Abstract
Upon binding of a Wnt ligand to the frizzled (FZD)-low density lipoprotein receptor related protein 5/6 (LRP5/6) receptor complex, the β-catenin destruction complex, composed of Axin1, adenomatous polyposis coli (APC), glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1), is immediately inactivated, which causes β-catenin stabilization. However, the molecular mechanism of signal transduction from the receptor complex to the β-catenin destruction complex is controversial. Here we show that Wnt3a treatment promotes the dissociation of the Axin1-APC complex in glioblastoma cells cultured in serum-free medium. Experiments with the GSK3 inhibitor BIO suggest that Axin1-APC dissociation was controlled by phosphorylation. Introduction of a phosphomimetic mutation into Thr160 of Axin1, located in the APC-binding region RGS, abrogated the interaction of Axin1 with APC. Consistent with these observations, the Axin1 phosphomimetic mutant lost the ability to reduce β-catenin stability and to repress β-catenin/TCF-dependent transcription. Taken together, our results suggest a novel mechanism of Wnt signaling through the dissociation of the β-catenin destruction complex by Axin1 Thr160 modification.
References
Nov 29, 1991·Science·P D McCreaB Gumbiner
Nov 1, 1974·Archives of Internal Medicine
Apr 18, 1998·The EMBO Journal·S IkedaA Kikuchi
Jun 6, 1998·The Journal of Biological Chemistry·S KishidaA Kikuchi
Apr 10, 1999·The Journal of Biological Chemistry·H YamamotoA Kikuchi
Aug 19, 2000·Science·Y KawasakiT Akiyama
Oct 14, 2003·PLoS Biology·Ethan LeeMarc W Kirschner
Jan 21, 2004·Molecular Cell·Keiko TamaiXi He
Dec 25, 2010·Cell·Vincent F TaelmanEdward M De Robertis
Jul 9, 2011·PloS One·Gokhan DemirkanPhilip A Gruppuso
Oct 21, 2011·Journal of Proteome Research·Maximiliane Hilger, Matthias Mann
Jun 12, 2012·Cell·Hans Clevers, Roel Nusse
Jun 12, 2012·Cell·Vivian S W LiHans Clevers
Sep 12, 2012·Oncogene·R Koyama-NasuT Akiyama
Nov 22, 2012·Cold Spring Harbor Perspectives in Biology·Jennifer L Stamos, William I Weis
Apr 13, 2013·Science·Sung-Eun KimXi He
May 21, 2013·Oncogene·R Koyama-NasuT Akiyama
Jul 31, 2013·Nature Chemical Biology·Sheng WangLin Li
Citations
Sep 1, 2015·Neurochemistry International·Kusumika GharamiSumantra Das
Jan 1, 2015·Seminars in Cell & Developmental Biology·Nellwyn Hagan, Ayal Ben-Zvi
Mar 2, 2018·Biological Reviews of the Cambridge Philosophical Society·Xiaoxiang ChengHongjie Zhang
Mar 8, 2019·Experimental and Molecular Pathology·Xue ChenJunfeng Li