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.
Molecular Neurobiology Program, Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
Albert H
AH
Kim
Hiroko
H
Yano
Han
H
Cho
Debra
D
Meyer
Bob
B
Monks
Ben
B
Margolis
Morris J
MJ
Birnbaum
Moses V
MV
Chao
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