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 Citations (Scopus)

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

Fingerprint

Zebrafish
Degradation
Mutation
Ovum
Cultured Cells
Chemical activation
Xenopus Proteins
Cells
Transcription
Xenopus
Proteolysis
Embryonic Structures
Genes
Fluxes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Broadus, M. R., Chen, T. W., Neitzel, L. R., Ng, V. H., Jodoin, J. N., Lee, L. A., ... 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

Identification of a Paralog-Specific Notch1 Intracellular Domain Degron. / Broadus, Matthew R.; Chen, Tony W.; Neitzel, Leif R.; Ng, Victoria H.; Jodoin, Jeanne N.; Lee, Laura A.; Salic, Adrian; Robbins, David J; Capobianco, Anthony J; Patton, James G.; Huppert, Stacey S.; Lee, Ethan.

In: Cell Reports, Vol. 15, No. 9, 31.05.2016, p. 1920-1929.

Research output: Contribution to journalArticle

Broadus, MR, Chen, TW, Neitzel, LR, Ng, VH, Jodoin, JN, Lee, LA, Salic, A, Robbins, DJ, Capobianco, AJ, Patton, JG, Huppert, SS & Lee, E 2016, 'Identification of a Paralog-Specific Notch1 Intracellular Domain Degron', Cell Reports, vol. 15, no. 9, pp. 1920-1929. https://doi.org/10.1016/j.celrep.2016.04.070
Broadus MR, Chen TW, Neitzel LR, Ng VH, Jodoin JN, Lee LA et al. Identification of a Paralog-Specific Notch1 Intracellular Domain Degron. Cell Reports. 2016 May 31;15(9):1920-1929. https://doi.org/10.1016/j.celrep.2016.04.070
Broadus, Matthew R. ; Chen, Tony W. ; Neitzel, Leif R. ; Ng, Victoria H. ; Jodoin, Jeanne N. ; Lee, Laura A. ; Salic, Adrian ; Robbins, David J ; Capobianco, Anthony J ; Patton, James G. ; Huppert, Stacey S. ; Lee, Ethan. / Identification of a Paralog-Specific Notch1 Intracellular Domain Degron. In: Cell Reports. 2016 ; Vol. 15, No. 9. pp. 1920-1929.
@article{e4d340a77d684bf788a046863ea0a303,
title = "Identification of a Paralog-Specific Notch1 Intracellular Domain Degron",
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.",
author = "Broadus, {Matthew R.} and Chen, {Tony W.} and Neitzel, {Leif R.} and Ng, {Victoria H.} and Jodoin, {Jeanne N.} and Lee, {Laura A.} and Adrian Salic and Robbins, {David J} and Capobianco, {Anthony J} and Patton, {James G.} and Huppert, {Stacey S.} and Ethan Lee",
year = "2016",
month = "5",
day = "31",
doi = "10.1016/j.celrep.2016.04.070",
language = "English (US)",
volume = "15",
pages = "1920--1929",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",

}

TY - JOUR

T1 - Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

AU - Broadus, Matthew R.

AU - Chen, Tony W.

AU - Neitzel, Leif R.

AU - Ng, Victoria H.

AU - Jodoin, Jeanne N.

AU - Lee, Laura A.

AU - Salic, Adrian

AU - Robbins, David J

AU - Capobianco, Anthony J

AU - Patton, James G.

AU - Huppert, Stacey S.

AU - Lee, Ethan

PY - 2016/5/31

Y1 - 2016/5/31

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84971328549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84971328549&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.04.070

DO - 10.1016/j.celrep.2016.04.070

M3 - Article

C2 - 27210761

AN - SCOPUS:84971328549

VL - 15

SP - 1920

EP - 1929

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 9

ER -