title: Phosphorylation of FE65 Ser610 by serum- and glucocorticoid-induced kinase 1 modulates Alzheimer's disease amyloid precursor protein processing.
abstract: Alzheimer's disease (AD) is a fatal neurodegenerative disease affecting 36 million people worldwide. Genetic and biochemical research indicate that the excessive generation of amyloid-β peptide (Aβ) from amyloid precursor protein (APP), is a major part of AD pathogenesis. FE65 is a brain-enriched adaptor protein that binds to APP. However, the role of FE65 in APP processing and the mechanisms that regulate binding of FE65 to APP are not fully understood. In the present study, we show that serum- and glucocorticoid-induced kinase 1 (SGK1) phosphorylates FE65 on Ser(610) and that this phosphorylation attenuates FE65 binding to APP. We also show that FE65 promotes amyloidogenic processing of APP and that FE65 Ser(610) phosphorylation inhibits this effect. Furthermore, we found that the effect of FE65 Ser(610) phosphorylation on APP processing is linked to a role of FE65 in metabolic turnover of APP via the proteasome. Thus FE65 influences APP degradation via the proteasome and phosphorylation of FE65 Ser(610) by SGK1 regulates binding of FE65 to APP, APP turnover and processing.
authors.affiliation: School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
authors.forename: Wan Ning Vanessa
authors.initials: WN
authors.lastname: Chow
authors.affiliation: School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
authors.forename: Jacky Chi Ki
authors.initials: JC
authors.lastname: Ngo
authors.affiliation: School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: King's College London, Randall Division of Cell and Molecular Biophysics, London SE1 1UL, U.K.
authors.forename: Yu Wai
authors.initials: YW
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
authors.forename: Ka Ming Vincent
authors.initials: KM
authors.lastname: Tam
authors.affiliation: School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR.
authors.forename: Ho Yin Edwin
authors.initials: HY
authors.lastname: Chan
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, U.K.
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
authors.affiliation: School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR kflau@cuhk.edu.hk.
authors.forename: Kwok-Fai
authors.initials: KF
authors.lastname: Lau
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D012694:Serine; D000099184:Serum-Glucocorticoid Regulated Kinases; C091042:APBB1 protein, human; C545487:APP protein, human; C509280:BACE1 protein, human
keywords: Alzheimer's disease; FE65; amyloid precursor protein (APP); amyloid-β peptide; protein degradation; serum- and glucocorticoid-induced kinase 1 (SGK1)