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J. Biol. Chem., Vol. 280, Issue 52, 42715-42722, December 30, 2005

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GSK-3 Directly Phosphorylates and Activates MARK2/PAR-1^*

From the Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan

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-3 (GSK-3), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3 in MARK2 activation. In vitro kinase reaction revealed that recombinant GSK-3 indeed phosphorylates MARK2, whereas it failed to phosphorylate Ser-262 of tau. Our further findings led us to conclude that GSK-3 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-3 or MARK2 by small interfering RNAs suppressed the level of phosphorylation on Ser-262. These results, respectively, indicated that GSK-3 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-3-MARK2 pathway. These findings are of interest in the context of the pathogenesis of AD.

Received for publication, July 21, 2005 , and in revised form, September 21, 2005.

^* This work was partly supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel. and Fax: 81-45-566-1557; E-mail: imoto{at}bio.keio.ac.jp.

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