Heterotrimeric G proteins and beta-catenin/TCF signaling
Sci. Signal., 11 May 2010
Vol. 3, Issue 121, p. ra37
[DOI: 10.1126/scisignal.2000647]
RESEARCH
Gβ Activates GSK3 to Promote LRP6-Mediated β-Catenin Transcriptional Activity
Kristin K. Jernigan1*, Christopher S. Cselenyi1*, Curtis A. Thorne1, Alison J. Hanson1, Emilios Tahinci1, Nicole Hajicek2,3, William M. Oldham4, Laura A. Lee1, Heidi E. Hamm4, John R. Hepler5, Tohru Kozasa2,3, Maurine E. Linder6, and Ethan Lee1,7
1 Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
2 Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA.
3 Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
4 Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
5 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
6 Department of Molecular Medicine, Cornell University, Ithaca, NY 14853, USA.
7 Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
* These authors contributed equally to this work.
Abstract: 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 β-catenin. We screened the and β subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes β-catenin degradation. We found that Go, Gq, Gi2, and Gβ inhibited β-catenin degradation. Gβ12 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-βARK (C-terminal domain of β-adrenergic receptor kinase), an inhibitor of Gβ, blocked LRP6 activity. Several components of the Wnt–β-catenin pathway formed a complex: Gβ12, LRP6, GSK3, axin, and dishevelled. We propose that free Gβ and G subunits, released from activated G proteins, act cooperatively to inhibit β-catenin degradation and activate β-catenin–mediated transcription.