Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


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


{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}

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).

Read the Full Text

Frizzled and LRP5/6 Receptors for Wnt/{beta}-Catenin Signaling.
B. T. MacDonald and X. He (2012)
Cold Spring Harb Perspect Biol 4, a007880
   Abstract »    Full Text »    PDF »
p53 and MicroRNA-34 Are Suppressors of Canonical Wnt Signaling.
N. H. Kim, H. S. Kim, N.-G. Kim, I. Lee, H.-S. Choi, X.-Y. Li, S. E. Kang, S. Y. Cha, J. K. Ryu, J. M. Na, et al. (2011)
Science Signaling 4, ra71
   Abstract »    Full Text »    PDF »
LRP6 Mediates cAMP Generation by G Protein-Coupled Receptors Through Regulating the Membrane Targeting of G{alpha}s.
M. Wan, J. Li, K. Herbst, J. Zhang, B. Yu, X. Wu, T. Qiu, W. Lei, C. Lindvall, B. O. Williams, et al. (2011)
Science Signaling 4, ra15
   Abstract »    Full Text »    PDF »
CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia.
S. Chen, M. Rong, A. Platteau, D. Hehre, H. Smith, P. Ruiz, J. Whitsett, E. Bancalari, and S. Wu (2011)
Am J Physiol Lung Cell Mol Physiol 300, L330-L340
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882