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

被引：176

作者：

Roncarati, R

Sestan, N

Scheinfeld, MH

Berechid, BE

Lopez, PA

Meucci, O

McGlade, JC

Rakic, P

D'Adamio, L

机构：

[1] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06520 USA

[2] Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA

[3] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA

[4] MCP Hahnemann Univ, Dept Pharmacol & Physiol, Philadelphia, PA 19102 USA

[5] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1X8, Canada

[6] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2002年 / 99卷 / 10期

关键词：

D O I：

10.1073/pnas.102192599

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The beta-amyloid precursor protein (APP) and the Notch receptor undergo intramembranous proteolysis by the Presenilin-dependent gamma-secretase. The cleavage of APP by gamma-secretase releases myloid-beta peptides, which have been implicated in the pathogensis of Alzheimer's disease, and the APP intracellular domain (AID), for which the function is not yet well understood. A similar gamma-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, gamma-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.

引用

页码：7102 / 7107

页数：6

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