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

RESEARCH ARTICLES

Editor's Summary

{gamma} for β-Catenin Stability
G proteins influence the Wnt–β-catenin pathway, which regulates various developmental processes; aberrant activity is associated with some cancers. The ligand Wnt interacts with a receptor complex that includes the seven-transmembrane protein Frizzled and the single-transmembrane protein LRP6 to activate the transcriptional regulatory activity of β-catenin. By screening the activity of purified G protein subunits in a Xenopus egg extract system, Jernigan et al. found that, in addition to a subset of G{alpha} subunits, the Gβ{gamma} subunit also stabilized β-catenin. Various biochemical analyses, including analysis of transfected mammalian cells and in vitro assays, along with the use of a Gβ{gamma}-selective inhibitor, suggested that Gβ{gamma} recruited the kinase GSK3 to the membrane. After membrane recruitment, GSK3 phosphorylated LRP6, which then inhibited the β-catenin degradation complex, allowing β-catenin to translocate to the nucleus and activate transcription. Additionally, the Gβ{gamma} inhibitor prevented axis duplication of Xenopus embryos under conditions of excess LRP6 activity, thus verifying in vivo a role for Gβ{gamma} in this pathway. The Gβ{gamma} inhibitor failed to block Wnt-mediated activation of β-catenin, which suggests that a receptor other than Frizzled may activate the G protein that contributes to β-catenin signaling.

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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