A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression
- PMID: 10581160
- DOI: 10.1006/bbrc.1999.1760
A GSK3beta phosphorylation site in axin modulates interaction with beta-catenin and Tcf-mediated gene expression
Abstract
Upon binding of a Wnt to its receptor, GSK3beta is inhibited through an unknown mechanism involving Dishevelled (Dsh), resulting in the dephosphorylation and stabilization of beta-catenin, which translocates to the nucleus and interacts with Lef/Tcf transcription factors to activate target gene expression. Axin is a scaffold protein which binds beta-catenin and GSK3beta (as well as several other proteins) and thus promotes the phosphorylation of beta-catenin. Here we report that Axin is phosphorylated on Ser and Thr residues in several regions in vivo, while only one region (amino acids 600-672) is efficiently phosphorylated by GSK3beta in vitro. Site-directed mutagenesis, together with in vitro and in vivo phosphorylation assays, demonstrates that Axin residues T609 and S614 are physiological GSK3beta targets. Substitutions for one or more of these residues, which lie within a beta-catenin binding site, reduce the ability of Axin to modulate Wnt-induced signaling in a Lef/Tcf reporter assay. These amino acid substitutions also reduce the binding between Axin and beta-catenin. We propose a model in which inhibition of GSK3beta activity upon Wnt signaling leads to the dephosphorylation of GSK3beta sites in Axin, resulting in the release of beta-catenin from the phosphorylation complex.
Copyright 1999 Academic Press.
Similar articles
-
A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/beta-catenin complex.Cell Mol Life Sci. 2005 Mar;62(5):606-18. doi: 10.1007/s00018-005-4507-7. Cell Mol Life Sci. 2005. PMID: 15747065
-
Signaling through beta-catenin and Lef/Tcf.Cell Mol Life Sci. 1999 Oct 30;56(5-6):523-37. doi: 10.1007/s000180050449. Cell Mol Life Sci. 1999. PMID: 11212302 Free PMC article. Review.
-
New steps in the Wnt/beta-catenin signal transduction pathway.Recent Prog Horm Res. 2000;55:225-36. Recent Prog Horm Res. 2000. PMID: 11036939 Review.
-
WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells.Biochem Biophys Res Commun. 1998 Jun 29;247(3):851-8. doi: 10.1006/bbrc.1998.8888. Biochem Biophys Res Commun. 1998. PMID: 9647782
-
Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin.EMBO J. 1998 Mar 2;17(5):1371-84. doi: 10.1093/emboj/17.5.1371. EMBO J. 1998. PMID: 9482734 Free PMC article.
Cited by
-
The scaffold protein AXIN1: gene ontology, signal network, and physiological function.Cell Commun Signal. 2024 Jan 30;22(1):77. doi: 10.1186/s12964-024-01482-4. Cell Commun Signal. 2024. PMID: 38291457 Free PMC article. Review.
-
Phosphorylation of axin within biomolecular condensates counteracts its tankyrase-mediated degradation.J Cell Sci. 2023 Oct 15;136(20):jcs261214. doi: 10.1242/jcs.261214. Epub 2023 Oct 27. J Cell Sci. 2023. PMID: 37721093 Free PMC article.
-
Identification of protein phosphatase 4 catalytic subunit as a Wnt promoting factor in pan-cancer and Xenopus early embryogenesis.Sci Rep. 2023 Jun 23;13(1):10240. doi: 10.1038/s41598-023-35719-y. Sci Rep. 2023. PMID: 37353511 Free PMC article.
-
Role of β-Catenin Activation in the Tumor Immune Microenvironment and Immunotherapy of Hepatocellular Carcinoma.Cancers (Basel). 2023 Apr 15;15(8):2311. doi: 10.3390/cancers15082311. Cancers (Basel). 2023. PMID: 37190239 Free PMC article. Review.
-
Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling.Front Oncol. 2022 Mar 14;12:858782. doi: 10.3389/fonc.2022.858782. eCollection 2022. Front Oncol. 2022. PMID: 35359365 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous