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

Seung H. Choi, Conchi Estarás, James J. Moresco, John R. Yates, Katherine A. Jones

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2473-2488
Number of pages16
JournalGenes and Development
Volume27
Issue number22
DOIs
StatePublished - Nov 15 2013
Externally publishedYes

Keywords

  • APC tumor suppressor
  • CtBP:RCOR1:LSD1
  • Transcription
  • Wnt signaling
  • α-catenin
  • β-catenin

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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