Fig. 10: Proposed model for regulation of Notch signaling by nutrients in blood cell progenitors.

Amino acids enter the cell through the transporter Slimfast (Slif), thereby stimulating the kinase TOR, which results in inhibition of autophagosome formation (yellow lines). Notch is endocytosed after ligand (Ser) binding, and Kuzbanian (Kuz)-dependent cleavage. The Notch Intracellular Domain (NICD) remains inserted in the membrane of early endosomes, which then mature into late endosomes and further into multivesicular bodies (black arrows). The NICD can be processed by the γ-secretase (γ-sec) at the limiting membrane of late endosomes or multivesicular bodes, and released to enter the nucleus, where it regulates transcription (green arrows). Alternatively, the NICD present at the limiting membrane of multivesicular bodies, can be internalized to end up in intraluminal vesicles. Fusion of multivesicular bodies with autophagosomes results in Notch-containing amphisomes, which fuse with lysosomes to form autolysosomes (red arrows), where Notch is finally degraded. Thus, nutrient availability regulates the abundance of autophagosomes (yellow arrows), which ultimately determines the extent of Notch lysosomal degradation (red arrows). If Notch is not degraded, it can be activated to control gene expression (green arrows).