JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins

Targeted gene disruption studies have established that the c‐Jun NH 2 ‐terminal kinase (JNK) is required for the stress‐induced release of mitochondrial cytochrome c and apoptosis, and that the Bax subfamily of Bcl‐2‐related proteins is essential for JNK‐dependent apoptosis. However, the mechanism b...

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Bibliographic Details
Published in:The EMBO journal 2004-04, Vol.23 (8), p.1889-1899
Main Authors: Tsuruta, Fuminori, Sunayama, Jun, Mori, Yasunori, Hattori, Seisuke, Shimizu, Shigeomi, Tsujimoto, Yoshihide, Yoshioka, Katsuji, Masuyama, Norihisa, Gotoh, Yukiko
Format: Article
Language:English
Subjects:
14-3-3
14-3-3 Proteins - chemistry
14-3-3 Proteins - genetics
14-3-3 Proteins - metabolism
Amino Acid Sequence
Animals
Apoptosis
Apoptosis Regulatory Proteins
Bax
bcl-2-Associated X Protein
Bcl-2-Like Protein 11
Carrier Proteins - metabolism
Cell Line
Chlorocebus aethiops
Cytochrome
Cytochromes c - metabolism
EMBO07
Humans
JNK
JNK Mitogen-Activated Protein Kinases - genetics
JNK Mitogen-Activated Protein Kinases - metabolism
Membrane Proteins - metabolism
Mitochondria - metabolism
Molecular Sequence Data
Mutation - genetics
Phosphorylation
Phosphoserine - metabolism
Protein Binding
Protein Serine-Threonine Kinases - metabolism
Protein Transport
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-bcl-2 - metabolism
Proto-Oncogene Proteins c-jun - metabolism
Sequence Alignment
Translocation
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Summary:Targeted gene disruption studies have established that the c‐Jun NH 2 ‐terminal kinase (JNK) is required for the stress‐induced release of mitochondrial cytochrome c and apoptosis, and that the Bax subfamily of Bcl‐2‐related proteins is essential for JNK‐dependent apoptosis. However, the mechanism by which JNK regulates Bax has remained unsolved. Here we demonstrate that activated JNK promotes Bax translocation to mitochondria through phosphorylation of 14‐3‐3, a cytoplasmic anchor of Bax. Phosphorylation of 14‐3‐3 led to dissociation of Bax from this protein. Expression of phosphorylation‐defective mutants of 14‐3‐3 blocked JNK‐induced Bax translocation to mitochondria, cytochrome c release and apoptosis. Collectively, these results have revealed a key mechanism of Bax regulation in stress‐induced apoptosis.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7600194