Phosphorylation of FE65 Ser610 by serum- and glucocorticoid-induced kinase 1 modulates Alzheimer's disease amyloid precursor protein processing

Biochem J. 2015 Sep 15;470(3):303-17. doi: 10.1042/BJ20141485. Epub 2015 Jul 17.

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.

Keywords: Alzheimer's disease; FE65; amyloid precursor protein (APP); amyloid-β peptide; protein degradation; serum- and glucocorticoid-induced kinase 1 (SGK1).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / chemistry
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • CHO Cells
  • COS Cells
  • Chlorocebus aethiops
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Stability
  • Proteolysis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Serine / chemistry

Substances

  • APBB1 protein, human
  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Immediate-Early Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Recombinant Proteins
  • Serine
  • Protein Serine-Threonine Kinases
  • serum-glucocorticoid regulated kinase
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Proteasome Endopeptidase Complex