Gβγ Activates GSK3 to Promote LRP6-Mediated β-Catenin Transcriptional Activity

Evidence from Drosophila and cultured cell studies supports a role for heterotrimeric guanosine triphosphate-binding proteins (G proteins) in Wnt signaling. Wnt inhibits the degradation of the transcriptional regulator beta-catenin. We screened the alpha and beta gamma subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes beta-catenin degradation. We found that G alpha(o), G alpha(q), G alpha(i2), and G beta gamma inhibited beta-catenin degradation. G beta(1 gamma 2) promoted the phosphorylation and activation of the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) by recruiting glycogen synthase kinase 3 (GSK3) to the membrane and enhancing its kinase activity. In both a reporter gene assay and an in vivo assay, c-beta ARK (C-terminal domain of beta-adrenergic receptor kinase), an inhibitor of G beta gamma, blocked LRP6 activity. Several components of the Wnt-beta-catenin pathway formed a complex: G beta(1 gamma 2), LRP6, GSK3, axin, and dishevelled. We propose that free G beta gamma and G alpha subunits, released from activated G proteins, act cooperatively to inhibit beta-catenin degradation and activate beta-catenin-mediated transcription.