α-Catenin interacts with APC to regulate β-catenin proteolysis and transcriptional repression of 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.
Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037 USA;
Seung H
SH
Choi
Conchi
C
Estarás
James J
JJ
Moresco
John R
JR
Yates
Katherine A
KA
Jones
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism*; D051178:alpha Catenin / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D051178:alpha Catenin; D051176:beta Catenin
APC tumor suppressor; CtBP:RCOR1:LSD1; Wnt signaling; transcription; α-catenin; β-catenin