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Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner

Santasabuj Das1, Jeonghee Cho, Irina Lambertz

  • 1Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA.

The Journal of Biological Chemistry
|April 19, 2005
PubMed

Insights

Tpl2 deficiency impairs signaling pathways in mouse cells, affecting ERK, JNK, and NF-kappaB activation differently depending on the stimulus. This study clarifies Tpl2

Area of Science:

  • Molecular and Cellular Biology
  • Immunology
  • Signal Transduction

Background:

  • Tpl2 (Tumor Progression Loss 2) is a kinase involved in immune cell signaling.
  • Previous studies indicated Tpl2 knockout mice have defects in lipopolysaccharide and death receptor signaling, specifically in ERK activation.

Purpose of the Study:

  • To investigate the role of Tpl2 in mediating signaling pathways, including ERK, JNK, and NF-kappaB, in response to TNF-alpha and IL-1beta.
  • To elucidate the specific mechanisms by which Tpl2 activation influences NF-kappaB transcriptional activity.

Main Methods:

  • Utilized Tpl2 knockout (Tpl2-/-) mouse embryonic fibroblasts (MEFs).
  • Stimulated MEFs with tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta).
  • Analyzed the activation of ERK, JNK, and NF-kappaB signaling pathways.
  • Investigated the interaction of Tpl2 with TRAF2 and RIP1 in TNF-alpha signaling.
  • Assessed NF-kappaB DNA binding and transcriptional activity, including p65 phosphorylation at Ser276.

Main Results:

  • Tpl2-/- MEFs showed defects in ERK, JNK, and NF-kappaB activation upon TNF-alpha stimulation, and only ERK activation defects with IL-1beta.
  • Tpl2 activation by TNF-alpha requires TRAF2 and RIP1 signaling.
  • Activated Tpl2 phosphorylates MKK4/SEK1, upstream of JNK, and enhances NF-kappaB transcriptional activity independently of p50/p65 nuclear translocation.
  • TNF-alpha signaling via Tpl2 promotes p65 phosphorylation at Ser276, enhancing NF-kappaB transcriptional activity without altering DNA binding.

Conclusions:

  • Tpl2 plays a critical role in TNF-alpha-induced JNK and NF-kappaB activation in MEFs.
  • The signaling defects observed in Tpl2-deficient cells are cell-type and stimulus-specific.
  • Tpl2 modulates NF-kappaB transcriptional activity through p65 phosphorylation, highlighting a distinct regulatory mechanism.

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