FRAT1 peptide decreases Abeta production in swAPP(751) cells.
Recently, LiCl has been shown to inhibit amyloid beta peptide secretion in association with diminished glycogen synthase kinase beta (GSK3beta) activity. However, it remains unclear if direct inhibition of GSK3beta activity will result in decreased Abeta production. Frequently rearranged in advanced T-cell lymphomas 1 (FRAT1) protein is a negative regulator of GSK3alpha/beta kinase activity. To examine whether direct inhibition of GSK3alpha/beta kinase activity can lower Abeta production, a FRAT1 peptide was expressed in swAPP(751) cells that produce high levels of Abeta. Our data demonstrate that cellular expression of FRAT1 peptide in swAPP(751) cells increases both GSK3alpha and beta phosphorylation on Ser21 and Ser9, respectively, while inhibiting kinase activity of both isoforms. Moreover, as a result of FRAT1 expression, the production of both total Abeta and Abeta(1-42) was significantly decreased. Thus, we provide evidence that direct regulation of GSK3alpha/beta by FRAT1 peptide significantly decreases Abeta production in swAPP(751) cells.
Lilly Research Laboratories, Eli Lilly and company, Lilly Corporate Center, Drop code 0510, Indianapolis, IN 46285, USA. li_baolin@lilly.com
Baolin
B
Li
John
J
Ryder
Yuan
Y
Su
Yan
Y
Zhou
Feng
F
Liu
Binhui
B
Ni
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C491819:FRAT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012694:Serine; D038362:Glycogen Synthase Kinase 3