title: FRAT-2 preferentially increases glycogen synthase kinase 3 beta-mediated phosphorylation of primed sites, which results in enhanced tau phosphorylation.
abstract: 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 beta (GSK3 beta), how specific proteins that interact with GSK3 beta 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 beta, and FRAT-1 has been shown to modulate the activity of GSK3 beta toward tau and other substrates. However, the effects of FRAT-2 on GSK3 beta activity and tau phosphorylation have not been examined. Therefore in this study the effects of FRAT-2 on GSK3 beta activity and tau phosphorylation were examined. In situ, FRAT-2 significantly increased GSK3 beta-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 beta 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 beta-mediated phosphorylation of a primed substrate to a greater extent than an unprimed substrate. In addition, FRAT-2 is phosphorylated by GSK3 beta. This is the first demonstration of a protein differentially regulating the activity of GSK3 beta toward primed and unprimed epitopes.
authors.affiliation: Department of Psychiatry, University of Alabama at Birmingham, Alabama 35294-0017, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Stoothoff
authors.forename: Jae-Hyeon
authors.initials: JH
authors.lastname: Cho
authors.forename: Roy P
authors.initials: RP
authors.lastname: McDonald
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004789:Enzyme Activation; D000939:Epitopes / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D000939:Epitopes; C491817:FRAT2 protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3