Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing

@article{Yu2000NicastrinMP,
  title={Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and $\beta$APP processing},
  author={Gang Yu and Masaki Nishimura and Shigeki Arawaka and Diane J Levitan and Lili Zhang and Anurag Tandon and You-Qiang Song and Ekaterina Rogaeva and Fusheng Chen and Toshitaka Kawarai and Agnes Supala and Lyne Lévesque and Haung Yu and Dun-Sheng Yang and Erin Holmes and Paul Milman and Yan Liang and Dong Mei Zhang and Dong Hong Xu and Christine Sato and Evgeny I. Rogaev and Marsha M. Smith and Christopher Janus and Yanni Zhang and Ruedi Aebersold and Lindsay A. Farrer and Sandro Sorbi and Amalia Cecilia Bruni and Paul E. Fraser and Peter St. George-Hyslop},
  journal={Nature},
  year={2000},
  volume={407},
  pages={48-54}
}
Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (A… 
Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila
TLDR
It is shown that, in Drosophila, loss of Nicastrin activity blocks the accumulation of Presenilin associated with the apical plasma membrane, abolishes PresenILin-dependent cleavage of the transmembrane domains of Notch and β-APP, and abrogates Notch signal transduction.
Nicastrin binds to membrane-tethered Notch
TLDR
Nicastrin has a similar role in processing Notch and βAPP, but the 312–369 domain may have differential effects on these activities, and it is reported that the Notch or βAPP pathways do not significantly compete with each other.
Co-expression of Nicastrin and Presenilin Rescues a Loss of Function Mutant of APH-1*
TLDR
It is concluded that cooperative effects may stabilize a trim-eric complex of APH-1a G122D together with PS1 and NCT, and that PS seems to contribute the catalytic core of the γ-secretase complex.
Mammalian APH-1 Interacts with Presenilin and Nicastrin and Is Required for Intramembrane Proteolysis of Amyloid-β Precursor Protein and Notch*
TLDR
Using co-immunoprecipitation and nickel affinity pull-down approaches, it is shown that mammalian APH-1, a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.
Presenilin and nicastrin regulate each other and determine amyloid β-peptide production via complex formation
TLDR
It is concluded that Nct and PS regulate each other and determine γ-secretase function via complex formation and down-regulation of Nct levels destabilized PS and strongly lowered levels of the high molecular weight PS1 complex.
Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype
TLDR
It is reported here that a genetic modifier on mouse distal chromosome 1, coinciding with the locus containing Nicastrin, influences presenilin-mediated Notch S3-site cleavage and the resultant Notch phenotype without affecting presenILin- mediated APP γ- site cleavage.
PS1 Interacts With and Facilitates β-Catenin Turnover
TLDR
Without doubt, this “regulated intramembrane proteolysis” takes a central role in both AD pathogenesis and development through regulating γ-secretase activity in APP cleavage and Notch signal transduction.
Nicastrin Is Required for Assembly of Presenilin/γ-Secretase Complexes to Mediate Notch Signaling and for Processing and Trafficking of β-Amyloid Precursor Protein in Mammals
TLDR
It is established that nicastrin is an essential component of the multimeric γ-secretase complex in mammals required for both γ -secretase activity and APP trafficking and suggest that Nicastrin may be a valuable therapeutic target for Alzheimer's disease.
Positive and Negative Regulation of the γ-Secretase Activity by Nicastrin in a Murine Model*
TLDR
It is demonstrated that Nicastrin-deficient mice showed a phenotype that is indistinguishable from PS1/PS2 double knock-out mice, whereas heterozygotes were healthy and viable, and thatNicastrin has both positive and negative functions in the regulation of γ-secretase activity.
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TLDR
It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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    Proceedings of the National Academy of Sciences of the United States of America
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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
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TLDR
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