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

Abduelhakem Ben-Addi, Agnes Mambole-Dema, Christine Brender, Stephen R Martin, Julia Janzen, Sven Kjaer, Stephen J Smerdon, Steven C Ley

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)E2394-E2403
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number23
Early online date27 May 2014
Publication statusPublished - 10 Jun 2014


  • 14-3-3 Proteins/genetics
  • Animals
  • Cells, Cultured
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase/metabolism
  • Immunoblotting
  • Lipopolysaccharides/pharmacology
  • MAP Kinase Kinase Kinases/genetics
  • MAP Kinase Signaling System
  • Macrophages/drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1/metabolism
  • Mitogen-Activated Protein Kinase 3/metabolism
  • NF-kappa B p50 Subunit/genetics
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins/genetics
  • Serine/genetics
  • Toll-Like Receptors/metabolism
  • Tumor Necrosis Factor-alpha/metabolism
  • inflammation
  • NF-κB
  • MAP3K8


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