GSK3α exhibits β-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 GSK3 beta, resulting in the transcription of Wnt target genes. In this study we have explored whether GSK3 alpha, a related isoform, can also regulate nuclear beta-catenin levels and whether this and the tau-directed kinase activity of GSK3 alpha are modulated by Wnt. GSK3 alpha or GSK3 beta and their substrates, beta-catenin and tau, were transiently expressed in mammalian cells. Immunoblotting revealed that GSK3 alpha reduces nuclear levels of beta-catenin, whilst reporter gene assays demonstrated that GSK3 alpha 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 GSK3 alpha and GSK3 beta. By immunoprecipitation we also found that axin-1, the beta-catenin destruction complex scaffold protein, binds GSK3 alpha. In the light of these findings GSK3 alpha warrants further investigation regarding its involvement in Wnt signalling and tauopathies such as Alzheimer's disease.