ArticleThe Journal of biological chemistry2005
Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components.
Article in The Journal of biological chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed.
- Expression of nicastrin, NICD1, and Hes1 in NCSTN knockout mice: implications for hidradenitis suppurativa, Alzheimer's, and liver cancer.European journal of medical research · 2024Article
- Notch signaling without the APH-2/nicastrin subunit of gamma secretase in Caenorhabditis elegans germline stem cells.Genetics · 2024Article
- New mechanism of metformin action mediated by lysosomal presenilin enhancer 2.Journal of diabetes investigation · 2023Article
- Hidradenitis Suppurativa: A Perspective on Genetic Factors Involved in the Disease.Biomedicines · 2022Article
- Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer's Disease.Neurotoxicity research · 2020Review
- A novel nicastrin mutation in a three-generation Dutch family with hidradenitis suppurativa: a search for functional significance.Journal of the European Academy of Dermatology and Venereology : JEADV · 2020Article
- NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner.Journal of experimental & clinical cancer research : CR · 2020Article
- BACE1 partial deletion induces synaptic plasticity deficit in adult mice.Scientific reports · 2019Article
- Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ-secretase modulators.The EMBO journal · 2019Article
- A novel triazole, NMK-T-057, induces autophagic cell death in breast cancer cells by inhibiting γ-secretase-mediated activation of Notch signaling.The Journal of biological chemistry · 2019Article
- SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aβ Accumulation and Memory Deficits in an AD Mouse.Frontiers in cellular neuroscience · 2019Article
- γ-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding.Frontiers in chemistry · 2018Article
- Chronic Cerebral Hypoperfusion Promotes Amyloid-Beta Pathogenesis via Activating β/γ-Secretases.Neurochemical research · 2017Article
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- ER-associated degradation regulates Alzheimer's amyloid pathology and memory function by modulating γ-secretase activity.Nature communications · 2017Article
- SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation.Molecular neurobiology · 2016Article
- SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity.Molecular metabolism · 2016Article
1 more citing papers are in PubMed but not listed here.
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11 authors.
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Abstract
gamma-Secretase, which is responsible for the intramembranous cleavage of Alzheimer beta-amyloid precursor protein and the signaling receptor Notch, is a multiprotein complex consisting of at least four components: presenilin (PS); nicastrin (Nct); APH-1 (anterior pharynx-defective-1); and presenilin enhancer-2 (PEN-2). Presenilin 1 (PS1) is known to be essential for the stability, interaction, and trafficking of the other PS1/gamma-secretase components. However, the precise functions of the other components remain elusive. Here, we investigated the functions of Nct within the PS1/gamma-secretase complex. We demonstrated that the loss of Nct expression in the embryonic fibroblast cells (Nct KO cells) results in dramatically decreased levels of APH-1, PEN-2, and PS1 fragments accompanied by a significant accumulation of full-length PS1. In the absence of Nct, PEN-2 and full-length PS1 are subjected to proteasome-mediated degradation, whereas the degradation of APH-1 is mediated by both proteasomal and lysosomal pathways. Unlike the case of wild type cells in which the gamma-secretase complex mainly locates in the trans-Golgi network, the majority of residual PEN-2, APH-1, and the uncleaved full-length PS1 in Nct KO cells reside in the endoplasmic reticulum, which remain associated with each other in the absence of Nct. Interestingly, significant amounts of full-length PS1 and PEN-2, but not APH-1, are detected on the plasma membrane in Nct KO cells, suggesting the Nct-independent cell surface delivery of the PEN-2.PS1. Finally, the diminished PEN-2 protein level in Nct-deficient cells can be partially restored by overexpression of exogenous PS1, APH-1, or PEN-2 individually or collectively, indicating a dispensable role for Nct in controlling PEN-2 level. Taken together, our study demonstrates a critical role of Nct in the stability and proper intracellular trafficking of other components of the PS1/ gamma-secretase complex but not in maintaining the association of PEN-2, APH-1, and full-length PS1.
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