title: Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation.
abstract: The Alcadeins (Alcs)/calsyntenins and the amyloid beta-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent gamma-cleavage that leads to the secretion of the amyloid beta-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid beta-protein may contribute to neural disorders.
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku Kita-12 Nishi-6, Sapporo 060-0812, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Araki
authors.forename: Naomi
authors.initials: N
authors.lastname: Miyagi
authors.forename: Naoko
authors.initials: N
authors.lastname: Kato
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshida
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Wada
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003470:Culture Media / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008954:Models, Biological; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D003470:Culture Media; D018076:DNA, Complementary; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human