title: GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt.
abstract: In the presence of a Wnt signal beta-catenin is spared from proteasomal degradation through a complex mechanism involving GSK3beta, resulting in the transcription of Wnt target genes. In this study we have explored whether GSK3alpha, a related isoform, can also regulate nuclear beta-catenin levels and whether this and the tau-directed kinase activity of GSK3alpha are modulated by Wnt. GSK3alpha or GSK3beta and their substrates, beta-catenin and tau, were transiently expressed in mammalian cells. Immunoblotting revealed that GSK3alpha reduces nuclear levels of beta-catenin, whilst reporter gene assays demonstrated that GSK3alpha inhibits beta-catenin-directed Tcf/Lef-dependent transcription. Moreover, activation of the Wnt pathway was found to attenuate both the beta-catenin- and the tau-directed kinase activities of GSK3alpha and GSK3beta. By immunoprecipitation we also found that axin-1, the beta-catenin destruction complex scaffold protein, binds GSK3alpha. In the light of these findings GSK3alpha warrants further investigation regarding its involvement in Wnt signalling and tauopathies such as Alzheimer's disease.
authors.affiliation: King's College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
authors.forename: Ayodeji A
authors.initials: AA
authors.lastname: Asuni
authors.forename: Claudie
authors.initials: C
authors.lastname: Hooper
authors.forename: C Hugh
authors.initials: CH
authors.lastname: Reynolds
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Brian H
authors.initials: BH
authors.lastname: Anderton
authors.forename: Richard
authors.initials: R
authors.lastname: Killick
mesh_terms: D000818:Animals; D060466:Axin Protein; D015153:Blotting, Western / Q000379:methods; D002461:Cell Line, Transformed; D006224:Cricetinae; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008156:Luciferases / Q000378:metabolism; D010802:Phylogeny; D012097:Repressor Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014162:Transfection / Q000379:methods; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism* / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C555451:AXIN1 protein, human; D060466:Axin Protein; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D016875:tau Proteins; D008156:Luciferases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha