Endocytic regulation of Notch activation and down-regulation (review).

Notch receptor signalling plays a central role in development and its misfunction has been linked to a number of diseases. In the cannonical Notch signalling pathway, ligand binding to Notch activates a series of proteolytic cleavages that release the Notch intracellular domain for trafficking to the nucleus, where it activates the transcription factor, Suppressor of Hairless (Su(H)). A number of recent papers have demonstrated the importance of endocytic trafficking of Notch and its ligands for both the activation and the down-regulation of the Notch receptor. These reports highlight uncertainty regarding the whereabouts in the cell where Notch activation occurs, and the form of the ligand that can induce signalling. In this review we speculate that, decision points between alternative trafficking pathways represent important regulatory nodes that may allow Notch signalling levels to be modulated by other developmental signals, providing context-dependency to Notch activation. We also review data that suggest that key proteolytic events, associated with Notch activation, may occur within the endocytic pathway or require prior endocytosis and recycling of Notch and its ligands to the cell surface. Sorting within the endocytic pathway, regulated by several different ubiquitin ligase proteins, may be involved in ensuring whether ligand and receptor are competent to signal. Furthermore, the utilisation of an alternative mechanism of Notch signalling, independent of Su(H), may depend on driving endocytic Notch into a specific compartment, in response to the activity of the ring finger domain protein, Deltex.