title: Complex regulation of γ-secretase: from obligatory to modulatory subunits.
abstract: γ-Secretase is a four subunit, 19-pass transmembrane enzyme that cleaves amyloid precursor protein (APP), catalyzing the formation of amyloid beta (Aβ) peptides that form amyloid plaques, which contribute to Alzheimer's disease (AD) pathogenesis. γ-Secretase also cleaves Notch, among many other type I transmembrane substrates. Despite its seemingly promiscuous enzymatic capacity, γ-secretase activity is tightly regulated. This regulation is a function of many cellular entities, including but not limited to the essential γ-secretase subunits, nonessential (modulatory) subunits, and γ-secretase substrates. Regulation is also accomplished by an array of cellular events, such as presenilin (active subunit of γ-secretase) endoproteolysis and hypoxia. In this review we discuss how γ-secretase is regulated with the hope that an advanced understanding of these mechanisms will aid in the development of effective therapeutics for γ-secretase-associated diseases like AD and Notch-addicted cancer.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center New York, NY, USA ; Biochemistry and Molecular Biology Program, Weill Graduate School of Medical Sciences of Cornell University New York, NY, USA.
authors.forename: Natalya
authors.initials: N
authors.lastname: Gertsik
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center New York, NY, USA ; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University New York, NY, USA.
authors.forename: Danica
authors.initials: D
authors.lastname: Chiu
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center New York, NY, USA ; Program of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University New York, NY, USA.
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
keywords: APP; Alzheimer’s disease; Hif-1α; Notch; presenilin; β-amyloid; γ-Secretase