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TRAF-dependent association of protein kinase Tpl2/COT1 (MAP3K8) with CD40

Henry Chan1, John C Reed

  • 1The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Biochemical and Biophysical Research Communications
|January 27, 2005
PubMed

Insights

Mitogen activated protein kinase kinase kinase-8 (MAP3K8), also known as Tpl2/COT1, is recruited to the CD40 receptor complex. Tpl2/COT1 plays a unique role in CD40 signaling, distinct from TNF signaling pathways.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Tumor necrosis factor (TNF)-family receptor CD40 signaling involves TNF receptor-associated factor (TRAF) proteins.
  • TRAF proteins activate protein kinases, leading to Nuclear Factor kappa B (NFkappaB) transcription factor induction.

Purpose of the Study:

  • To investigate the role of MAP3K8 (Tpl2/COT1) in CD40 receptor signaling.
  • To determine if Tpl2/COT1 is recruited to the CD40 complex and its mechanism of action.

Main Methods:

  • Utilized catalytically inactive mutants and knockout fibroblasts to assess Tpl2/COT1 function in CD40 signaling.
  • Employed dominant-negative Tpl2 to map its position within the signaling pathway.
  • Compared CD40 signaling with TNF signaling to highlight pathway specificity.

Main Results:

  • Mitogen activated protein kinase kinase kinase-8 (MAP3K8), Tpl2/COT1, is recruited to the CD40 complex via TRAF-binding sites.
  • Tpl2/COT1 participates in CD40-mediated IkappaB kinase activation and NFkappaB promoter induction, but not TNF signaling.
  • Tpl2 knockout fibroblasts show deficiencies in CD40 but not TNF signaling.
  • Tpl2 functions downstream of TRAFs and upstream of the TAK1/TAB1 complex in the IKK/NFkappaB pathway.

Conclusions:

  • Tpl2/COT1 plays a unique and essential role in CD40 signaling, distinct from its role in TNF signaling.
  • Demonstrates differential utilization of MAP3Ks by CD40 and TNFR1.
  • Highlights the TRAF-dependence of Tpl2 association with the CD40 receptor complex.

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