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

doi:10.1016/j.celrep.2016.04.070

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Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

Journal article

Open access

Peer reviewed

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, …

Cell reports (Cambridge), Vol.15(9), pp.1920-1929

2016-05-31

DOI: https://doi.org/10.1016/j.celrep.2016.04.070

PMCID: PMC4889555

PMID: 27210761

Abstract

Xenopus

Amino Acid Sequence

F-Box Proteins - metabolism

Humans

Embryo, Nonmammalian - metabolism

Receptor, Notch1 - chemistry

Ubiquitin-Protein Ligases - metabolism

Receptor, Notch1 - metabolism

Mutation - genetics

Zebrafish - embryology

Regulatory Sequences, Nucleic Acid - genetics

Sequence Homology, Amino Acid

Animals

Proteolysis

HEK293 Cells

Muscle Proteins - metabolism

Protein Binding

Protein Domains

Cell Extracts

Transcription, Genetic

Protein Stability

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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.108 Molecular & Cell Biology - Cancer & Development; 1.108.579 Drosophila
Web Of Science research areas: Cell Biology
ESI research areas: Molecular Biology & Genetics

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Details

Title: Identification of a Paralog-Specific Notch1 Intracellular Domain Degron
Creators: Matthew R Broadus - Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Tony W Chen - Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Leif R Neitzel - Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Victoria H Ng - Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Jeanne N Jodoin - Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
Laura A Lee - Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
Adrian Salic - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
David J Robbins - Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Anthony J Capobianco - Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL 33136, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
James G Patton - Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA
Stacey S Huppert - Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: stacey.huppert@cchmc.org
Ethan Lee - Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Ingram Cancer Center, Vanderbilt Medical Center, Nashville, TN 37232, USA. Electronic address: ethan.lee@vanderbilt.edu
Publication Details: Cell reports (Cambridge), Vol.15(9), pp.1920-1929
Publisher: United States
Grant note: P30 CA068485 / NCI NIH HHS R01 DK078640 / NIDDK NIH HHS R01 CA125044 / NCI NIH HHS R01 GM081635 / NIGMS NIH HHS R01 EY024354 / NEI NIH HHS T32 CA119925 / NCI NIH HHS R01 GM092924 / NIGMS NIH HHS T32 HD007502 / NICHD NIH HHS R01 GM110041 / NIGMS NIH HHS R01 GM103926 / NIGMS NIH HHS R01 CA083736 / NCI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Surgery; UMMG Dept of Surgery - Div of Surgical Oncology
Language: English
Resource Type: Journal article
PMID: 27210761
PMCID: PMC4889555
Record Identifier: 991031559006202976