Abstract
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.
Highlights
The cytoplasmic domain of Amyloid precursor protein (APP) (APPcyt) is composed of 47 amino acid residues, and its phosphorylation at Thr668 is suggested to play an important role in controlling the metabolism and physiological functioning of APP (6 –9)
We demonstrated that phosphorylation of APP and amyloid precursor-like protein 2 (APLP2) is induced by JNK family proteins in response to cellular stress and is regulated by one of their binding proteins, X11L
What kind of JNK protein kinases can phosphorylate APP? JNK protein kinases are encoded by three genes, Jnk1, Jnk2, and Jnk3, which are highly homologous and are involved in signaling apoptosis, stress responses, and proliferation [18]
Summary
The cytoplasmic domain of APP (APPcyt) is composed of 47 amino acid residues, and its phosphorylation at Thr668 (with respect to the numbering conversion for the APP 695 isoform) is suggested to play an important role in controlling the metabolism and physiological functioning of APP (6 –9). Phosphorylation of APLP2 at Thr736 was mediated by all of the JNK kinases that we examined (Fig. 1C, upper panel). We examined the involvement of endogenous JNK in stress-induced APP phosphorylation using selective kinase inhibitors in HEK293 cells stably expressing APP.
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