Notch 1 interacts with the amyloid precursor protein in a Numb‐independent manner

Abstract

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.

Co-localization of the amyloid precursor protein and Notch intracellular domains in nuclear transcription factories

“…Cross-talk between different signaling pathways is a common phenomenon. APP and Notch signaling pathways interact at various points, including direct interactions of Notch and APP (15,40) or competition for binding proteins such as Fe65, Jip1 or Numb, which can physically associate with AICD and NICD (16,19,49). A recent report showed that NICD can repress AFT-mediated transcription by direct interaction (21).…”

“…Bar, 7.5 μm in A upper, 5 μm in A lower, 20 μm in B upper, 10 μm in B lower, 5 μm in C. APP and Notch interact at different levels of their nuclear signaling pathways and their intracellular domains co-localize in transcription factories. Notch and APP can directly interact (1) at the plasma membrane (PM) (15,40). Both proteins undergo ectodomain shedding by the same α-secretases and regulated intramembrane proteolysis by γ-secretase complexes (13,29) leading to competition for these proteolytic cleavages (2) that are necessary for the translocation of the intracellular domains to the nucleus (N).…”

Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system

“…Binding has been reported for extracellular matrix components, including heparan sulfate (Multhaup, 1994;Small et al, 1994), collagen (Beher et al, 1996) and fibulin 1 (Ohsawa et al, 2001); zinc and copper ions (Turner et al, 2003); and the lipoprotein receptors, scavenger receptor A (SantiagoGarcia et al, 2001) and LRP (Kounnas et al, 1995). More recently identified extracellular proteins that can interact with APP include F-spondin (also known as spondin 1) (Ho and Sudhof, 2004;Hoe et al, 2005), Drosophila FASII (Ashley et al, 2005), BRI2 (ITM2B) (Fotinopoulou et al, 2005;Matsuda et al, 2005), APLP1, APLP2 and APP itself (Soba et al, 2005), Notch family members (Fassa et al, 2005;Fischer et al, 2005;Oh et al, 2005;Chen et al, 2006), LRRTM3 (Majercak et al, 2006) and NgR (RTN4R) (Park et al, 2006). Some of these proteins can influence candidate downstream signaling pathways or APP processing.…”

Notch signaling in the brain: In good and bad times

“…Early reports suggest that Notch1 and APP coprecipitate in brain lysates and that they interact through their transmembrane domain (Fassa et al, 2005;Kim et al, 2007). It was also shown that the APP intracellular domain (AICD), through interaction with Numb, can down-regulate Notch signaling (Roncarati et al, 2002) (Fig.…”