JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis.
Trophic factor deprivation (TFD) activates c-Jun N-terminal kinases (JNKs), culminating in coordinate AP1-dependent transactivation of the BH3-only BCL-2 proteins BIM(EL) and HRK, which in turn are critical for BAX-dependent cytochrome c release, caspase activation, and apoptosis. Here, we report that TFD caused not only induction but also phosphorylation of BIM(EL). Mitochondrially localized JNKs but not upstream activators, like mixed-lineage kinases (MLKs) or mitogen-activated protein kinase kinases (MKKs), specifically phosphorylated BIM(EL) at Ser65, potentiating its proapoptotic activity. Inhibition of the JNK pathway attenuated BIM(EL) expression, prevented BIM(EL) phosphorylation, and abrogated TFD-induced apoptosis. Conversely, activation of this pathway promoted BIM(EL) expression and phosphorylation, causing BIM- and BAX-dependent cell death. Thus, JNKs regulate the proapoptotic activity of BIM(EL) during TFD, both transcriptionally and posttranslationally.
Putcha
Girish V
GV
Department of Neurology and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Le
Siyuan
S
Frank
Stephan
S
Besirli
Cagri G
CG
Clark
Kim
K
Chu
Boyang
B
Alix
Shari
S
Youle
Richard J
RJ
LaMarche
Art
A
Maroney
Anna C
AC
Johnson
Eugene M
EM
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007106:Immune Sera / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020932:Nerve Growth Factor / Q000276:immunology / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D012694:Serine / Q000235:genetics; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D017783:Superior Cervical Ganglion; D014162:Transfection; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; C494828:Bax protein, rat; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D002352:Carrier Proteins; D007106:Immune Sera; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D012694:Serine; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases