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Updated: Aug 16, 2026

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development
09:32

Light-mediated Reversible Modulation of the Mitogen-activated Protein Kinase Pathway during Cell Differentiation and Xenopus Embryonic Development

Published on: June 15, 2017

MEKK4 is an effector of the embryonic TRAF4 for JNK activation

Amy N Abell1, Gary L Johnson

  • 1Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7365, USA.

The Journal of Biological Chemistry
|September 15, 2005
PubMed

Insights

Tumor necrosis factor receptor-associated factor 4 (TRAF4) activates c-Jun N-terminal kinase (JNK) by interacting with and stimulating MEKK4 kinase activity. This study identifies MEKK4 as the key kinase in TRAF4-mediated JNK pathway regulation.

Area of Science:

  • Cellular biology
  • Molecular signaling pathways
  • Signal transduction

Background:

  • Tumor necrosis factor receptor-associated factor 4 (TRAF4) is known to activate the JNK pathway.
  • The precise molecular mechanism by which TRAF4 activates JNK has remained elusive.

Purpose of the Study:

  • To elucidate the mechanism of TRAF4-mediated JNK activation.
  • To identify the upstream kinase responsible for TRAF4's effect on the JNK pathway.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate protein-protein interactions.
  • Immunofluorescence microscopy for cellular colocalization studies.
  • Kinase activity assays and analysis of JNK pathway activation using kinase-inactive mutants.

Main Results:

  • Endogenous TRAF4 and MEKK4 were found to associate in human cells and mouse embryos.
  • TRAF4 interacts with the kinase domain of MEKK4, and this interaction stimulates MEKK4 kinase activity via promoting MEKK4 oligomerization.
  • Co-expression of TRAF4 and MEKK4 synergistically activates JNK, an effect dependent on MEKK4 kinase activity and inhibited by TRAF domain expression.

Conclusions:

  • MEKK4 is identified as the MAPK kinase kinase that mediates TRAF4 regulation of the JNK pathway.
  • TRAF4 stimulates MEKK4 kinase activity, leading to downstream JNK activation.
  • This interaction is crucial for understanding TRAF4's role in cellular signaling.

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