Deubiquitinase USP10 regulates Notch signaling in the endothelium

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 und...

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Bibliographic Details
Authors: Lim, R, Sugino, T, Nolte, H, Andrade, J, Zimmermann, B, Shi, C, Doddaballapur, A, Ong, Y T, Wilhelm, K, Fasse, J W D, Ernst, A, Kaulich, M, Husnjak, K, Boettger, T, Guenther, S, Braun, T, Krüger, M, Benedito, Rui, Dikic, I, Potente, M
Format: article
Publication Date:2019
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/9685
Online Access:http://hdl.handle.net/20.500.12105/9685
Access Level:Open access
Keyword:Animals
Endothelium, Vascular
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Mice
Mice, Knockout
Neovascularization, Physiologic
Protein Domains
Protein Stability
RNA, Small Interfering
Receptor, Notch1
Signal Transduction
Ubiquitin Thiolesterase
Proteolysis
Description
Summary: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.

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