title: Glycogen synthase kinase-3β2 has lower phosphorylation activity to tau than glycogen synthase kinase-3β1.
abstract: Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that phosphorylate protein substrates involved in Alzheimer's disease (AD), such as microtubule-associated protein tau and amyloid precursor protein (APP). GSK-3β consists of two splice variants; the major short form (GSK-3β1) distributes in many organs and the minor long form (GSK-3β2), whose structural difference is the insert of only 13 amino acid residues to the C-terminal side of the catalytic site of GSK-3β1, is present in central nervous system. However, the physiological significances of the two variants are unclear. Here we examined whether the phosphorylation activities of two variants to tau and APP are different in cells. We found that GSK-3β2 has lower phosphorylation activity to tau at AD-relevant epitope (Ser396) than GSK-3β1 in cells, whereas the two variants exhibit equivalent levels of phosphorylation activities to APP. Recombinant GSK-3β2 has also lower phosphorylation activity to tau than GSK-3β1 in vitro, although the phosphorylation activities of the two variants to a synthetic peptide substrate pGS-2 are comparable. Furthermore, the deletion of the C-terminal tail (CT) of GSK-3β2 resulted in considerable reduction of tau phosphorylation activity as compared with GSK-3β1, suggesting that the lower phosphorylation activity of GSK-3β2 to tau is attributed to weak interaction with tau through its unique higher-order structure of CT constructed by the 13 amino acids insertion. Such information may provide a clue for understanding of the physiological significance of the two splice variants of GSK-3β and a new insight into the regulation of tau phosphorylation in central nervous system.
authors.affiliation: Department of Biochemistry, Faculty of Pharmaceutical Science, Tokyo University of Science, Noda, Chiba 278–8510, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Saeki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Machida
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Ryoko
authors.initials: R
authors.lastname: Takasawa
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Tanuma
mesh_terms: D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D020033:Protein Isoforms; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3