GSK3α exhibits β‐catenin and tau directed kinase activities that are modulated by Wnt

In the presence of a Wnt signal ?-catenin is spared from proteasomal degradation through a complex mechanism involving GSK3?, resulting in the transcription of Wnt target genes. In this study we have explored whether GSK3?, a related isoform, can also regulate nuclear ?-catenin levels and whether this and the tau-directed kinase activity of GSK3? are modulated by Wnt. GSK3? or GSK3? and their substrates, ?-catenin and tau, were transiently expressed in mammalian cells. Immunoblotting revealed that GSK3? reduces nuclear levels of ?-catenin, whilst reporter gene assays demonstrated that GSK3? inhibits ?-catenin-directed Tcf/Lef-dependent transcription. Moreover, activation of the Wnt pathway was found to attenuate both the ?-catenin- and the tau-directed kinase activities of GSK3? and GSK3?. By immunoprecipitation we also found that axin-1, the ?-catenin destruction complex scaffold protein, binds GSK3?. In the light of these findings GSK3? warrants further investigation regarding its involvement in Wnt signalling and tauopathies such as Alzheimer's disease.