GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt.
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.
Asuni
Ayodeji A
AA
King's College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK.
Hooper
Claudie
C
Reynolds
C Hugh
CH
Lovestone
Simon
S
Anderton
Brian H
BH
Killick
Richard
R
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*
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