title: Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis.
abstract: The inactivation of glycogen synthase kinase (GSK)3 has been proposed to play important roles in insulin and Wnt signalling. To define the role that inactivation of GSK3 plays, we generated homozygous knockin mice in which the protein kinase B phosphorylation sites on GSK3alpha (Ser21) and GSK3beta (Ser9) were changed to Ala. The knockin mice were viable and were not diabetic. Using these mice we show that inactivation of GSK3beta rather than GSK3alpha is the major route by which insulin activates muscle glycogen synthase. In contrast, we demonstrate that the activation of muscle glycogen synthase by contraction, the stimulation of muscle glucose uptake by insulin, or the activation of hepatic glycogen synthase by glucose do not require GSK3 phosphorylation on Ser21/Ser9. GSK3 also becomes inhibited in the Wnt-signalling pathway, by a poorly defined mechanism. In GSK3alpha/GSK3beta homozygous knockin cells, Wnt3a induces normal inactivation of GSK3, as judged by the stabilisation of beta-catenin and stimulation of Wnt-dependent transcription. These results establish the function of Ser21/Ser9 phosphorylation in several processes in which GSK3 inactivation has previously been implicated.
authors.affiliation: MRC Protein Phosphorylation Unit, MSI/WTB Complex, University of Dundee, Dundee, Scotland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: McManus
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Armit
authors.forename: Leah
authors.initials: L
authors.lastname: Ronaldson
authors.forename: Natalia
authors.initials: N
authors.lastname: Shpiro
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Marquez
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D007328:Insulin; D011506:Proteins; D011518:Proto-Oncogene Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D006003:Glycogen; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha