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Deubiquitinase USP10 regulates Notch signaling in the endothelium

Deubiquitinase fine-tunes Notch signaling The branching of blood vessels is controlled in part by signaling through Notch receptor proteins. When NOTCH1 binds its ligand DLL4, the intracellular domain (NICD1) is cleaved from the receptor and works with other proteins to regulate gene transcription. In a screen for proteins that interacted with NICD1 in human cells in culture, Lim et al. identified the deubiquitinase USP10. NICD1 is rapidly ubiquitinated and degraded in cells, but interaction of NICD1 with USP10 counteracts ubiquitination of NICD1 and stimulates Notch signaling. Genetic experiments in mice support a role for USP10 in fine-tuning Notch signaling during vascular morphogenesis. Science, this issue p. 188 A deubiquitinase inhibits degradation of the Notch intracellular domain. 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.