The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling

The β-amyloid precursor protein (APP) and the Notch receptor undergo intramembranous proteolysis by the Presenilin-dependent γ-secretase. The cleavage of APP by γ-secretase releases amyloid-β peptides, which have been implicated in the pathogenesis of Alzheimer's disease, and the APP intracellular domain (AID), for which the function is not yet well understood. A similar γ-secretase-mediated cleavage of the Notch receptor liberates the Notch intracellular domain (NICD). NICD translocates to the nucleus and activates the transcription of genes that regulate the generation, differentiation, and survival of neuronal cells. Hence, some of the effects of APP signaling and Alzheimer's disease pathology may be mediated by the interaction of APP and Notch. Here, we show that membrane-tethered APP binds to the cytosolic Notch inhibitors Numb and Numb-like in mouse brain lysates. AID also binds Numb and Numb-like, and represses Notch activity when released by APP. Thus, γ-secretase may have opposing effects on Notch signaling; positive by cleaving Notch and generating NICD, and negative by processing APP and generating AID, which inhibits the function of NICD.

[1]  R. Roncarati,et al.  Jun NH2-terminal Kinase (JNK) Interacting Protein 1 (JIP1) Binds the Cytoplasmic Domain of the Alzheimer's β-Amyloid Precursor Protein (APP)* , 2002, The Journal of Biological Chemistry.

[2]  A. Israël,et al.  Notch from Neurodevelopment to Neurodegeneration: Keeping the Fate , 2002, Research and Perspectives in Alzheimer’s Disease.

[3]  S. Pimplikar,et al.  The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. H. Kim,et al.  Characterization of a Presenilin-mediated Amyloid Precursor Protein Carboxyl-terminal Fragment γ , 2001, The Journal of Biological Chemistry.

[5]  D. Selkoe,et al.  The Intracellular Domain of the β-Amyloid Precursor Protein Is Stabilized by Fe65 and Translocates to the Nucleus in a Notch-like Manner* , 2001, The Journal of Biological Chemistry.

[6]  Y. Ihara,et al.  Distinct Intramembrane Cleavage of the β-Amyloid Precursor Protein Family Resembling γ-Secretase-like Cleavage of Notch* , 2001, The Journal of Biological Chemistry.

[7]  B. de Strooper,et al.  The amyloid precursor protein (APP)‐cytoplasmic fragment generated by γ‐secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture , 2001, Journal of neurochemistry.

[8]  Klaus Fuchs,et al.  Presenilin‐dependent γ‐secretase processing of β‐amyloid precursor protein at a site corresponding to the S3 cleavage of Notch , 2001 .

[9]  M. Wolfe,et al.  A Portrait of Alzheimer Secretases--New Features and Familiar Faces , 2001, Science.

[10]  Thomas C. Südhof,et al.  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60 , 2001, Science.

[11]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[12]  T. Russo,et al.  The β-Amyloid Precursor Protein Functions as a Cytosolic Anchoring Site That Prevents Fe65 Nuclear Translocation* , 2001, The Journal of Biological Chemistry.

[13]  G. Struhl,et al.  Presenilin-mediated transmembrane cleavage is required for Notch signal transduction in Drosophila. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Golde,et al.  A Novel γ-Secretase Assay Based on Detection of the Putative C-terminal Fragment-γ of Amyloid β Protein Precursor* , 2000, The Journal of Biological Chemistry.

[15]  F. D. Miller,et al.  Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain , 2000, Journal of neurochemistry.

[16]  B. Strooper,et al.  Total inactivation of γ–secretase activity in presenilin-deficient embryonic stem cells , 2000, Nature Cell Biology.

[17]  A. Bernstein,et al.  Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1 , 2000, Nature Cell Biology.

[18]  C. Broeckhoven,et al.  Binding Partners of Alzheimer's Disease Proteins: Are They Physiologically Relevant? , 2000, Neurobiology of Disease.

[19]  J. Hsieh,et al.  SKIP, a CBF1-Associated Protein, Interacts with the Ankyrin Repeat Domain of NotchIC To Facilitate NotchIC Function , 2000, Molecular and Cellular Biology.

[20]  M. Tabaton,et al.  Generation of an Apoptotic Intracellular Peptide by γ-Secretase Cleavage of Alzheimer's Amyloid ß Protein Precursor , 2000 .

[21]  Anirvan Ghosh,et al.  Nuclear Notch1 signaling and the regulation of dendritic development , 2000, Nature Neuroscience.

[22]  J. Franklin,et al.  Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1 , 1999, Current Biology.

[23]  Dho Se,et al.  Characterization of four mammalian numb protein isoforms. Identification of cytoplasmic and membrane-associated variants of the phosphotyrosine binding domain. , 1999 .

[24]  B. Strooper,et al.  The presenilins in Alzheimer's disease--proteolysis holds the key. , 1999, Science.

[25]  H. Lipshitz,et al.  Distinct human NUMB isoforms regulate differentiation vs. proliferation in the neuronal lineage. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[26]  B. Hyman,et al.  Notch1 inhibits neurite outgrowth in postmitotic primary neurons , 1999, Neuroscience.

[27]  S. Artavanis-Tsakonas,et al.  Notch signaling: cell fate control and signal integration in development. , 1999, Science.

[28]  P. Rakic,et al.  Processing of the notch ligand delta by the metalloprotease Kuzbanian. , 1999, Science.

[29]  D L Price,et al.  Alzheimer's disease: genetic studies and transgenic models. , 1998, Annual review of genetics.

[30]  S. Minoguchi,et al.  Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. , 1997, Development.

[31]  Y. Jan,et al.  Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis. , 1997, Development.

[32]  A. Mccarthy.  Development , 1996, Current Opinion in Neurobiology.

[33]  H. Weintraub,et al.  Signal transduction by activated mNotch: importance of proteolytic processing and its regulation by the extracellular domain. , 1996, Proceedings of the National Academy of Sciences of the United States of America.