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PMID:16157600

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Citation

Abell, AN and Johnson, GL (2005) MEKK4 is an effector of the embryonic TRAF4 for JNK activation. J. Biol. Chem. 280:35793-6

Abstract

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.

Links

PubMed Online version:10.1074/jbc.C500260200

Keywords

Animals; Blotting, Western; COS Cells; Cell Line; Cells, Cultured; Cercopithecus aethiops; Cytoplasm/metabolism; DNA, Complementary/metabolism; Dimerization; Enzyme Activation; Genetic Vectors; Humans; Immunoprecipitation; K562 Cells; MAP Kinase Kinase 4/metabolism; MAP Kinase Kinase Kinase 4/metabolism; MAP Kinase Kinase Kinase 4/physiology; Mice; Microscopy, Fluorescence; Mutation; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Signal Transduction; TNF Receptor-Associated Factor 4; Transfection; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:M3K4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q61382

F

Seeded From UniProt

complete

MOUSE:M3K4

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:M3K4

enables

GO:0004672: protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:M3K4

involved_in

GO:0043507: positive regulation of JUN kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:M3K4

involved_in

GO:0035556: intracellular signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRAF4

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O08648

F

Seeded From UniProt

complete

HUMAN:TRAF4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y6R4

F

Seeded From UniProt

complete

HUMAN:TRAF4

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TRAF4

involved_in

GO:0046330: positive regulation of JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TRAF4

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:M3K4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BUZ4

F

Seeded From UniProt

complete


See also

References

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