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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Arabidopsis Proteins, Carrier Proteins, Cell Survival, Cells, Cultured, Central Nervous System Diseases, Fetus, Gene Deletion, Gene Expression, Glutamic Acid, Hippocampus, Humans, JNK Mitogen-Activated Protein Kinases, Kainic Acid, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases, Neurons, Neurotoxins, Plant Proteins, Potassium Channels, Protein Binding, Rats, Rats, Sprague-Dawley, Receptors, Glutamate, Signal Transduction
Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Arabidopsis Proteins, Carrier Proteins, Cell Survival, Cells, Cultured, Central Nervous System Diseases, Fetus, Gene Deletion, Gene Expression, Glutamic Acid, Hippocampus, Humans, JNK Mitogen-Activated Protein Kinases, Kainic Acid, Mice, Mice, Knockout, Mitogen-Activated Protein Kinases, Neurons, Neurotoxins, Plant Proteins, Potassium Channels, Protein Binding, Rats, Rats, Sprague-Dawley, Receptors, Glutamate, Signal Transduction
Neuron
Date: Aug. 15, 2002
PubMed ID: 12194869
View in: Pubmed Google Scholar
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