Figure 2.

Endocytosis, endosomal sorting, and lysosome‐dependent degradation of epidermal growth factor receptor (EGFR) (left) and Notch (right). (Left) Stimulation of EGFR with epidermal growth factor (EGF) induces the activation and phosphorylation of EGFR. Ubiquitin ligases (E3) including c‐Cbl associate with the intracytoplasmic region of EGFR, which then ubiquitinates EGFR on multiple lysine residues (Ub indicates a single ubiquitin moiety attached to the EGFR). Ubiquitinated EGFR is internalized and transported to the early endosomes. Endosomal sorting complex required for transport (ESCRT)‐0 recognizes the ubiquitinated EGFR and recruits the downstream complex ESCRT‐I. (At this point, EGFR can still deliver a signal, but the signal seems to be terminated by the sequestration of the activated EGFR into the intraluminal vesicles [ILV] of the multivesicular bodies [MVB] later in the process.) The ubiquitinated EGFR is transferred to ESCRT‐II, and then to ESCRT‐III. EGFR is deubiquitinated by association molecule with the SH3 domains of STAM (AMSH) and ubiquitin‐specific peptidase Y (UBPY). The ESCRT complexes are then dissociated, and EGFR is sorted into the ILV within the MVB. Fusion of the MVB with the lysosome results in the degradation of EGFR and other MVB contents in an acid peptidase‐dependent manner. On early endosomes, some of the EGFR is deubiquitinated by UBPY and AMSH (not shown), sorted into the tubular portion of the endosomes, and recycled back to the cell surface via recycling endosomes. (Right) Notch heading for the endosome is ubiquitinated by E3 including Itch (AIP4 in human and Su[dx] in Drosophila) and WWP1, and internalized. ESCRT‐0 captures the ubiquitinated Notch, and it is handed off to ESCRT‐I, ‐II, and ‐III sequentially. Notch that is sorted into the ILV is degraded by the lysosomal acid peptidase. The Notch cellular domain (Notch‐IC) can be produced by proteolysis at the cell surface as well as on the endosomes.