Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

Matthew R. Broadus, Tony W. Chen, Leif R. Neitzel, Victoria H. Ng, Jeanne N. Jodoin, Laura A. Lee, Adrian Salic, David J Robbins, Anthony J Capobianco, James G. Patton, Stacey S. Huppert, Ethan Lee

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1920-1929
Number of pages10
JournalCell Reports
Volume15
Issue number9
DOIs
StatePublished - May 31 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Broadus, M. R., Chen, T. W., Neitzel, L. R., Ng, V. H., Jodoin, J. N., Lee, L. A., Salic, A., Robbins, D. J., Capobianco, A. J., Patton, J. G., Huppert, S. S., & Lee, E. (2016). Identification of a Paralog-Specific Notch1 Intracellular Domain Degron. Cell Reports, 15(9), 1920-1929. https://doi.org/10.1016/j.celrep.2016.04.070