Monoubiquitination and endocytosis direct γ-secretase cleavage of activated Notch receptor
Open Access
- 5 July 2004
- journal article
- Published by Rockefeller University Press in Journal of Cell Biology
- Vol. 166 (1) , 73-83
Abstract
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, ΔEu. We identified the lysine residue targeted by the monoubiquitination event and confirmed its importance for activation of Notch receptor by its ligand, Delta-like 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.Keywords
This publication has 66 references indexed in Scilit:
- A CBP Binding Transcriptional Repressor Produced by the PS1/ϵ-Cleavage of N-Cadherin Is Inhibited by PS1 FAD MutationsCell, 2003
- Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal MembraneJournal of Biological Chemistry, 2003
- Familial Alzheimer Disease-linked Presenilin 1 Variants Enhance Production of Both Aβ1–40 and Aβ1–42 Peptides That Are Only Partially Sensitive to a Potent Aspartyl Protease Transition State Inhibitor of “γ-Secretase”Journal of Biological Chemistry, 2003
- Endocytosis-mediated downregulation of LIN-12/Notch upon Ras activation in Caenorhabditis elegansNature, 2002
- Presenilin-dependent Intramembrane Proteolysis of CD44 Leads to the Liberation of Its Intracellular Domain and the Secretion of an Aβ-like PeptideJournal of Biological Chemistry, 2002
- A family of Rhomboid intramembrane proteases activates all Drosophila membrane‐tethered EGF ligandsThe EMBO Journal, 2002
- c-Cbl Binding and Ubiquitin-dependent Lysosomal Degradation of Membrane-associated Notch1Journal of Biological Chemistry, 2002
- Endogenous Presenilin-1 Targets to Endocytic Rather Than Biosynthetic CompartmentsMolecular and Cellular Neuroscience, 2000
- Cell Surface Presenilin-1 Participates in the γ-Secretase-like Proteolysis of NotchJournal of Biological Chemistry, 1999
- Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 InteractionNeurobiology of Disease, 1999