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

Abstract

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

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

“…Intriguingly, loss of APC, a component of the β-catenin destruction complex and actin-nucleating factor (Moseley et al, 2007;Okada et al, 2010), has also been found to increase DNA damage and genomic instability (Aoki et al, 2007;Fodde et al, 2001a;Meniel et al, 2015). APC has been shown to translocate into the nucleus, bind both α-and β-catenin and inhibit transcription (Choi et al, 2013), which is reminiscent of the role of nuclear α-catenin (Daugherty et al, 2014;McCrea and Gottardi, 2016). Furthermore, nuclear APC is directly recruited to sites of DNA damage repair (Kouzmenko et al, 2008) and has been implicated in base excision repair (Narayan and Sharma, 2015).…”

“…We and others have previously shown that αE-catenin (also known as CTNNA1; originally identified in epithelia, but now recognized as the most ubiquitously expressed α-catenin isoform, and thus hereafter referred to as α-catenin) can accumulate in the nucleus in a WNT/β-catenin-dependent manner (Choi et al, 2013;Daugherty et al, 2014;Giannini et al, 2000;Merdek et al, 2004). Nuclear α-catenin attenuates transcription of WNT pathwayresponsive genes via β-catenin.…”

α-catenin

“…and degradation by stabilizing its binding to APC. 37 On the other hand, the interaction of α-catenin with APC leads to nuclear translocation of APC and formation of a protein complex consisting of APC:α-catenin:β-catenin and the CtBP:CoREST:LSD1 histone H3K4 demethylase, which inhibits the transcription of Wnt target genes. 37 Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts its interaction with APC but not β-catenin and releases the transcriptional repression of Wnt target genes.…”

“…37 On the other hand, the interaction of α-catenin with APC leads to nuclear translocation of APC and formation of a protein complex consisting of APC:α-catenin:β-catenin and the CtBP:CoREST:LSD1 histone H3K4 demethylase, which inhibits the transcription of Wnt target genes. 37 Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts its interaction with APC but not β-catenin and releases the transcriptional repression of Wnt target genes. 37 These experiments demonstrate that α-catenin can suppress Wnt signaling by promoting β-catenin degradation, by hindering nuclear translocation of β-catenin, by preventing formation of the β-catenin-TCF-DNA complex, or by recruiting APC to the β-catenin-TCF complex (Fig.…”

“…37 Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts its interaction with APC but not β-catenin and releases the transcriptional repression of Wnt target genes. 37 These experiments demonstrate that α-catenin can suppress Wnt signaling by promoting β-catenin degradation, by hindering nuclear translocation of β-catenin, by preventing formation of the β-catenin-TCF-DNA complex, or by recruiting APC to the β-catenin-TCF complex (Fig. 1).…”