Taru Hidenori, Suzuki Toshiharu
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku Kita-12 Nishi-6, Sapporo 060-0812, Japan.
J Biol Chem. 2004 May 14;279(20):21628-36. doi: 10.1074/jbc.M312007200. Epub 2004 Feb 17.
Beta-amyloid precursor protein (APP) is the precursor of beta-amyloid (Abeta), which is implicated in Alzheimer's disease pathogenesis. APP complements amyloid precursor-like protein 2 (APLP2), and together they play essential physiological roles. Phosphorylation at the Thr(668) residue of APP (with respect to the numbering conversion for the APP 695 isoform) and the Thr(736) residue of APLP2 (with respect to the numbering conversion for the APLP2 763 isoform) in their cytoplasmic domains acts as a molecular switch for their protein-protein interaction and is implicated in neural function(s) and/or Alzheimer's disease pathogenesis. Here we demonstrate that both APP and APLP2 can be phosphorylated by JNK at the Thr(668) and Thr(736) residues, respectively, in response to cellular stress. X11-like (X11L, also referred to as X11beta and Mint2), which is a member of the mammalian LIN-10 protein family and a possible regulator of Abeta production, elevated APP and APLP2 phosphorylation probably by facilitating JNK-mediated phosphorylation, whereas other members of the family, X11 and X11L2, did not. These observations revealed an involvement of X11L in the phosphorylation of APP family proteins in cellular stress and suggest that X11L protein may be important in the physiology of APP family proteins as well as in the regulation of Abeta production.
β-淀粉样前体蛋白（APP）是β-淀粉样蛋白（Aβ）的前体，与阿尔茨海默病的发病机制有关。APP与淀粉样前体样蛋白2（APLP2）互补，它们共同发挥重要的生理作用。APP胞质结构域中Thr（668）残基（相对于APP 695异构体的编号转换）和APLP2胞质结构域中Thr（736）残基（相对于APLP2 763异构体的编号转换）的磷酸化作为其蛋白质-蛋白质相互作用的分子开关，并与神经功能和/或阿尔茨海默病的发病机制有关。在这里，我们证明，响应细胞应激时，JNK可分别使APP和APLP2在Thr（668）和Thr（736）残基处发生磷酸化。X11样蛋白（X11L，也称为X11β和Mint2）是哺乳动物LIN-10蛋白家族的成员，可能是Aβ产生的调节因子，它可能通过促进JNK介导的磷酸化来提高APP和APLP2的磷酸化水平，而该家族的其他成员X11和X11L2则没有这种作用。这些观察结果揭示了X11L在细胞应激时参与APP家族蛋白的磷酸化过程，并表明X11L蛋白在APP家族蛋白的生理学以及Aβ产生的调节中可能很重要。
