It is well established that Notch signalling is activated in response to ligand binding through a series of proteolytic cleavages that release the Notch intracellular domain, allowing it to translocate to the nucleus to regulate downstream target gene expression. However there is still much to learn about the mechanisms that can bring about these proteolytic events in the numerous physiological contexts in which signal activation occurs. A number of studies have suggested that endocytosis of Notch contributes to the signal activation process, but the molecular details are unclear and controversial. There is conflicting data as to whether endocytosis of the receptor is essential for ligand-induced signalling or supplements it. Other studies have revealed that Notch can be activated in the endosomal pathway, independently of its ligands, through the activity of Deltex, a Ring-domain Ubiquitin ligase that binds to the Notch intracellular domain. However, it is unclear how the Deltex-activation mechanism relates to that of ligand-induced signalling, or to ectopic Notch signalling brought about by disruption of ESCRT complexes that affect multivesicular body formation. This review will address these issues and argue that the data are best reconciled by proposing distinct activation mechanisms in different cellular locations that contribute to the cellular pool of the soluble Notch intracellular domain. The resulting signalling network may provide developmental robustness to environmental and genetic variation.
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