Akt1 regulates a JNK scaffold during excitotoxic apoptosis.
Cell survival is determined by a balance among signaling cascades, including those that recruit the Akt and JNK pathways. Here we describe a novel interaction between Akt1 and JNK interacting protein 1 (JIP1), a JNK pathway scaffold. Direct association between Akt1 and JIP1 was observed in primary neurons. Neuronal exposure to an excitotoxic stimulus decreased the Akt1-JIP1 interaction and concomitantly increased association between JIP1 and JNK. Akt1 interaction with JIP1 inhibited JIP1-mediated potentiation of JNK activity by decreasing JIP1 binding to specific JNK pathway kinases. Consistent with this view, neurons from Akt1-deficient mice exhibited higher susceptibility to kainate than wild-type littermates. Overexpression of Akt1 mutants that bind JIP1 reduced excitotoxic apoptosis. These results suggest that Akt1 binding to JIP1 acts as a regulatory gate preventing JNK activation, which is released under conditions of excitotoxic injury.
Kim
Albert H
AH
Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Yano
Hiroko
H
Cho
Han
H
Meyer
Debra
D
Monks
Bob
B
Margolis
Ben
B
Birnbaum
Morris J
MJ
Chao
Moses V
MV
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D029681:Arabidopsis Proteins; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005333:Fetus; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007608:Kainic Acid / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000235:genetics / Q000378:metabolism*; D010940:Plant Proteins / Q000187:drug effects / Q000235:genetics; D015221:Potassium Channels / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D029681:Arabidopsis Proteins; D002352:Carrier Proteins; C490666:MAPK8IP1 protein, human; C490665:Mapk8ip protein, mouse; C110528:Mapk8ip1 protein, rat; D009498:Neurotoxins; D010940:Plant Proteins; D015221:Potassium Channels; D017470:Receptors, Glutamate; C074500:AKT1 protein, Arabidopsis; D018698:Glutamic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D007608:Kainic Acid