Figure 2.

Mechanisms underlying ligand-induced Notch processing. Upon ligand engagement, the signal-sending cell exerts a pulling force on the Notch receptor by internalizing the ligand and Notch extracellular domain. Simultaneously, the residual portion of the Notch receptor is endocytosed into the signal-receiving cell via Ras-related protein 5 (Rab5)-positive vesicles, where it is cleaved by ADAMs (red scissors). This first cleavage event primes the Notch receptor for a subsequent cleavage by γ-secretase complex (blue scissors) in the endosome, which releases intracellular Notch (ICN) from the membrane and allows it to transmigrate to the nucleus. Alternatively, the Notch receptor can be escorted by endosomal sorting complexes required for transport proteins (ESCRT) to the lysosome where it is degraded.