The Notch signaling pathway plays a role in cell fate specification in many metazoans. A critical aspect of Notch activation involves proteolysis of the Notch receptor. This cleavage event requires Presenilin as a component of a large multiprotein complex, gamma-secretase. This complex mediates a similar cleavage event of the beta-amyloid precursor protein (APP). The transmembrane protein Nicastrin has been found to associate with Presenilin, Notch, and APP. Recent biochemical and genetic studies have focused on elucidating the function of this protein.
"Ncstn has been implicated to be a substrate receptor, essential for APP and Notch cleavage (Kopan & Goate, 2002; Shah et al., 2005). A number of studies have suggested that ncstn forms with Aph-1, an initial scaffolding precomplex, upon which the active c-secretase complex is formed (Yu et al., 2000), and ncstn has also been implicated in PS1 regulation and stability (Edbauer et al., 2002). "
[Show abstract][Hide abstract] ABSTRACT: Production of Aβ by γ-secretase is a key event in Alzheimer's disease (AD). The γ-secretase complex consists of Presenilin (PS) 1 or 2, Nicastrin (ncstn), Pen-2 and Aph-1 and cleaves type I transmembrane proteins, including the amyloid precursor protein (APP). Although ncstn is widely accepted as an essential component of the complex required for γ-secretase activity, recent in vitro studies have suggested that ncstn is dispensable for APP processing and Aβ production. The focus of this study was to answer this controversy and evaluate the role of ncstn in Aβ generation and the development of the amyloid-related phenotype in the mouse brain. To eliminate ncstn expression in the mouse brain we used a ncstn conditional knock-out mouse that we mated with an established AD transgenic mouse model (5XFAD) and a neuronal Cre expressing transgenic mouse (CamKIIα-iCre), to generate AD mice (5XFAD/CamKIIα-iCre/ncstn(f/f) mice) where ncstn was conditionally inactivated in the brain. 5XFAD/CamKIIα-iCre/ncstn(f/f) mice at 10 week of age developed a neurodegenerative phenotype with a significant reduction in Aβ production and formation of Aβ aggregates, and absence of amyloid plaques. Inactivation of nctsn resulted in substantial accumulation of APP-CTFs and altered PS1 expression. These results reveal a key role for ncstn in modulating Aβ production and amyloid plaque formation in vivo and suggest ncstn as a target in AD therapeutics. This article is protected by copyright. All rights reserved.
"The NCT gene is located on chromosome 1q23, a region that is linked to an AD susceptibility locus . NCT performs a critical function in gamma-secretase complex activation and in the Abeta generation associated with AD pathogenesis , , , . NCT is a 709-amino acid single-pass membrane protein, and is the most abundant subunit of the gamma-secretase complex; the protein harbors a number of glycosylation sites within its large extracellular domain (ECD) , . "
[Show abstract][Hide abstract] ABSTRACT: The gamma-secretase complex is involved in the intramembranous proteolysis of a variety of substrates, including the amyloid precursor protein and the Notch receptor. Nicastrin (NCT) is an essential component of the gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we determined that serum- and glucocorticoid-induced protein kinase 1 (SGK1) markedly reduced the protein stability of NCT. The SGK1 kinase activity was decisive for NCT degradation and endogenous SGK1 inhibited gamma-secretase activity. SGK1 downregulates NCT protein levels via proteasomal and lysosomal pathways. Furthermore, SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. Collectively, our findings indicate that SGK1 is a gamma-secretase regulator presumably effective through phosphorylation and degradation of NCT.
PLoS ONE 05/2012; 7(5):e37111. DOI:10.1371/journal.pone.0037111 · 3.23 Impact Factor
"However, compared to β-secretase, γ-secretase is less understood. It is known that transmembrane proteins PS1 and PS2 (Strooper and Annaert, 2001), and nicastrin (Kopan and Goate, 2002) are required for the activity of γ-secretase. γ-secretase is involved in the cleavage of other integral membrane proteins including Notch (Strooper and Annaert, 2001), CD44 receptor (Okamoto et al., 2001). "
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