Notch 1 interacts with the amyloid precursor protein in a Numb-independent manner.
We hypothesized that the physical interaction between the amyloid precursor protein (APP) and Notch 1 (N1) may be mediating the reported cross-talk between the respective signaling pathways. Immunoprecipitation of mouse N1 (mN1) or extracellular domain truncated mN1 (mN1-TM, mimics TACE-produced membrane-bound C-terminal fragment) specifically coprecipitated APP(751). Conversely, immunoprecipitation of APP(751) specifically coprecipitated mN1, furin-generated membrane-bound mN1 C-terminal fragment (f.mN1-TM), or mN1-TM. The London mutation of APP did not affect the APP(751)/mN1 interaction. Coexpression of APP(751) and mN1 did not affect APP processing or production of mN1 intracellular domain (mNICD). The APP(751)/mN1 interaction was Numb-independent, insofar as it was observed in HEK293 cells that lack detectable levels of Numb and was unaffected by the expression of exogenous Numb or deletion of the APP cytoplasmic domain, including the Numb-binding YENPTY sequence. This interaction was unaffected even when the N-terminal 647 amino acids of APP were replaced by a sequence of secreted alkaline phosphatase. These data combined with data showing interaction between mN1-TM and APP(751) suggest that their transmebrane domains and short sequences around them are sufficient for the interaction and that APP(751) and mN1 interact in cis. Our results imply novel functions of APP and/or N1 that derive from their interaction.
Fassa
Angeliki
A
Division of Animal and Human Physiology, Department of Biology, National and Kapodistrian University of Athens, Panepistimiopolis, Ilisia, Athens, Greece.
Mehta
Pankaj
P
Efthimiopoulos
Spiros
S
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology*; D051881:Receptor, Notch1 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; C106293:Numb protein, mouse; D010446:Peptide Fragments; D051881:Receptor, Notch1