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Science. 2019 Apr 12;364(6436):188-193. doi: 10.1126/science.aat0778.

Deubiquitinase USP10 regulates Notch signaling in the endothelium.

Author information

1
Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
2
Institute for Genetics and Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50931 Cologne, Germany.
3
Institute of Biochemistry II, Faculty of Medicine, Goethe University, D-60590 Frankfurt am Main, Germany.
4
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology TMP, D-60590 Frankfurt am Main, Germany.
5
Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.
6
Molecular Genetics of Angiogenesis Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain.
7
Buchmann Institute for Molecular Life Sciences, Goethe University, D-60438 Frankfurt am Main, Germany.
8
Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany. michael.potente@mpi-bn.mpg.de.
9
DZHK (German Center for Cardiovascular Research), partner site Frankfurt Rhine-Main, D-13347 Berlin, Germany.
10
International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.
#
Contributed equally

Abstract

Notch signaling is a core patterning module for vascular morphogenesis that codetermines the sprouting behavior of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability and diminished Notch-induced target gene expression in ECs. In mice, the loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase that fine-tunes endothelial Notch responses during angiogenic sprouting.

PMID:
30975888
DOI:
10.1126/science.aat0778
[Indexed for MEDLINE]

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