Monoubiquitination and Endocytosis Direct γ-Secretase Cleavage of Activated Notch Receptor
Activation of mammalian Notch receptor by its ligands induces TNFα-converting enzyme-dependent ectodomain shedding, followed by intramembrane proteolysis due to presenilin (PS)-dependent γ-secretase activity. Here, we demonstrate that a new modification, a monoubiquitination, as well as clathrin-dep...
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Published in | The Journal of cell biology Vol. 166; no. 1; pp. 73 - 83 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Rockefeller University Press
05.07.2004
The Rockefeller University Press |
Subjects | |
Online Access | Get full text |
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Summary: | Activation of mammalian Notch receptor by its ligands induces TNFα-converting enzyme-dependent ectodomain shedding, followed by intramembrane proteolysis due to presenilin (PS)-dependent γ-secretase activity. Here, we demonstrate that a new modification, a monoubiquitination, as well as clathrin-dependent endocytosis, is required for γ-secretase processing of a constitutively active Notch derivative, ΔE, which mimics the TNFα-converting enzyme-processing product. PS interacts with this modified form of ΔE, Δ Eu. We identified the lysine residue targeted by the monoubiquitination event and confirmed its importance for activation of Notch receptor by its ligand, Deltalike 1. We propose a new model where monoubiquitination and endocytosis of Notch are a prerequisite for its PS-dependent cleavage, and discuss its relevance for other γ-secretase substrates. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Address correspondence to Christel Brou, Unité de Biologie Moléculaire de l'Expression Génique, URA 2582, CNRS, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France. Tel.: (33) 1-40-61-30-38. Fax: (33) 1-40-61-30-40. email: cbrou@pasteur.fr Abbreviations used in this paper: APP, amyloid β precursor protein; CY3-Tf, CY3-labeled transferrin; ICv, intracellular domain of Notch1; PS, presenilin; TACE, TNFα-converting enzyme; TM, transmembrane; WT, wild type. |
ISSN: | 0021-9525 1540-8140 |
DOI: | 10.1083/jcb.200310098 |