Role of APP phosphorylation in FE65-dependent gene transactivation mediated by AICD.
Consecutive cleavages of Alzheimer's amyloid beta-protein precursor (APP) generate intracellular domain fragment (AICD). Interaction of APP and/or AICD with the adaptor protein FE65 is thought to modulate the metabolism of APP and the function of AICD. Phosphorylation or amino acid substitution of APP and AICD at threonine 668 (Thr668) suppresses their association with FE65. Here, we analyzed the function of APP and AICD phosphorylation in the nuclear translocation of FE65. In brain, AICD was present as phosphorylated and non-phosphorylated forms with non-phosphorylated AICD being dominantly detected in the nucleus. However, a mutant AICD (AICDa), in which Thr668 of AICD was replaced with Ala, was also mostly localized to the nucleus. These observations indicate that phosphorylation of AICD does not regulate the translocation of FE65 and that FE65 does not accompany AICD into the nucleus. APP was known to tether FE65 to the membrane. We found that phosphorylation of APP liberated membrane-bound FE65, which was then translocated into the nucleus where it up-regulated gene transactivation mediated by AICD, which was translocated into the nucleus independently of FE65. Therefore, phosphorylation of APP but not AICD modulates FE65-dependent gene transactivation mediated by AICD through the regulation of FE65 intracellular localization.
Nakaya
Tadashi
T
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Suzuki
Toshiharu
T
D021581:Active Transport, Cell Nucleus; D000409:Alanine / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D013912:Threonine; D000409:Alanine