pathway during inflammatory responses, but it can transform cells following C-terminal truncation. IκB kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure. Here, we show that TPL-2 Ser-400 phosphorylation by IKK and TPL-2 Ser-443 autophosphorylation cooperated to trigger TPL-2 association with 14-3-3. Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity, which was essential for TPL-2 activation of ERK-1/2. The binding of 14-3-3 to TPL-2 was also indispensible for lipopolysaccharide-induced production of tumor necrosis factor by macrophages, which is regulated by TPL-2 independently of ERK-1/2 activation. Our data identify a key step in the activation of TPL-2 signaling and provide a mechanistic insight into how C-terminal deletion triggers the oncogenic potential of TPL-2 by rendering its kinase activity independent of 14-3-3 binding.
authors.affiliation: Divisions of Immune Cell Biology.
authors.forename: Abduelhakem
authors.initials: A
authors.lastname: Ben-Addi
authors.affiliation: Divisions of Immune Cell Biology.
authors.forename: Agnes
authors.initials: A
authors.lastname: Mambole-Dema
authors.affiliation: Divisions of Immune Cell Biology.
authors.forename: Christine
authors.initials: C
authors.lastname: Brender
authors.affiliation: Physical Biochemistry.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.affiliation: Divisions of Immune Cell Biology.
authors.forename: Julia
authors.initials: J
authors.lastname: Janzen
authors.affiliation: Protein Purification Facility (PPF), Cancer Research UK, London Research Institute, London WC2A 3PX, United Kingdom.
authors.forename: Sven
authors.initials: S
authors.lastname: Kjaer
authors.affiliation: Molecular Structure, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom; and.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smerdon
authors.affiliation: Divisions of Immune Cell Biology, sley@nimr.mrc.ac.uk.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C073701:Nfkb1 protein, mouse; D012694:Serine; D051550:I-kappa B Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse
keywords: MAP3K8; NF-κB; inflammation