Identification of a Paralog-Specific Notch1 Intracellular Domain Degron
Name
Broadus-2016-Identification of a.pdf
Size
3.28 MB
Format
Adobe PDF
Checksum (MD5)
21faa75d6987ed92ace31cfd463d73fa
Author(s)
Broadus, Matthew R.
Chen, Tony W.
Neitzel, Leif R.
Ng, Victoria H.
Jodoin, Jeanne
Lee, Laura A.
Salic, Adrian
Robbins, David J.
Capobianco, Anthony J.
Patton, James G.
Date Issued
May 2016
Journal
Cell Reports
Publisher
Elsevier
Citation
Broadus, Matthew R., Tony W. Chen, Leif R. Neitzel, Victoria H. Ng, Jeanne N. Jodoin, Laura A. Lee, Adrian Salic, et al. “Identification of a Paralog-Specific Notch1 Intracellular Domain Degron.” Cell Reports 15, no. 9 (May 2016): 1920-1929.
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.celrep.2016.04.070
