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Sci. Signal., 11 May 2010
Vol. 3, Issue 121, p. ra37
Gβ 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 subunits, the Gβ 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-selective inhibitor, suggested that Gβ 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 inhibitor prevented axis duplication of Xenopus embryos under conditions of excess LRP6 activity, thus verifying in vivo a role for Gβ in this pathway. The Gβ 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 Activates GSK3 to Promote LRP6-Mediated β-Catenin Transcriptional Activity. Sci. Signal.3, ra37 (2010).