- Jernigan KK, Cselenyi CS, Thorne CA, Hanson AJ, Tahinci E, Hajicek N, Oldham WM, Lee LA, Hamm HE, Hepler JR, Kozasa T, Linder ME, Lee E. Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity. Science signaling. 2010 May 11;3(121). ra37. PMID: 20460648 [PubMed]. PMCID: PMC3088111. NIHMSID: NIHMS290684.
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 betagamma subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes beta-catenin degradation. We found that Galpha(o), Galpha(q), Galpha(i2), and Gbetagamma inhibited beta-catenin degradation. Gbeta(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-betaARK (C-terminal domain of beta-adrenergic receptor kinase), an inhibitor of Gbetagamma, blocked LRP6 activity. Several components of the Wnt-beta-catenin pathway formed a complex: Gbeta(1)gamma(2), LRP6, GSK3, axin, and dishevelled. We propose that free Gbetagamma and Galpha subunits, released from activated G proteins, act cooperatively to inhibit beta-catenin degradation and activate beta-catenin-mediated transcription.