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alpha-Catenin interacts with APC to regulate beta-catenin proteolysis and transcriptional repression of Wnt target genes

Academic Article
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Overview

authors

  • Choi, S. H.
  • Estaras, C.
  • Moresco, J. J.
  • Yates III, John
  • Jones, K. A.

publication date

  • November 2013

journal

  • Genes & Development  Journal

abstract

  • Mutation of the adenomatous polyposis coli (APC) tumor suppressor stabilizes ?-catenin and aberrantly reactivates Wnt/?-catenin target genes in colon cancer. APC mutants in cancer frequently lack the conserved catenin inhibitory domain (CID), which is essential for ?-catenin proteolysis. Here we show that the APC CID interacts with ?-catenin, a Hippo signaling regulator and heterodimeric partner of ?-catenin at cell:cell adherens junctions. Importantly, ?-catenin promotes ?-catenin ubiquitylation and proteolysis by stabilizing its association with APC and protecting the phosphodegron. Moreover, ?-catenin ubiquitylation requires binding to ?-catenin. Multidimensional protein identification technology (MudPIT) proteomics of multiple Wnt regulatory complexes reveals that ?-catenin binds with ?-catenin to LEF-1/TCF DNA-binding proteins in Wnt3a signaling cells and recruits APC in a complex with the CtBP:CoREST:LSD1 histone H3K4 demethylase to regulate transcription and ?-catenin occupancy at Wnt target genes. Interestingly, tyrosine phosphorylation of ?-catenin at Y177 disrupts binding to APC but not ?-catenin and prevents repression of Wnt target genes in transformed cells. Chromatin immunoprecipitation studies further show that ?-catenin and APC are recruited with ?-catenin to Wnt response elements in human embryonic stem cells (hESCs). Knockdown of ?-catenin in hESCs prevents the switch-off of Wnt/?-catenin transcription and promotes endodermal differentiation. Our findings indicate a role for ?-catenin in the APC destruction complex and at Wnt target genes.
  • Mutation of the adenomatous polyposis coli (APC) tumor suppressor stabilizes β-catenin and aberrantly reactivates Wnt/β-catenin target genes in colon cancer. APC mutants in cancer frequently lack the conserved catenin inhibitory domain (CID), which is essential for β-catenin proteolysis. Here we show that the APC CID interacts with α-catenin, a Hippo signaling regulator and heterodimeric partner of β-catenin at cell:cell adherens junctions. Importantly, α-catenin promotes β-catenin ubiquitylation and proteolysis by stabilizing its association with APC and protecting the phosphodegron. Moreover, β-catenin ubiquitylation requires binding to α-catenin. Multidimensional protein identification technology (MudPIT) proteomics of multiple Wnt regulatory complexes reveals that α-catenin binds with β-catenin to LEF-1/TCF DNA-binding proteins in Wnt3a signaling cells and recruits APC in a complex with the CtBP:CoREST:LSD1 histone H3K4 demethylase to regulate transcription and β-catenin occupancy at Wnt target genes. Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts binding to APC but not β-catenin and prevents repression of Wnt target genes in transformed cells. Chromatin immunoprecipitation studies further show that α-catenin and APC are recruited with β-catenin to Wnt response elements in human embryonic stem cells (hESCs). Knockdown of α-catenin in hESCs prevents the switch-off of Wnt/β-catenin transcription and promotes endodermal differentiation. Our findings indicate a role for α-catenin in the APC destruction complex and at Wnt target genes.

subject areas

  • Adenomatous Polyposis Coli Protein
  • Cell Differentiation
  • Embryonic Stem Cells
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Protein Binding
  • Proteolysis
  • Signal Transduction
  • Ubiquitination
  • Wnt Proteins
  • alpha Catenin
  • beta Catenin
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Research

keywords

  • APC tumor suppressor
  • CtBP:RCOR1:LSD1
  • Wnt signaling
  • alpha-catenin
  • beta-catenin
  • transcription
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Identity

PubMed Central ID

  • PMC3841736

International Standard Serial Number (ISSN)

  • 0890-9369

Digital Object Identifier (DOI)

  • 10.1101/gad.229062.113

PubMed ID

  • 24240237
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Additional Document Info

start page

  • 2473

end page

  • 2488

volume

  • 27

issue

  • 22

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