Secretion of the Notch-1 Abeta-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 Abeta-like peptide (Nbeta)) should be produced. Here we showed that Nbeta species are indeed secreted during the process of Notch signaling. We identified mainly two distinct molecular species of novel Nbeta, Nbeta21 and C-terminally elongated Nbeta25, which were produced in an approximately 5:1 ratio. This process is reminiscent of the production of Alzheimer disease-associated Abeta. PS pathogenic mutants increased the production of the longer species of Abeta (Abeta42) 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 Nbeta. Strikingly, chemicals that modify the Abeta42 level caused parallel changes in the Nbeta25 level. These results demonstrated that the characteristics of C-terminal elongation of Nbeta and Abeta 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 Abeta- or Nbeta-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 Abeta42 production.
Okochi
Masayasu
M
Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. mokochi@psy.med.osaka-u.ac.jp
Fukumori
Akio
A
Jiang
Jingwei
J
Itoh
Naohiro
N
Kimura
Ryo
R
Steiner
Harald
H
Haass
Christian
C
Tagami
Shinji
S
Takeda
Masatoshi
M
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D053764:Presenilin-1; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; D018076:DNA, Complementary; D008024:Ligands; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C508853:PSEN1 protein, human; D010455:Peptides; D053764:Presenilin-1; D051881:Receptor, Notch1; D004247:DNA