title: Role of human GKN1 on APP processing in gastric cancer.
abstract: Gastrokine 1 (GKN1) is highly expressed in gastric tissue and is secreted into the stomach but is not expressed in gastric cancer. GKN1 belongs to the BRICHOS domain family and plays a major role in maintaining gastric mucosa integrity. We previously demonstrated that a recombinant human GKN1 protein was able to interact with the amyloid precursor protein (APP) and was endowed with an anti-amyloidogenic property because it inhibited polymerization of the Aβ(1-40) peptide released from APP upon its partial hydrolysis. Here, we report that GKN1 can act as a physiological suppressor of Aβ production in gastric cancer cells. GKN1 blocked the access of γ-secretase to APP, thereby facilitating the cleavage of APP by α- and β-secretases. GKN1 directly interacted with APP C-terminal fragments, C83 and C99. In addition, it did not affect γ-secretase activity in gastric cancer cells because it did not alter Notch1 processing. GKN1-mediated inhibition of APP processing might represent a new approach for the prevention and therapy of Alzheimer's disease (AD).
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Chiara Stella
authors.initials: CS
authors.lastname: Di Stadio
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Altieri
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Minopoli
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Miselli
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy. Electronic address: emilia.rippa@unina.it.
authors.forename: Emilia
authors.initials: E
authors.lastname: Rippa
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy; CEINGE, Advanced Biotechnology Scarl, Via Gaetano Salvatore 486, I-80145, Naples, Italy. Electronic address: paolo.arcari@unina.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arcari
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D036361:Peptide Hormones / Q000378:metabolism*; D011485:Protein Binding; D013274:Stomach Neoplasms / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; C477000:GKN1 protein, human; D036361:Peptide Hormones; D053829:Amyloid Precursor Protein Secretases
keywords: APP processing; BRICHOS domain; Gamma-secretase; Gastrokine 1; Notch 1