Modulating the strength of cadherin adhesion: evidence for a novel adhesion complex

Abstract

Adherens junctions and desmosomes are critical for embryogenesis and the integrity of adult tissues. To form these junctions, classical cadherins interact via α- and β-catenin with the actin cytoskeleton, whereas desmosomal cadherins interact with the intermediate filament system. Here, we used a hormone-activated mutant N-cadherin expressed in fibroblasts to show the existence of a novel classical cadherin adhesion system. N-cadherin was fused at its C-terminus to a modified estrogen receptor ligand-binding domain (NcadER) that binds 4-hydroxytamoxifen (4OHT) and expressed in L cells, which lack an endogenous cadherin. Cells with the mutant cadherin (LNER cells) aggregated in the absence of 4OHT, but only in its presence formed tightly compacted aggregates like those formed by L cells expressing wild-type N-cadherin (LN cells). Compaction of LNER cells treated with 4OHT was accompanied by elevated levels of p120ctn in NcadER immunoprecipitates, compared to immunoprecipitates of non-treated cells, but without changes in α- and β-catenin, or actin. Compaction induced by 4OHT was also accompanied by increased interaction of the NcadER with the cytoskeleton and increased vimentin organization. Vimentin co-immunoprecipitated with the NcadER/catenin complex, suggesting an interaction between cadherin and vimentin. The mechanism by which vimentin interacts with the cadherin appears to involve p120ctn as it co-immunoprecipitates and colocalizes with vimentin in the parent L cells, which lack a cadherin and α- and β-catenins. Disrupting the actin cytoskeleton with cytochalasin B inhibited aggregation, whereas knocking down vimentin with specific siRNAs inhibited compaction. Based on our results we propose that a vimentin-based classical cadherin complex functions together with the actin-based complex to promote strong cell-cell adhesion in fibroblasts.

A dominant vimentin mutant upregulates Hsp70 and the activity of the ubiquitin-proteasome system, and causes posterior cataracts in transgenic mice

“…Furthermore, we have shown for the first time that, in contrast to desminopathies and Alexander disease, vimentin-containing aggregates are not terminal but transient structures that ultimately become degraded, even in postmitotic cells (Omary et al, 2004;Li et al, 2002). This activity is in line with findings on the dynamic behaviour of disease-type keratin aggregates in cultured cells but in contrast to certain polyglutamine inclusions (Werner et al, 2004;Kim et al, 2005).…”

“…In contrast to the keratin-desmosome linkage which has been extensively studied and is well defined by disease mutations, very little is known about how vimentin or any of the other IF proteins are attached to adhesion complexes in the lens (Fuchs and Cleveland, 1998;Getsios et al, 2004). In fibroblasts, p120 ctn has been suggested to link vimentin to N-cadherin, whereas in endothelial cells plakoglobin and desmoplakin connect vimentin to VEcadherin (Kim et al, 2005;Kowalczyk et al, 1998;Lampugnani and Dejana, 1997). Given that mutations in desmosomal proteins In control sections, both proteins were distributed underneath the plasma membrane.…”

BMP signalling controls the malignant potential of ascites-derived human epithelial ovarian cancer spheroids via AKT kinase activation

“…By analysing several markers for EMT, we observed that EOC cells induce an EMT phenotype during spheroid formation, defined by a substantial decrease in the gene expression of the cell-cell adhesion molecule E-cadherin. This implies that EOC spheroid compaction likely depends on additional molecules or processes, such as fibronectin, vimentin or actomyosin-mediated contractility as seen in other spheroid systems [2,[37][38][39]. Since endogenous BMP signalling is reduced during spheroid formation, we propose that induction of the EMT phenotype in EOC spheroid cells does not require activation of BMP signalling.…”

“…During the initial stages of spheroid formation, cell-cell adhesion is primarily mediated by the actions of integrins and cadherins [20,36,37]. By analysing several markers for EMT, we observed that EOC cells induce an EMT phenotype during spheroid formation, defined by a substantial decrease in the gene expression of the cell-cell adhesion molecule E-cadherin.…”

Construction and characteristics of an E-cadherin-related three-dimensional suspension growth model of ovarian cancer

“…Kin suggested that members of the cadherin family play an important role in the formation of MCS suspensions13. Shane demonstrated that tight junctions among HT29 colon tumor cells in MCS suspensions desensitized the cells to cytotoxic drugs and that disruption of E-cadherin–mediated cell-cell adhesion could restore the sensitivity to chemotherapeutics14.…”