Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex.
The amyloid precursor protein (APP) is a type I transmembrane protein translocated to neuronal terminals, whose function is still unknown. The C-terminus of APP mediates its interaction with cellular adaptor and signaling proteins, some of which signal to the stress-activated protein kinase (SAPK) pathway. Here we show that ASK1, a ... MAPKKK that activates two SAPKs, c-Jun N-terminal-kinase (JNK) and p38, is present in a complex containing APP, phospho-MKK6, JIP1 and JNK1. In primary neurons deprived of growth factors, as well as in brains of (FAD)APP-transgenic mice, ASK1 was upregulated in neuronal projections, where it interacted with APP. In non-transgenic brains, ASK1 and APP associated mainly in the ER. Our results indicate that recruitment of ASK1 to stress-signaling complexes assembled with APP may be triggered and enhanced by cellular stress. Thus, ASK1 may be the apical MAPKKK in a signaling complex assembled with APP as a response to stress.
Mesh Terms:
Amyloid beta-Protein Precursor, Animals, Cell Line, Endoplasmic Reticulum, Humans, Immunoblotting, Immunohistochemistry, Immunoprecipitation, MAP Kinase Kinase 6, MAP Kinase Kinase Kinase 5, Mice, Mice, Transgenic, Microscopy, Confocal, Mitogen-Activated Protein Kinase 8, Neurons, Oxidative Stress, Protein Transport, Signal Transduction, Synaptic Vesicles
Amyloid beta-Protein Precursor, Animals, Cell Line, Endoplasmic Reticulum, Humans, Immunoblotting, Immunohistochemistry, Immunoprecipitation, MAP Kinase Kinase 6, MAP Kinase Kinase Kinase 5, Mice, Mice, Transgenic, Microscopy, Confocal, Mitogen-Activated Protein Kinase 8, Neurons, Oxidative Stress, Protein Transport, Signal Transduction, Synaptic Vesicles
Neurobiol. Dis.
Date: Oct. 01, 2007
PubMed ID: 17719230
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