Pamrén A, Wanngren J, Tjernberg LO, Winblad B, Bhat R, Näslund J, Karlström H.
Mutations in nicastrin protein differentially affect amyloid beta-peptide production and Notch protein processing.
J Biol Chem. 2011 Sep 9;286(36):31153-8.
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Karlstrom, Naslund, and colleagues now provide evidence that two conserved cysteine residues (C213 and C230) in the nicastrin ectodomain can differentially affect γ-secretase processing of APP and Notch. The authors showed that mutating these residues results in reduced APP processing while Notch processing is minimally impacted. Their studies suggest that targeting nicastrin might represent a valid strategy of inhibiting amyloid production without affecting Notch processing for Alzheimer’s therapy. In an independent study published in Oncogene, Iwatsubo, Tomita, and colleagues showed that targeting the nicastrin ectodomain by a monoclonal antibody (A5226A) can neutralize γ-secretase activity by recognizing a site at or close to the substrate recognition pocket in mature nicastrin (Hayashi et al., 2012). Moreover, this antibody abolished the γ-secretase activity-dependent growth of cancer cells in a xenograft model. Together, these studies raise the important prospect of targeting different sites on the nicastrin ectodomain for Alzheimer's and cancer therapies.
Both studies are partially based on testing and extending the model that nicastrin is a γ-secretase substrate receptor (Shah et al., 2005; Dries et al., 2009), and both studies conclude that their observations are consistent with this model. The Karlstrom paper also provided evidence that the nicastrin E333A affects intrinsic γ-secretase activity; the Iwatsubo paper showed that the A5226A antibody neutralizes γ-secretase activity by competing with the substrate binding. These studies thus add credence to the role of nicastrin in substrate recognition. Considering that a parallel mechanism has been observed in another intramembrane protease (Li et al., 2009; Dries et al., 2009), the concept of nicastrin as a substrate receptor is compelling. The Iwatsubo and Karlstrom studies now provide a proof of concept and a mechanistic basis for targeting this function of nicastrin for developing therapeutics for cancer and Alzheimer’s disease.
Shah S, Lee SF, Tabuchi K, Hao YH, Yu C, LaPlant Q, Ball H, Dann CE, Südhof T, Yu G.
Nicastrin functions as a gamma-secretase-substrate receptor.
Cell. 2005 Aug 12;122(3):435-47.
Dries DR, Shah S, Han YH, Yu C, Yu S, Shearman MS, Yu G.
Glu-333 of nicastrin directly participates in gamma-secretase activity.
J Biol Chem. 2009 Oct 23;284(43):29714-24.
Li X, Wang B, Feng L, Kang H, Qi Y, Wang J, Shi Y.
Cleavage of RseA by RseP requires a carboxyl-terminal hydrophobic amino acid following DegS cleavage.
Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14837-42.
Dries DR, Yu G.
Rip exposed: how ectodomain shedding regulates the proteolytic processing of transmembrane substrates.
Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14737-8.
Hayashi I, Takatori S, Urano Y, Miyake Y, Takagi J, Sakata-Yanagimoto M, Iwanari H, Osawa S, Morohashi Y, Li T, Wong PC, Chiba S, Kodama T, Hamakubo T, Tomita T, Iwatsubo T.
Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin.
Oncogene. 2011 Jul 4;