Deubiquitinase USP10 regulates Notch signaling in the endothelium

• Published in: Science (American Association for the Advancement of Science) Vol. 364; no. 6436; pp. 188 - 193
• Main 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, R, Dikic, I, Potente, M
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 12-04-2019
• Subjects: Angiogenesis; Blood vessels; Cell culture; Deactivation; Ectopic expression; Endothelial cells; Endothelium; Gene expression; Inactivation; Intracellular; Kinases; Mice; Morphogenesis; Notch1 protein; Peptidase; Proteins; Signaling; Transcription; Ubiquitin; Ubiquitination
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aat0778

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
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.