Autoregulation of E-cadherin expression by cadherin–cadherin interactions

Abstract

Transcriptional repression of E-cadherin, characteristic of epithelial to mesenchymal transition, is often found also during tumor cell invasion. At metastases, migratory fibroblasts sometimes revert to an epithelial phenotype, by a process involving regulation of the E-cadherin–β-catenin complex. We investigated the molecular basis of this regulation, using human colon cancer cells with aberrantly activated β-catenin signaling. Sparse cultures mimicked invasive tumor cells, displaying low levels of E-cadherin due to transcriptional repression of E-cadherin by Slug. Slug was induced by β-catenin signaling and, independently, by ERK. Dense cultures resembled a differentiated epithelium with high levels of E-cadherin and β-catenin in adherens junctions. In such cells, β-catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable. Disruption of E-cadherin–mediated contacts resulted in nuclear localization and signaling by β-catenin, induction of Slug and inhibition of E-cadherin transcription, without changes in ErbB-1/2 and ERK activation. This autoregulation of E-cadherin by cell–cell adhesion involving Slug, β-catenin and ERK could be important in tumorigenesis.

E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via β-catenin-Egr1-mediated PTEN expression

“…E-cadherin levels were increased in dense cultures and this was associated with increased levels of PTEN and reduced activation of the PI3K/Akt signaling pathway in OVCAR-3 and SKOV-3 ovarian cancer cells. Previous studies have suggested a link between reduced b-catenin signaling and upregulation of E-cadherin (Weng et al, 2002;Conacci-Sorrell et al, 2003). These studies support our observation that b-catenin loss induces E-cadherin levels in sparse SKOV-3 ovarian cancer cells.…”

“…These data strongly indicate that loss of E-cadherin promotes the growth of SKOV-3 cells by activating the PI3K/Akt signaling pathway. Because E-cadherin has been shown to inhibit bcatenin signaling (Gottardi et al, 2001;Stockinger et al, 2001;Conacci-Sorrell et al, 2003), we therefore examined the effects of E-cadherin loss on b-catenin signaling. Downregulation of E-cadherin in SKOV-3 cells resulted in the loss of b-catenin from sites of cell-cell contact, as assessed by immunocytochemistry ( Figure 3D).…”

“…Previous studies in colon cancer cell lines have shown that E-cadherin levels increase in dense compared with sparse cultures, and that this depends on the junctional control of b-catenin signaling (Conacci-Sorrell et al, 2003). Therefore, we next examined whether cell density influences E-cadherin levels and whether such changes in E-cadherin contribute, in turn, to the subsequent regulation of PTEN levels in a b-catenin-dependent manner.…”

“…b-Catenin was originally identified as a cytoplasmic component of adherens junctions, in which it associates with E-cadherin and, via a-catenin, the actin cytoskeleton (Kemler, 1993;Geiger et al, 1995). In addition, b-catenin is the main effector of Wnt signaling in the nucleus, in which it interacts with lymphoid enhancer factor/T-cell factor (LEF/TCF) transcription factors to regulate the expression of genes involved in cell growth control, such as cyclin D1 (van Noort and Clevers, 2002;Conacci-Sorrell et al, 2003). In the absence of Wnt signaling, cytosolic b-catenin is constantly phosphorylated by a degradation complex consisting of glycogen synthase kinase-3b (GSK3b), axin adenomatous polyposis coli and casein kinase 1, thereby targeting b-catenin for proteasomal degradation (van Noort and Clevers, 2002).…”

E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells

“…b-Ctn interacts directly with the E-cadh cytoplasmic tail, whereas a-ctn binds to b-ctn and links the complex to the actin cytoskeleton; p120-ctn binds directly to the juxtamembrane domain of the E-cadh tail but not to a-ctn (Niessen and Gottardi, 2008). E-cadh-containing AJs ensure that the cytoplasmic pool of both b-ctn and p120-ctn is maintained at low levels, preventing their translocation to the nucleus and transcriptional activation through b-ctn/TCF-LEF or repression through p120-ctn/KAISO (Conacci-Sorrell et al, 2003;van Hengel and Van Roy, 2007). E-cadh was initially considered a structural protein; however, recent evidence suggests a role for E-cadh in transducing outside-in signals.…”