FIGURE 16-36 Notch/Delta signaling pathway. In the absence of Delta, the transmembrane subunit of Notch on a responding cell is noncovalently associated with its extracellular subunit; the extracellular domain is folded so that it cannot be cleaved by the cell-surface protease ADAM 10. Binding of Notch to its ligand Delta on an adjacent signaling cell (step 1) is followed by endocytosis of Delta by the signaling cell, stretching the Notch extracellular domain so that ADAM 10 can cleave it (step 2). The released Notch extracellular domain remains bound to Delta and is endocytosed by the signaling cell (step 3). Next the nicastrin subunit (colored red) of the four-protein γ-secretase complex binds to the stump generated by ADAM 10 (step 4), and then the protease, presenilin 1, catalyzes an intramembrane cleavage that releases the cytosolic segment of Notch (step 5). Following translocation to the nucleus, this Notch segment interacts with several transcription factors to affect expression of genes that in turn influence the determination of cell fate during development (step 6). See D. Seals and S. Courtneidge, 2003, Gene Dev. 17:7, and L. Meloty-Kapella et al., 2012, Dev. Cell 22:1299.