Novel Mediators of Amyloid Precursor Protein Signaling

Multiple recent reports implicate amyloid precursor protein (APP) signaling in the pathogenesis of Alzheimer's disease, but the APP-dependent signaling network involved has not been defined. Here, we report a novel consensus sequence for interaction with the PDZ-1 and PDZ-2 domains of the APP-i...

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Bibliographic Details
Published in:The Journal of neuroscience 2009-12, Vol.29 (50), p.15703-15712
Main Authors: Swistowski, Andrzej, Zhang, Qiang, Orcholski, Mark E, Crippen, Danielle, Vitelli, Cathy, Kurakin, Alexei, Bredesen, Dale E
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - physiology
Amyloid beta-Protein Precursor - chemistry
Amyloid beta-Protein Precursor - metabolism
Amyloid beta-Protein Precursor - physiology
Cadherins - chemistry
Cadherins - physiology
Carrier Proteins - chemistry
Carrier Proteins - physiology
Cell Line
High-Throughput Screening Assays
Humans
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - physiology
PDZ Domains - physiology
Protein Binding - physiology
Protein Interaction Mapping
Protein Structure, Tertiary
Signal Transduction - physiology
Transcriptional Activation - physiology
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Summary:Multiple recent reports implicate amyloid precursor protein (APP) signaling in the pathogenesis of Alzheimer's disease, but the APP-dependent signaling network involved has not been defined. Here, we report a novel consensus sequence for interaction with the PDZ-1 and PDZ-2 domains of the APP-interacting proteins Mint1, Mint2, and Mint3 (X11alpha, X11beta, and X11gamma), and multiple novel interactors for these proteins, with the finding that transcriptional coactivators are highly represented among these interactors. Furthermore, we show that Mint3 interaction with a set of the transcriptional coactivators leads to nuclear localization and transactivation, whereas interaction of the same set with Mint1 or Mint2 prevents nuclear localization and transactivation. These results define new mediators of the signal transduction network mediated by APP.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.4351-09.2009