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J. Biol. Chem., Vol. 280, Issue 1, 270-276, January 7, 2005

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FRAT-2 Preferentially Increases Glycogen Synthase Kinase 3-mediated Phosphorylation of Primed Sites, Which Results in Enhanced Tau Phosphorylation^*

William H. Stoothoff, Jae-Hyeon Cho, Roy P. McDonald, and Gail V. W. Johnson

From the Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017

Tau is a microtubule-associated protein found primarily in neurons, and its function is regulated by site-specific phosphorylation. Although it is well established that tau is phosphorylated at both primed and unprimed epitopes by glycogen synthase kinase 3 (GSK3), how specific proteins that interact with GSK3 regulate tau phosphorylation has not been thoroughly examined. Members of the FRAT (frequently rearranged in advanced T-cell lymphoma) protein family have been shown to interact with GSK3, and FRAT-1 has been shown to modulate the activity of GSK3 toward tau and other substrates. However, the effects of FRAT-2 on GSK3 activity and tau phosphorylation have not been examined. Therefore in this study the effects of FRAT-2 on GSK3 activity and tau phosphorylation were examined. In situ, FRAT-2 significantly increased GSK3-mediated phosphorylation of tau at a primed epitope while not significantly affecting the phosphorylation of unprimed sites. Co-immunoprecipitation studies revealed that association of FRAT-2 with GSK3 resulted in a significant increase in phosphorylation of a primed substrate but did not alter phosphorylation of an unprimed substrate. Further, in vitro assays using recombinant proteins directly demonstrated that FRAT-2 enhances GSK3-mediated phosphorylation of a primed substrate to a greater extent than an unprimed substrate. In addition, FRAT-2 is phosphorylated by GSK3. This is the first demonstration of a protein differentially regulating the activity of GSK3 toward primed and unprimed epitopes.

Received for publication, September 1, 2004 , and in revised form, October 29, 2004.

^* This work was supported by a grant from the Alzheimer's Association. 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 correspondence should be addressed: Dept. of Psychiatry, 1720 7th Ave. S., SC1061, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35294-0017. Tel.: 205-934-2465; Fax: 205-934-3709; E-mail: gvwj{at}uab.edu.

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