Notch signaling occurs through direct interaction between Notch, the receptor, and its ligands, presented on the surface of neighboring cells. Endocytosis has been shown to be essential for Notch signal activation in both signal-sending and signal-receiving cells, and numerous genes involved in vesicle trafficking have recently been shown to act as key regulators of the pathway. Defects in vesicle trafficking can lead to gain- or loss-of-function defects in a context-dependent manner. Here, we discuss how endocytosis and vesicle trafficking regulate Notch signaling in both signal-sending and signal-receiving cells. We will introduce the key players in different trafficking steps, and further illustrate how they impact the signal outcome. Some of these players act as general factors and modulate Notch signaling in all contexts, whereas others modulate signaling in a context-specific fashion. We also discuss Notch signaling during mechanosensory organ development in the fly to exemplify how endocytosis and vesicle trafficking are effectively used to determine correct cell fates. In summary, endocytosis plays an essential role in Notch signaling, whereas intracellular vesicle trafficking often plays a context-dependent or regulatory role, leading to divergent outcomes in different developmental contexts.
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