Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity.

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
Sci Signal. 2010 3 (121): ra37

PMID: 20460648 · PMCID: PMC3088111 · DOI:10.1126/scisignal.2000647

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.

MeSH Terms (15)

Animals beta-Adrenergic Receptor Kinases beta Catenin Drosophila melanogaster Glycogen Synthase Kinase 3 GTP-Binding Protein beta Subunits GTP-Binding Protein gamma Subunits HeLa Cells Humans LDL-Receptor Related Proteins Low Density Lipoprotein Receptor-Related Protein-6 Signal Transduction Transcription, Genetic Wnt Proteins Xenopus laevis

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