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Sci. Signal., 11 May 2010
Vol. 3, Issue 121, p. ra37
[DOI: 10.1126/scisignal.2000647]

RESEARCH ARTICLES

{gamma} 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{dagger}

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 {alpha} and β{gamma} subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes β-catenin degradation. We found that G{alpha}o, G{alpha}q, G{alpha}i2, and Gβ{gamma} inhibited β-catenin degradation. Gβ1{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-βARK (C-terminal domain of β-adrenergic receptor kinase), an inhibitor of Gβ{gamma}, blocked LRP6 activity. Several components of the Wnt–β-catenin pathway formed a complex: Gβ1{gamma}2, LRP6, GSK3, axin, and dishevelled. We propose that free Gβ{gamma} and G{alpha} subunits, released from activated G proteins, act cooperatively to inhibit β-catenin degradation and activate β-catenin–mediated transcription.

{dagger} To whom correspondence should be addressed. E-mail: ethan.lee{at}vanderbilt.edu

Citation: K. K. Jernigan, C. S. Cselenyi, C. A. Thorne, A. J. Hanson, E. Tahinci, N. Hajicek, W. M. Oldham, L. A. Lee, H. E. Hamm, J. R. Hepler, T. Kozasa, M. E. Linder, E. Lee, Gβ{gamma} Activates GSK3 to Promote LRP6-Mediated β-Catenin Transcriptional Activity. Sci. Signal. 3, ra37 (2010).

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