a-Catenin interacts with APC to regulate -catenin proteolysis and transcriptional repression of Wnt target genes. Choi SH 2013 et al.
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 a-catenin, a Hippo signaling regulator and heterodimeric partner of -catenin at cell:cell adherens junctions. Importantly, a-catenin promotes -catenin ubiquitylation and proteolysis by stabilizing its association with APC and protecting the phosphodegron. Moreover, -catenin ubiquitylation requires binding to a-catenin. Multidimensional protein identification technology (MudPIT) proteomics of multiple Wnt regulatory complexes reveals that a-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 a-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 a-catenin and APC are recruited with -catenin to Wnt response elements in human embryonic stem cells (hESCs). Knockdown of a-catenin in hESCs prevents the switch-off of Wnt/-catenin transcription and promotes endodermal differentiation. Our findings indicate a role for a-catenin in the APC destruction complex and at Wnt target genes.
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E-cadherin is a transmembrane glycoprotein responsible for physical connection of epithelial cells through
Ca(2+)-binding regions in its extracellular domain. E-cadherin-mediated cell-cell adhesion is effected by 3 cytoplasmic
proteins known as catenins alpha, beta, and gamma. These catenins are thought to work as connectors that anchor the
E-cadherin to the cytoskeletal actin bundle through the cadherin cytoplasmic domain. Dysfunction of this adhesion
complex causes dissociation of cancer cells from primary tumor nodules, thus possibly contributing to cancer invasion
and metastasis.
Upstream of Hippo signaling.
Sundfeldt K, et al 2000 reported the E-cadherin-catenin complex in the rat ovary and cell-specific
expression during folliculogenesis and luteal formation. The cadherins and their cytoplasmic counterparts, the catenins, form the adherens junctions, which are of importance for tissue integrity and barrier
functions. The study
examined the cell-specific localization and temporal expression of epithelial
cadherin (E-cadherin) and alpha- and beta-catenin during follicular
development, ovulation and corpus luteum formation in the immature
gonadotrophin- and oestrogen-stimulated rat ovary. Immunohistochemistry and
immunoblotting demonstrated the expression of E-cadherin in theca and
interstitial cells of immature ovaries before and after injection of equine
chorionic gonadotrophin (eCG). E-cadherin was not detected in granulosa cells,
except in the preantral follicles located to the inner region of the ovary.
The content of E-cadherin in theca and interstitial cells decreased after an
ovulatory dose of hCG. Granulosa cells of apoptotic follicles did not express
E-cadherin. Oestrogen treatment (diethylstilboestrol) of immature rats for up
to 3 days did not result in a measurable expression of E-cadherin in granulosa
cells, alpha- and beta-catenin were expressed in all ovarian compartments. The
concentration of beta-catenin was constant during the follicular phase,
whereas the content of alpha-catenin decreased in granulosa cells after
treatment with diethylstilboestrol or hCG. The expression of alpha-catenin was
also reduced in theca and. interstitial cells after hCG. alpha- and
beta-catenin were present in most ovarian cells at all stages of
folliculogenesis. The restricted
expression of E-cadherin in granulosa cells of preantral follicles indicates a
role in the recruitment of these follicles to subsequent cycles. The specific
decrease of alpha-catenin in granulosa cells and the reduction of both
alpha-catenin and E-cadherin in theca cells of ovulatory follicles might
reflect some of the molecular changes in cell-cell adhesion associated with
ovulation and luteinization.
Davies BR, et al reported the epression of E-cadherin, alpha-catenin and beta-catenin in normal ovarian surface epithelium and epithelial ovarian cancers.
Khan-Dawood FS, reported immunocytochemical localization and expression of E-cadherin and beta-catenin in the human corpus luteum.
beta-catenin was observed in the
cytoplasm of the luteal cells. Abundant expression of E-cadherin was observed by
Western analysis in the early luteal phase and the level of expression was
significantly different from that observed in the mid- and late luteal phase corpora
lutea. In contrast the concentrations of beta-catenin were higher in the mid-luteal
phase compared to the early luteal phase.
Follicle stages
Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum