Secretion of the Notch-1 Aβ-like peptide during Notch signaling

The canonical pathway of Notch signaling is mediated by regulated intramembrane proteolysis ( RIP). In the pathway, ligand binding results in sequential proteolysis of the Notch receptor, and presenilin (PS)-dependent intramembrane proteolysis at the interface between the membrane and cytosol liberates the Notch-1 intracellular domain (NICD), a transcription modifier. Because the degradation of the Notch-1 transmembrane domain is thought to require an additional cleavage near the middle of the transmembrane domain, extracellular small peptides (Notch-1 A beta-like peptide (N beta)) should be produced. Here we showed that N beta species are indeed secreted during the process of Notch signaling. We identified mainly two distinct molecular species of novel N beta, N beta 21 and C-terminally elongated N beta 25, which were produced in an similar to 5: 1 ratio. This process is reminiscent of the production of Alzheimer disease-associated A beta. PS pathogenic mutants increased the production of the longer species of A beta(A beta 42) from beta-amyloid protein precursor. We revealed that several Alzheimer disease mutants also cause a parallel increase in the secretion of the longer form of N beta. Strikingly, chemicals that modify the A beta 42 level caused parallel changes in the N beta 25 level. These results demonstrated that the characteristics of C-terminal elongation of N beta and A beta are almost identical. In addition, because many other type 1 membrane-bound receptors release intracellular domains by PS-dependent intramembrane proteolysis, we suspect that the release of A beta- or N beta-like peptides is a common feature of the proteolysis during RIP signaling. We anticipate that this study will open the door to searches for markers of RIP signaling and surrogate markers for A beta 42 production.