Development of Akt-activated GSK3β inhibitory peptide

• Published in: Biochemical and biophysical research communications Vol. 434; no. 4; pp. 735 - 739
• Main Authors: Kim, Jin-Sik, Piao, Shunfu, Lee, Eunjin, Yoon, Bo-Young, Moon, Hyung Ryong, Lee, Jaewon, Jung, Yunjin, Ha, Nam-Chul
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-05-2013
• Subjects: Akt; Amino Acid Motifs - genetics; Amino Acid Sequence; Blotting, Western; Diabete mellitus; Drug discovery; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK3β; Hep G2 Cells; Humans; Hypoglycemic Agents - pharmacology; Insulin - pharmacology; Low Density Lipoprotein Receptor-Related Protein-6 - genetics; Microscopy, Confocal; Molecular Sequence Data; Mutation; Peptides - genetics; Peptides - metabolism; Peptides - pharmacology; Phosphorylation - drug effects; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; GSK3β; Diabete mellitus; Akt; Drug discovery
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.03.103

•We designed a novel peptide sequence to inhibit GSK3beta.•Activation of the peptide requires the kinase activities of Akt and GSK3beta.•GSK3beta is inhibited by the peptide only in response to the insulin signaling.•We propose a novel concept to develop a drug.
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.