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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.

Pubmed ID: 12194869

Authors

  • Kim AH
  • Yano H
  • Cho H
  • Meyer D
  • Monks B
  • Margolis B
  • Birnbaum MJ
  • Chao MV

Journal

Neuron

Publication Data

August 15, 2002

Associated Grants

  • Agency: NCI NIH HHS, Id: CA56490
  • Agency: NICHD NIH HHS, Id: HD23315
  • Agency: NINDS NIH HHS, Id: NS21072

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