Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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

J Biol Chem 281(12): 7890-8

Authors/Editors: Okochi M
Jiang J
Itoh N
Kimura R
Steiner H
Haass C
Tagami S
Takeda M
Publication Date: 2006
Type of Publication: Journal Article

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 Aβ-like peptide (Nβ)) should be produced. Here we showed that Nβ species are indeed secreted during the process of Notch signaling. We identified mainly two distinct molecular species of novel Nβ, Nβ21 and C-terminally elongated Nβ25, which were produced in an approximately 5:1 ratio. This process is reminiscent of the production of Alzheimer disease-associated Aβ. PS pathogenic mutants increased the production of the longer species of Aβ (Aβ42) from β-amyloid protein precursor. We revealed that several Alzheimer disease mutants also cause a parallel increase in the secretion of the longer form of Nβ. Strikingly, chemicals that modify the Aβ42 level caused parallel changes in the Nβ25 level. These results demonstrated that the characteristics of C-terminal elongation of Nβ and Aβ 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 Aβ- or Nβ-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 Aβ42 production.

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