A schematic model of endosomal microdomains and Notch activation caused by ESCRTs knockdown and Notch mutants. Dx directs Notch to clathrin (and ESCRT-0)-positive endocytic route and facilitates lysosome-dependent Notch activation while Su(dx) promotes Notch endocytosis via a lipid raft-type membrane subdomain which can activate the signal in ADAM10-dependent manner. ESCRT-I knockdown and mutation in the Notch PPxY motif induce Notch activation through the raft pathway, whereas ESCRT-III knockdown and C-terminal truncations of Notch can switch the route from raft-type pathway to the ADAM10-independent Dx/clathrin pathway.