GSK-3β directly phosphorylates and activates MARK2/PAR-1

Shinichi Kosuga, Etsu Tashiro, Toshifumi Kajioka, Mayumi Ueki, Yoshifumi Shimizu, Masaya Imoto

研究成果: Article査読

44 被引用数 (Scopus)

抄録

In Alzheimer disease (AD), the microtubule-associated protein tau is found hyperphosphorylated in paired helical filaments. Among many phosphorylated sites in tau, Ser-262 is the major site for abnormal phosphorylation of tau in AD brain. The kinase known to phosphorylate this particular site is MARK2, whose activation mechanism is yet to be studied. Our first finding that treatment of cells with LiCl, a selective inhibitor of another major tau kinase, glycogen synthase kinase-3β (GSK-3β), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3β in MARK2 activation. In vitro kinase reaction revealed that recombinant GSK-3β indeed phosphorylates MARK2, whereas it failed to phosphorylate Ser-262 of tau. Our further findings led us to conclude that GSK-3β phosphorylates MARK2 on Ser-212, one of the two reported phosphorylation sites (Thr-208 and Ser-212) found in the activation loop of MARK2. Down-regulation of either GSK-3β or MARK2 by small interfering RNAs suppressed the level of phosphorylation on Ser-262. These results, respectively, indicated that GSK-3β is responsible for phosphorylating Ser-262 of tau through phosphorylation and activation of MARK2 and that the phosphorylation of tau at this particular site is predominantly mediated by a GSK-3β-MARK2 pathway. These findings are of interest in the context of the pathogenesis of AD.

本文言語English
ページ(範囲)42715-42722
ページ数8
ジャーナルJournal of Biological Chemistry
280
52
DOI
出版ステータスPublished - 2005 12 30

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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