Common use of Gordon Clause in Contracts

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Therefore, cross-signaling between adhesion receptors should be a common phenomenon to support the orchestrated changes of cells’ connec- tions to the substrate and to the neighboring cells during tissue remodeling. Recently, we have demonstrated that the epithelial cell adhesion molecule Ep-CAM negatively modulates cadherin-mediated adhesions in direct relation to its expression levels. Here, we used E-cadherin/ α -catenin chimera constructs to define the site of Ep-CAM’s nega- tive effect on cadherin-mediated adhesions. Murine L-cells transfected with either E- cadherin/ α -catenin fusion protein, or E-cadherin fused to the carboxy-terminal half of α-catenin, were subsequently supertransfected with an inducible Ep-CAM construct. Introduction of Ep-CAM altered the cell’s morphology, weakened the strength of cell- cell interactions, and decreased the cytoskeleton-bound fraction of the cadherin/cate- nin chimeras in both cell models. Furthermore, expression of Ep-CAM induced restruc- turing of F-actin, with changes in thickness and orientation of the actin filaments. The results showed that Ep-CAM affects E-cadherin-mediated adhesions without involve- ment of β-catenin by disrupting the link between α-catenin and F-actin. The latter is likely achieved through remodeling of the actin cytoskeleton by Ep-CAM, possibly through pp120. Various adhesion molecules that mediate cell’s interactions with the substrate and the neighbouring cells are recognized to play an important role in defining the cell fate, differentiation, and other biological characteristics [1,2]. Data are accumulating that adhesion receptors do function not only as physical interconnectors between vari- ous cell types and substrates, but represent an important group of signal-transducing modalities, participating in tissue morphogenesis [3-7]. Cross-signaling between adhesion receptors is likely to be a common phenome- non, being partly responsible for the orchestrated changes in the number and composi- tion of cellular adhesion receptors during cell migration or differentiation. For exam- ple, in keratinocytes undergoing terminal differentiation and stratification, a decrease of β1-integrin expression is evidently related to an upregulation of E-cadherin, and is negatively controlled by the formation of E-cadherin-mediated adhesions [8 -10]. Furthermore, the flexible and rapid changes of N-cadherin activity in migrating cells of the neural crest were shown to be controlled by signals from β1 and β3 integrins [11]. Recently, β1-integrin expression was also reported to result in a decrease of total cadhe- rin and α-catenin protein levels, together with redistribution of cadherin and α-catenin from the detergent insoluble fraction to the detergent soluble fraction [12]. In mamma- ry epithelial cells, blocking of β1 integrin was demonstrated to suppress the metastatic potential of cells, likely by upregulating E-cadherin adhesions [13]. Lampe et al. [14] demonstrated the subtle interactions in keratinocytes between α3β1, adhesion to lami- nin-5, and Rho signaling, which promotes intercellular communication mediated by gap junctions, while Braga described the impinge of the Rho family of small GTPases on the regulation of cadherindependent adhesion and epithelial morphology [15]. We have previously demonstrated that the epithelial cell adhesion molecule Ep-CAM negatively affects the cadherin-mediated adhesions in direct proportion to its expres- sion levels [16]. Ep-CAM is a calcium-independent homophillic cell adhesion molecule of 39-42 kDa [17,18] which is expressed by the majority of epithelial tissues, excluding the adult squamous epithelium and some epithelium-derived cell types, such as hepato- cytes [19,20]. However, de novo expression of Ep-CAM can be observed for these cell types as well, during active cell proliferation in embryogenesis, or at the early stages of tumorgenesis [19,21]. Ep-CAM does not structurally resemble any of the major families of the adhe- sion molecules (cadherins, selectins, integrins, or cell adhesion molecules of the Ig superfamily). It is a type I transmembrane glycoprotein, consisting of an extracellular domain, containing two EGF-like repeats, and a short cytoplasmic domain of 26 amino acids in which two binding sites for α-actinin are present (for review see Balzar et al. [22]). α-Actinin is required to stabilize the intercellular adhesions mediated by Ep- CAM, by connecting Ep-CAM to F-actin [23]. We have demonstrated that the cytoplas- mic domain of Ep-CAM is required for its negative effect on cadherins [16]. Upon over- expression of Ep-CAM, it was observed that cadherin adhesions dissociate, which leads to accumulation of detergent-soluble E-cadherin/β- catenin complexes, and to a decre- ase in total cellular α-catenin [16]. This may be the result of the E-cadherin/β-catenin complex dissociating from α-catenin anchored to F-actin, or, alternatively, the total preexisting E-cadherin/β-catenin/α-catenin complex is eliminated from the surface and destined for degradation via internalization, and the observed cytoplasmic E-cad- herin/β-catenin complexes represent newly synthesized proteins. We used in this study cell lines transfected either with E-cadherin or with chimera proteins composed of E-cadherin directly linked to α-catenin [24]. Super- transfection of Ep-CAM in these cell lines had a dramatic effect on (1) morphology, (2) the aggregation ability of cells, (3) on subcellular localization, and (4) on the degree of detergent extractability of chimera proteins. Both tested fusion molecules were affected by expression of Ep-CAM, independent of the involvement β-catenin present in the cadherin adhesions. Therefore, we suggest that Ep-CAM expression affects the link between α-catenin and F-actin within the E-cadherin-mediated adhesion complex as a result of the Factin network being reconstructed, possibly through pp120.