A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain

@article{Strooper1999AP,
  title={A presenilin-1-dependent $\gamma$-secretase-like protease mediates release of Notch intracellular domain},
  author={Bart De Strooper and Wim Annaert and Philippe Cupers and Paul Saftig and Katleen Craessaerts and Jeff S. Mumm and Eric H. Schroeter and Vincent Schrijvers and Michael S. Wolfe and William J. Ray and Alison M. Goate and Raphael Kopan},
  journal={Nature},
  year={1999},
  volume={398},
  pages={518-522}
}
Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of γ-secretase-mediated cleavage of β-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by γ-secretase… 
Cell Surface Presenilin-1 Participates in the γ-Secretase-like Proteolysis of Notch*
TLDR
It is shown that PS1 aspartate mutants were indistinguishable from wild-type PS1 in their ability to bind Notch or traffic with it to the cell surface, and did not alter the secretion of Notch.
Secretion of the Notch-1 Aβ-like Peptide during Notch Signaling*
TLDR
It is shown that Nβ species are indeed secreted during the process of Notch signaling, and chemicals that modify the Aβ42 level caused parallel changes in the Nβ25 level, and the characteristics of C-terminal elongation of Nβ and Aβ are almost identical.
The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and γ-secretase
TLDR
It is demonstrated here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner, and that Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.
γ-Secretase-regulated Proteolysis of the Notch Receptor by Mitochondrial Intermediate Peptidase*
TLDR
The sequential and regulated proteolysis by γ-secretase and MIPEP suggests a new means by which Notch function can be modulated.
Notch1 and Amyloid Precursor Protein Are Competitive Substrates for Presenilin1-dependent γ-Secretase Cleavage*
TLDR
Two complementary approaches suggest that APP and Notch1 are physiologically relevant competitive substrates for γ-secretase activity.
Implication of APP secretases in notch signaling
TLDR
Interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans, and the anticipated interference of γ-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.
Presenilins and γ-Secretase Inhibitors Affect Intracellular Trafficking and Cell Surface Localization of the γ-Secretase Complex Components*
TLDR
It is found that PEN-2 is retained in the endoplasmic reticulum and has a much shorter half-life in PS-deficient cells than in wild type cells, suggesting that PSs are required for maintaining the stability and proper subcellular trafficking of PEN, suggesting an essential role for PSs in intracellular trafficking of the γ-secretase components.
γ-Secretase Mediated Proteolysis: At the Cutting Edge of Notch Signaling
TLDR
The molecular details involved in ectodomain shedding and intramembrane cleavage events as well as the importance of endocytosis and endosomal sorting as key regulators of γ-secretase cleavage of Notch have begun to emerge as an exciting research area in cell biology.
Presenilin-dependent γ-Secretase-like Intramembrane Cleavage of ErbB4*
TLDR
The study indicates that ErbB4 represents a first receptor tyrosine kinase that undergoes intramembrane proteolysis and may mediate a novel signaling function independent of its canonical role as a receptor tyrose kinase.
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References

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TLDR
It is shown that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL.
The Notch1 receptor is cleaved constitutively by a furin-like convertase.
TLDR
The results confirm and extend recent reports indicating that the Notch receptor exists at the plasma membrane as a heterodimeric molecule, but disagree as to the nature of the protease that is responsible for the cleavage that takes place in the extracellular region.
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TLDR
The results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.
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  • W. Ray, M. Yao, A. Goate
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
TLDR
The results suggest that the genetic relationship between presenilins and the Notch signaling pathway derives from a direct physical association between these proteins in the secretory pathway.
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TLDR
Mice generated with targeted disruptions of PS1 alleles exhibited abnormal patterning of the axial skeleton and spinal ganglia, phenotypes traced to defects in somite segmentation and differentiation, suggesting PS1 is required for the spatiotemporal expression of Notch 1 and Dll 1, which are essential for somite segmentsation and maintenance of somite borders.
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TLDR
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TLDR
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TLDR
It is demonstrated that wt and mutant PS1 and PS2 proteins form complexes with APP in living cells, strongly supporting the hypothesis that mutant PS interacts withAPP in a way that enhances the intramembranous proteolysis of the latter by a gamma-secretase cleaving at Abeta42.
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