In the presence of a Wnt signal β-catenin is spared from proteasomal degradation through a complex mechanism involving GSK3β, resulting in the transcription of Wnt target genes. In this study we have explored whether GSK3α, a related isoform, can also regulate nuclear β-catenin levels and whether this and the tau-directed kinase activity of GSK3α are modulated by Wnt. GSK3α or GSK3β and their substrates, β-catenin and tau, were transiently expressed in mammalian cells. Immunoblotting revealed that GSK3α reduces nuclear levels of β-catenin, whilst reporter gene assays demonstrated that GSK3α inhibits β-catenin-directed Tcf/Lef-dependent transcription. Moreover, activation of the Wnt pathway was found to attenuate both the β-catenin- and the tau-directed kinase activities of GSK3α and GSK3β. By immunoprecipitation we also found that axin-1, the β-catenin destruction complex scaffold protein, binds GSK3α. In the light of these findings GSK3α warrants further investigation regarding its involvement in Wnt signalling and tauopathies such as Alzheimer's disease.