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J. Biol. Chem., Vol. 279, Issue 25, 26105-26114, June 18, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/25/26105    most recent M308298200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yuan, Z. Articles by Paudel, H. K. Search for Related Content PubMed PubMed Citation Articles by Yuan, Z. Articles by Paudel, H. K. Social Bookmarking                      What's this?

14-3-3 Binds to and Mediates Phosphorylation of Microtubule-associated Tau Protein by Ser⁹-phosphorylated Glycogen Synthase Kinase 3 in the Brain^*

Zongfei Yuan, Alka Agarwal-Mawal, and Hemant K. Paudel¶

From the Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital and the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3T 1E2, Canada

In mammalian brain, tau, glycogen synthase kinase 3 (GSK3), and 14-3-3, a phosphoserine-binding protein, are parts of a multiprotein tau phosphorylation complex. Within the complex, 14-3-3 simultaneously binds to tau and GSK3 (Agarwal-Mawal, A., Qureshi, H. Y., Cafferty, P. W., Yuan, Z., Han, D., Lin, R., and Paudel, H. K. (2003) J. Biol. Chem. 278, 12722–12728). The molecular mechanism by which 14-3-3 connects GSK3 to tau within the complex is not clear. In this study, we find that GSK3 within the tau phosphorylation complex is phosphorylated on Ser⁹. From extracts of rat brain and rat primary cultured neurons, Ser⁹-phosphorylated GSK3 precipitates with glutathione-agarose beads coated with glutathione S-transferase-14-3-3. Similarly, from rat brain extract, Ser⁹-phosphorylated GSK3 co-immunoprecipitates with tau. In vitro, 14-3-3 binds to GSK3 only when the kinase is phosphorylated on Ser⁹. In transfected HEK-293 cells, 14-3-3 binds to Ser⁹-phosphorylated GSK3 and does not bind to GSK3 (S9A). Tau, on the other hand, binds to both GSK3 (WT) and GSK3 (S9A). Moreover, 14-3-3 enhances the binding of tau with Ser⁹-phosphorylated GSK3 by 3-fold but not with GSK3 (S9A). Similarly, 14-3-3 stimulates phosphorylation of tau by Ser⁹-phosphorylated GSK3 but not by GSK3 (S9A). In transfected HEK-293 cells, Ser⁹ phosphorylation suppresses GSK3-catalyzed tau phosphorylation in the absence of 14-3-3. In the presence of 14-3-3, however, Ser⁹-phosphorylated GSK3 remains active and phosphorylates tau. Our data indicate that within the tau phosphorylation complex, 14-3-3 connects Ser⁹-phosphorylated GSK3 to tau and Ser⁹-phosphorylated GSK3 phosphorylates tau.

Received for publication, July 30, 2003 , and in revised form, February 16, 2004.

^* This work was supported by grants from the Canadian Institute of Health Research, the American Health Assistance Foundation, and the Alzheimer Society of Canada. 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.

^¶ To whom all correspondence should be addressed: Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, 3755 Cote Ste-Catherine, Montreal, Quebec H3T 1E2, Canada. Tel.: 514-340-8222 (ext. 4866); Fax: 514-340-8295; E-mail: hemant.paudel{at}mcgill.ca.

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