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Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing

Eugene Varfolomeev1, Heather Maecker, Darcie Sharp

  • 1Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.

The Journal of Biological Chemistry
|October 18, 2005
PubMed

Insights

Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) activates kinase pathways via a secondary signaling complex, distinct from its cell death pathway. This mechanism enhances immune responses and potentially aids in clearing apoptotic cells.

Area of Science:

  • Cellular signaling pathways
  • Immunology
  • Apoptosis research

Background:

  • Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) primarily induces apoptosis via caspases.
  • Tumor necrosis factor (TNF) activates gene transcription through inhibitor of kappaB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) pathways.
  • The mechanisms by which Apo2L/TRAIL stimulates these kinases and its relation to apoptosis remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying Apo2L/TRAIL-mediated kinase pathway activation.
  • To investigate the role of secondary signaling complexes in Apo2L/TRAIL signaling.
  • To understand the functional consequences of Apo2L/TRAIL-induced kinase activation.

Main Methods:

  • Analysis of primary and secondary signaling complex formation after Apo2L/TRAIL stimulation.
  • Investigating the requirement of specific proteins (FADD, caspase-8, RIP1, TRAF2, NEMO) for kinase activation.
  • Measuring the secretion of chemokines (interleukin-8, monocyte chemoattractant protein-1) and assessing macrophage migration.

Main Results:

  • Apo2L/TRAIL induces a secondary signaling complex containing FADD, caspase-8, RIP1, TRAF2, and NEMO/IKKgamma, following primary death-inducing signaling complex (DISC) assembly.
  • Secondary complex formation and subsequent activation of JNK, p38, and IKK pathways are dependent on specific components like FADD, caspase-8, RIP1, TRAF2, and NEMO.
  • Apo2L/TRAIL stimulation led to the secretion of IL-8 and MCP-1, enhancing macrophage migration.

Conclusions:

  • Apo2L/TRAIL utilizes a distinct secondary signaling complex to activate kinase pathways, sharing components with TNF signaling.
  • This kinase activation by Apo2L/TRAIL contributes to immune cell recruitment.
  • Kinase activation by Apo2L/TRAIL may facilitate the clearance of apoptotic cells through enhanced phagocytosis.

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