Regulation of FE65 nuclear translocation and function by amyloid beta-protein precursor in osmotically stressed cells.
FE65, a neural adaptor protein, interacts with amyloid beta-protein precursor (APP) and is known to regulate amyloid beta generation from APP. FE65 also associates with nuclear proteins; however, its physiological function in the nucleus remains unclear. A fixed population of cytoplasmic FE65 is tethered to membranes by binding APP. This membrane-tethered FE65 is liberated from membranes by APP phosphorylation, which is facilitated by a stress-activated protein kinase in sorbitol-treated cells. Here we show that liberated FE65, which is distinct from "virgin" FE65 in the cytoplasm, translocates into the nucleus and accumulates in the nuclear matrix forming a patched structure. Targeting of FE65 into the nuclear matrix was suppressed by the APP intracellular domain fragment, which is generated by consecutive cleavages of APP. Thus, nuclear translocation of FE65 is under the regulation of APP. In the nucleus, FE65 induced gammaH2AX, which plays an important role in DNA repair as a cellular response by stress-damaged cells. These observations suggest that APP-regulated FE65 plays an important role in the early stress response of cells and that FE65 deregulated from APP induces apoptosis.
Nakaya
Tadashi
T
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Kawai
Tomoko
T
Suzuki
Toshiharu
T
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D015530:Nuclear Matrix / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009997:Osmotic Pressure / Q000187:drug effects; D013012:Sorbitol / Q000494:pharmacology; D013549:Sweetening Agents / Q000494:pharmacology
C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; C468783:H2AX protein, human; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D013549:Sweetening Agents; C475961:gamma-H2AX protein, mouse; D013012:Sorbitol; D000255:Adenosine Triphosphate