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

Roberta Roncarati, Nenad Šestan, Meir H. Scheinfeld, Bridget E. Berechid, Peter A. Lopez, Olimpia Meucci, Jane C. McGlade, Pasko Rakic, Luciano D'Adamio

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7102-7107
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number10
DOIs
StatePublished - May 14 2002

Fingerprint

Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Notch Receptors
Amyloid
Alzheimer Disease
Presenilins
Proteolysis
Cell Survival
Pathology
Peptides
Membranes
Brain
Genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling. / Roncarati, Roberta; Šestan, Nenad; Scheinfeld, Meir H.; Berechid, Bridget E.; Lopez, Peter A.; Meucci, Olimpia; McGlade, Jane C.; Rakic, Pasko; D'Adamio, Luciano.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 10, 14.05.2002, p. 7102-7107.

Research output: Contribution to journalArticle

Roncarati, Roberta ; Šestan, Nenad ; Scheinfeld, Meir H. ; Berechid, Bridget E. ; Lopez, Peter A. ; Meucci, Olimpia ; McGlade, Jane C. ; Rakic, Pasko ; D'Adamio, Luciano. / The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 10. pp. 7102-7107.
@article{926baacf00dd4471a7841c0bb951e072,
title = "The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling",
abstract = "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.",
author = "Roberta Roncarati and Nenad Šestan and Scheinfeld, {Meir H.} and Berechid, {Bridget E.} and Lopez, {Peter A.} and Olimpia Meucci and McGlade, {Jane C.} and Pasko Rakic and Luciano D'Adamio",
year = "2002",
month = "5",
day = "14",
doi = "10.1073/pnas.102192599",
language = "English (US)",
volume = "99",
pages = "7102--7107",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "10",

}

TY - JOUR

T1 - The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling

AU - Roncarati, Roberta

AU - Šestan, Nenad

AU - Scheinfeld, Meir H.

AU - Berechid, Bridget E.

AU - Lopez, Peter A.

AU - Meucci, Olimpia

AU - McGlade, Jane C.

AU - Rakic, Pasko

AU - D'Adamio, Luciano

PY - 2002/5/14

Y1 - 2002/5/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037076398&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037076398&partnerID=8YFLogxK

U2 - 10.1073/pnas.102192599

DO - 10.1073/pnas.102192599

M3 - Article

VL - 99

SP - 7102

EP - 7107

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 10

ER -