MEKK4 is an effector of the embryonic TRAF4 for JNK activation.
TRAF4 has previously been shown to activate JNK through an unknown mechanism. Here, we show that endogenous TRAF4 and MEKK4 associate in both human K562 cells and mouse E10.5 embryos. TRAF4 interacts with the kinase domain of MEKK4. However, this association does not require MEKK4 kinase activity. The interaction of MEKK4 and TRAF4 are further demonstrated by the colocalization of TRAF4 and MEKK4 in cells. Importantly, although TRAF4 has little or no ability to activate JNK independently, coexpression of TRAF4 and MEKK4 results in synergistic activation of JNK that is inhibited by a kinase-inactive mutant of MEKK4, MEKK4K1361R. MEKK4 binds the TRAF domain of TRAF4 and MEKK4/TRAF4 activation of JNK is inhibited by expression of the TRAF domain. Furthermore, TRAF4 stimulates MEKK4 kinase activity by promoting MEKK4 oligomerization and JNK activation can be stimulated by chemical induction of MEKK4 dimerization. The findings identify MEKK4 as the MAPK kinase kinase for TRAF4 regulation of the JNK pathway.
Abell
Amy N
AN
Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7365, USA.
Johnson
Gary L
GL
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004789:Enzyme Activation; D005822:Genetic Vectors; D006801:Humans; D047468:Immunoprecipitation; D020014:K562 Cells; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048768:MAP Kinase Kinase Kinase 4 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D053449:TNF Receptor-Associated Factor 4; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000502:physiology*
D018076:DNA, Complementary; D053449:TNF Receptor-Associated Factor 4; C506367:TRAF4 protein, human; C506368:Traf4 protein, mouse; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D048768:MAP Kinase Kinase Kinase 4; D048670:MAP Kinase Kinase 4