Article
- The EMBO Journal (2007) 26, 1511 - 1521
- doi:10.1038/sj.emboj.7601607
Published online: 22 February 2007
Subject Category:
Protein phosphatase 1 regulates assembly and function of the 
-catenin degradation complex
Wen Luo1, Annita Peterson1, Benjamin A Garcia2,a, Gary Coombs1, Bente Kofahl3, Reinhart Heinrich3, Jeffrey Shabanowitz2, Donald F Hunt2,4, H Joseph Yost1,5,6 and David M Virshup1,5,6
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA
- Department of Chemistry, University of Virginia, Charlottesville, VA, USA
- Department of Theoretical Biophysics, Institute of Biology, Humboldt University Berlin, Berlin, Germany
- Department of Pathology, University of Virginia, Charlottesville, VA, USA
- Department of Pediatrics, University of Utah, Salt Lake City, UT, USA
- Center for Children at the Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
Correspondence to:
David M Virshup, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112-5550, USA. Tel.: +1 801 585 3408; Fax: +1 801 587 9415; E-mail: david.virshup@hci.utah.edu
aPresent address: Institute for Genomic Biology, University of Illinois, Champaign-Urbana, Urbana, IL 61801, USA
Received 16 August 2006; Accepted 23 January 2007
Abstract
The Wnt/
-catenin signaling pathway is critical in both cellular proliferation and organismal development. However, how the -catenin degradation complex is inhibited upon Wnt activation remains unclear. Using a directed RNAi screen we find that protein phosphatase 1 (PP1), a ubiquitous serine/threonine phosphatase, is a novel potent positive physiologic regulator of the Wnt/-catenin signaling pathway. PP1 expression synergistically activates, and inhibition of PP1 inhibits, Wnt/-catenin signaling in Drosophila and mammalian cells as well as in Xenopus embryos. The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin. Inhibition of PP1 leads to enhanced phosphorylation of specific sites on axin by casein kinase I. Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active -catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine -catenin transcriptional activity. Specific inhibition of PP1 in this pathway may offer therapeutic approaches to disorders with increased -catenin signaling.
Keywords:
- Axin,
- CKI,
- GSK3; PP1,
- Wnt/-catenin
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Retinoid signalling in the development of the central nervous system
Nature Reviews Neuroscience Review (01 Nov 2002)
NEWS AND VIEWS
A nuclear escort for β-catenin
Nature Cell Biology News and Views (01 Jul 2004)
It takes more than two to tango: Dishevelled polymerization and Wnt signaling
Nature Structural & Molecular Biology News and Views (01 Jun 2007)
RESEARCH
Identification of IGFBP-6 as an effector of the tumor suppressor activity of SEMA3B
Oncogene Original Article
Constitutively active Rheb induces oncogenic transformation
Oncogene Original Article
