Phosphorylation of amyloid precursor protein (APP) at Tyr687 regulates APP processing by alpha- and gamma-secretase.
Abnormal proteolytic processing of amyloid precursor protein (APP) is a pathologic feature of Alzheimer's disease. Recent studies have demonstrated that serine/threonine phosphorylation specifically at amino-acid residue Thr668 (APP695 numbering) regulates APP processing. In this study, we investigated the possibility that tyrosine phosphorylation of APP regulates APP processing. A tyrosine kinase inhibitor decreased expression of the C83 fragment which is a cleaved product of APP by alpha-secretase. By overexpressing APP mutant proteins, Tyr687 was found to be the major tyrosine kinase phosphorylation site. Expression of the C83 fragment was decreased in APPY687A-expressing cells relative to APP wild-type (APPWT)-expressing cells, which likely reflects the different cellular localization patterns of these two proteins. Expression of APP intracellular domain (AICD) which is a cleaved product of the C83 fragment by gamma-secretase was decreased in C83Y687A-expressing cells. These results suggest that phosphorylation of APP at Tyr687 regulates APP processing by alpha- and gamma-secretases, determining the expression level of AICD.
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto 606-8501, Japan.
Keita
K
Takahashi
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto 606-8501, Japan. Electronic address: tniidome@pharm.kyoto-u.ac.jp.
Tetsuhiro
T
Niidome
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Akinori
A
Akaike
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto 606-8501, Japan.
Takeshi
T
Kihara
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto University, Kyoto 606-8501, Japan. Electronic address: hsugimot@pharm.kyoto-u.ac.jp.
Hachiro
H
Sugimoto
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D014443:Tyrosine; D053829:Amyloid Precursor Protein Secretases