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- W2078163062 endingPage "2665" @default.
- W2078163062 startingPage "2654" @default.
- W2078163062 abstract "Hyperphosphorylation of microtubule-associated protein tau is thought to contribute to Alzheimer’s disease (AD) pathogenesis. We previously showed that DNA damage-activated cell cycle checkpoint kinases Chk1 and Chk2 phosphorylate tau at an AD-related site and enhance tau toxicity, suggesting potential roles of these kinases in AD. The purpose of this study is to systematically identify which sites in tau are directly phosphorylated by Chk1 and Chk2. Using recombinant human tau phosphorylated by Chk1 and Chk2 in vitro, we first analyzed tau phosphorylation at the AD-related sites by Western blot with phospho-tau-specific antibodies. Second, to globally identify phosphorylated sites in tau, liquid chromatography–tandem mass spectrometry (LC–MS3) was employed. These systematic analyses identified a total of 27 Ser/Thr residues as Chk1- or Chk2- target sites. None of them were proline-directed kinase targets. Many of these sites are located within the microtubule-binding domain and C-terminal domain, whose phosphorylation has been shown to reduce tau binding to microtubules and/or has been implicated in tau toxicity. Among these 27 sites, 13 sites have been identified to be phosphorylated in AD brains. Since DNA damage is accumulated in diseased brains, Chk1 and Chk2 may be involved in tau phosphorylation and toxicity in AD pathogenesis." @default.
- W2078163062 created "2016-06-24" @default.
- W2078163062 creator A5004483141 @default.
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- W2078163062 creator A5042162699 @default.
- W2078163062 creator A5048063862 @default.
- W2078163062 creator A5079033274 @default.
- W2078163062 date "2013-04-26" @default.
- W2078163062 modified "2023-10-18" @default.
- W2078163062 title "Global Analysis of Phosphorylation of Tau by the Checkpoint Kinases Chk1 and Chk2 <i>in vitro</i>" @default.
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- W2078163062 doi "https://doi.org/10.1021/pr400008f" @default.
- W2078163062 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3757556" @default.
- W2078163062 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23550703" @default.
- W2078163062 hasPublicationYear "2013" @default.