title: Development of Akt-activated GSK3β inhibitory peptide.
abstract: Abnormal overexpression of GSK3β has been implicated in insulin resistance. Although many potent GSK3β inhibitors have been developed as drug candidates for anti-insulin resistance, the inhibitors are prone to show side effects because they interfere with normal GSK3β function without regulation. Recently, it was reported that the PPPSPxS motifs in the Wnt coreceptor LRP6 were able to directly inhibit GSK3β only when the motif was phosphorylated. Here, we generated a new GSK3β inhibitory peptide that can be activated by Akt by combining the PPPSPxS motif and an Akt target sequence. The peptide exhibited an inhibitory effect on GSK3β only when it was phosphorylated by Akt in a purified system and in cells when stimulated by insulin. Thus, our findings provide a novel concept for drugs against diseases that are involved in the abnormal GSK3β activity, including type 2 diabetes mellitus.
authors.affiliation: Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jin-Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Shunfu
authors.initials: S
authors.lastname: Piao
authors.forename: Eunjin
authors.initials: E
authors.lastname: Lee
authors.forename: Bo-Young
authors.initials: BY
authors.lastname: Yoon
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
authors.forename: Nam-Chul
authors.initials: NC
authors.lastname: Ha
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D015153:Blotting, Western; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3