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