Identification of a Paralog-Specific Notch1 Intracellular Domain Degron.

Broadus MR, Chen TW, Neitzel LR, Ng VH, Jodoin JN, Lee LA, Salic A, Robbins DJ, Capobianco AJ, Patton JG, Huppert SS, Lee E
Cell Rep. 2016 15 (9): 1920-9

PMID: 27210761 · PMCID: PMC4889555 · DOI:10.1016/j.celrep.2016.04.070

Upon Notch pathway activation, the receptor is cleaved to release the Notch intracellular domain (NICD), which translocates to the nucleus to activate gene transcription. Using Xenopus egg extracts, we have identified a Notch1-specific destruction signal (N1-Box). We show that mutations in the N1-Box inhibit NICD1 degradation and that the N1-Box is transferable for the promotion of degradation of heterologous proteins in Xenopus egg extracts and in cultured human cells. Mutation of the N1-Box enhances Notch1 activity in cultured human cells and zebrafish embryos. Human cancer mutations within the N1-Box enhance Notch1 signaling in transgenic zebrafish, highlighting the physiological relevance of this destruction signal. We find that binding of the Notch nuclear factor, CSL, to the N1-Box blocks NICD1 turnover. Our studies reveal a mechanism by which degradation of NICD1 is regulated by the N1-Box to minimize stochastic flux and to establish a threshold for Notch1 pathway activation.

Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

MeSH Terms (20)

Amino Acid Sequence Animals Cell Extracts Embryo, Nonmammalian F-Box Proteins HEK293 Cells Humans Muscle Proteins Mutation Protein Binding Protein Domains Protein Stability Proteolysis Receptor, Notch1 Regulatory Sequences, Nucleic Acid Sequence Homology, Amino Acid Transcription, Genetic Ubiquitin-Protein Ligases Xenopus Zebrafish

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