Three Functions of Cadherins in Cell Adhesion
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Abstract:
Cadherins are transmembrane proteins that mediate cell-cell adhesion in animals. By regulating contact formation and stability, cadherins play a crucial role in tissue morphogenesis and homeostasis. Here, we review the three major functions of cadherins in cell-cell contact formation and stability. Two of those functions lead to a decrease in interfacial tension at the forming cell-cell contact, thereby promoting contact expansion--first, by providing adhesion tension that lowers interfacial tension at the cell-cell contact, and second, by signaling to the actomyosin cytoskeleton in order to reduce cortex tension and thus interfacial tension at the contact. The third function of cadherins in cell-cell contact formation is to stabilize the contact by resisting mechanical forces that pull on the contact.Keywords:
Contact inhibition
Cell Cortex
Tissue morphogenesis during development is dependent on activities of the cadherin family of cell–cell adhesion proteins that includes classical cadherins, protocadherins, and atypical cadherins (Fat, Dachsous, and Flamingo). The extracellular domain of cadherins contains characteristic repeats that regulate homophilic and heterophilic interactions during adhesion and cell sorting. Although cadherins may have originated to facilitate mechanical cell–cell adhesion, they have evolved to function in many other aspects of morphogenesis. These additional roles rely on cadherin interactions with a wide range of binding partners that modify their expression and adhesion activity by local regulation of the actin cytoskeleton and diverse signaling pathways. Here we examine how different members of the cadherin family act in different developmental contexts, and discuss the mechanisms involved.
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The carboxyl terminus-truncated cadherin (nonfunctional cadherin) has no cell adhesion activity probably because of its failure to associate with cytoplasmic proteins called alpha and beta catenin. To rescue this nonfunctional cadherin as adhesion molecules, we constructed three cDNAs for fusion proteins between nonfunctional E-cadherin and alpha catenin, nE alpha, nE alpha N, and nE alpha C, where the intact, amino-terminal and carboxy-terminal half of alpha catenin, respectively, were directly linked to the nonfunctional E-cadherin, and introduced them into mouse L cells. The subcellular distribution and cell adhesion activity of nE alpha and nE alpha C molecules was similar to those of intact E-cadherin transfectants: they bound to cytoskeletons, were concentrated at cell-cell adhesion sites and showed strong cell adhesion activity. nE alpha N molecules, which also bound to cytoskeletons, showed very poor cell adhesion activity. Taken together, we conclude that in the formation of the cadherin-catenin complex, the mechanical association of alpha catenin, especially its carboxy-terminal half, with E-cadherin is a key step for the cadherin-mediated cell adhesion. Close comparison revealed that the behavior of nE alpha molecules during cytokinesis was quite different from that of intact E-cadherin, and that the intercellular motility, i.e., the cell movement in a confluent sheet, was significantly suppressed in nE alpha transfectants although it was facilitated in E-cadherin transfectants. Considering that nE alpha was not associated with endogenous beta catenin in transfectants, the difference in the nature of cell adhesion between nE alpha and intact E-cadherin transfectants may be explained by the function of beta catenin. The possible functions of beta catenin are discussed with a special reference to its role as a negative regulator for the cadherin-mediated cell adhesion system.
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Cell shape changes underlie a large set of biological processes ranging from cell division to cell motility. Stereotyped patterns of cell shape changes also determine tissue remodeling events such as extension or invagination. In vitro and cell culture systems have been essential to understanding the fundamental physical principles of subcellular mechanics. These are now complemented by studies in developing organisms that emphasize how cell and tissue morphogenesis emerge from the interplay between force-generating machines, such as actomyosin networks, and adhesive clusters that transmit tensile forces at the cell cortex and stabilize cell-cell and cell-substrate interfaces. Both force production and transmission are self-organizing phenomena whose adaptive features are essential during tissue morphogenesis. A new era is opening that emphasizes the similarities of and allows comparisons between distant dynamic biological phenomena because they rely on core machineries that control universal features of cytomechanics.
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Tissue morphogenesis is driven by coordinated cellular deformations. Recent studies have shown that these changes in cell shape are powered by intracellular contractile networks comprising actin filaments, actin cross-linkers and myosin motors. The subcellular forces generated by such actomyosin networks are precisely regulated and are transmitted to the cell cortex of adjacent cells and to the extracellular environment by adhesive clusters comprising cadherins or integrins. Here, and in the accompanying poster, we provide an overview of the mechanics, principles and regulation of actomyosin-driven cellular tension driving tissue morphogenesis.
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E-cadherin is found at the junctions of epithelial cells. Besides mediating cell-cell adhesion through homophilic interactions (E-cadherin from one cell binding to E-cadherin on an adjacent cell), E-cadherin mediates contact inhibition of cell growth, and loss of E-cadherin is associated with tumorigenesis. As a result of the many molecular interactions that occur between cells at junctions, it has been unclear whether E-cadherin alone can inhibit cell growth in the absence of cell contact. Perrais et al . devised an experimental system designed to monitor the effects of ligation of E-cadherin on the growth of single cells. The authors exposed single epithelial cells, attached to fibronectin-coated coverslips, to microspheres coated with chimeric proteins of the extracellular domain of E-cadherin fused to the immunoglobulin Fc domain (Fc-hE). Exposure of single cells to Fc-hE-microspheres resulted in decreased BrdU incorporation (a marker of DNA replication), as measured by immunofluorescence microscopy, compared with that in cells exposed to control microspheres, which indicates that ligation of E-cadherin on these cells resulted in decreased cellular proliferation. Cadherins mediate cell-cell adhesion in part through interactions of their cytoplasmic domains with catenins. Through the use of mutated forms of E-cadherin in epithelial cell lines, the authors found that the β-catenin binding domain of E-cadherin was necessary for the inhibition of cellular proliferation. Knockdown of β-catenin by siRNA eliminated E-cadherin-mediated inhibition of cell growth, resulting in increased cellular proliferation. E-cadherin-mediated inhibition of cell growth, however, was not dependent on β-catenin-dependent transcriptional activation. Ligation of E-cadherin by Fc-hE-microspheres inhibited cell growth stimulated by epidermal growth factor (EGF) in epithelial cell lines. This effect of E-cadherin was also dependent on the presence of β-catenin. Whereas E-cadherin ligation did not inhibit either the autophosphorylation of the EGF receptor (EGFR) or EGFR-mediated activation of extracellular signal-regulated kinase (ERK), it did inhibit the transphosphorylation of the Tyr845 residue of EGFR and the subsequent activation of signal transducer and activator of transcription 5 (STAT5). Together these data suggest that homophilic ligation of E-cadherin can inhibit cell growth and EGFR signaling independently of cell-cell contact. M. Perrais, X. Chen, M. Perez-Moreno, B. M. Gumbiner, E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. Mol. Biol. Cell 18 , 2013-2025 (2007). [Abstract] [Full Text]
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Cell–cell interaction
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