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Leading Article the Importance of the E-Cadherin-Catenin Complex In Gut 1997; 41: 581–584 581 Gut Gut: first published as 10.1136/gut.41.5.581 on 1 November 1997. Downloaded from Leading article The importance of the E-cadherin-catenin complex in the maintenance of intestinal epithelial homoeostasis: more than intercellular glue? Introduction important in mediating the retention of lymphocytes The intestinal epithelium is characterised by rapid cell within the epithelium in a tissue specific fashion.11 turnover, with pluripotential stem cells in the crypts of The critical importance of E-cadherin to normal develop- Lieberkühn providing a continuous supply of cells which ment and tissue function is demonstrated by the lethality of are directed into a variety of maturation pathways. Devel- E-cadherin gene knockouts in mice, at a very early stage in opment and maintenance of normal intestinal epithelial embryogenesis.12 13 Reduced or absent expression of morphology requires regulation of daughter cells’ prolifera- E-cadherin has been described in a variety of epithelial tive status, lineage allocation, migration, diVerentiation, malignancies due to mutation, hypermethylation of the and apoptosis.1 It has become increasingly evident that E-cadherin promotor,14 abnormal transcription, or post- co-ordination of these processes and the consequent transcriptional modification by tyrosine phosphorylation.15 16 generation of the characteristic intestinal epithelial archi- These abnormalities are associated with aggressive his- tecture are highly dependent on intercellular and cell- topathological characteristics such as increased tumour matrix adhesive interactions.2 These adhesive events are invasiveness and metastasis,17 18 , and in some cases with not random, but through selective interactions, organise poor survival,19 20 leading to the suggestion of a role for cells into diverse and highly distinctive patterns. Connec- E-cadherin as a tumour suppresser.21 22 tions of cell junctions such as desmosomes, hemidesomo- somes, and adherens junctions to the actin cytoskeleton, thus allow maintenance of cell polarity and tissue http://gut.bmj.com/ architecture.3 Variation in the functional state of these The catenins adhesive mechanisms is critical to the dynamic processes The functions of E-cadherin are mediated through its link- necessary for tissue morphogenesis in the embryo,4 where age to the actin cytoskeleton via a number of cytoplasmic 23 many morphogenetic events are correlated with a unique plaque proteins known as the catenins (fig 1). The spatiotemporal pattern of cadherin expression.5 Such vari- catenins seem to be critical both to the function of cadherin 24 ation is also critical to the maintenance of this highly com- mediated adhesion and to the transduction of signals ini- 25 plex architecture in various physiological and pathological tiated at the cell surface by the adhesion receptors. on September 28, 2021 by guest. Protected copyright. states, such as migration of cells up the crypt-villus axis6 â-catenin forms a complex with E-cadherin, while 26 and repair of mucosal injuries. In view of these facts, it is á-catenin links this complex to the actin cytoskeleton. not surprising that many cell adhesion molecules have been â-catenin shows a high degree of homology to armadillo,a implicated in cell signalling pathways.78 segment polarity gene in Drosophila, which is an essential component of the WNT signalling pathway that controls developmental patterning in both Drosophila27 and Xenopus E-cadherin: a cell-cell adhesion receptor embryos.28 â-catenin undergoes tyrosine phosphorylation E-cadherin is a member of the large cadherin superfamily in response to growth factor stimulation resulting in and is the predominant intercellular adhesion molecule reduced adhesion,29 and is therefore thought to act as a expressed by intestinal epithelial cells.3 It is a calcium regulatory component of the cadherin-catenin complex, dependent transmembrane protein which forms a key and to link signal transduction to intercellular adhesion. component of adherens junctions. E-cadherin molecules Disruption of the â-catenin gene prevents normal develop- form dimers at the cell surface, which interdigitate with ment of embryonic ectoderm, and causes early lethality.30 other E-cadherin molecules on adjacent epithelial cells Finally, ã-catenin bears homology to â-catenin and is iden- resulting in the formation of cell adhesion “zippers” (fig tical to desmosomal plakoglobin. â- and ã-catenins appear 1).910E-cadherin has classically been thought to be exclu- to form mutually exclusive complexes with E-cadherin,31 sively involved in homotypic cell-cell interactions; however, although both form similar interactions with a number of evidence has emerged suggesting a heterophillic interac- proteins implicated in signal transduction, control of tion with áEâ7 integrin on the surface of lymphocytes. áEâ7 proliferation and pathogenesis of neoplasia, including the is expressed predominantly on intra-epithelial lym- epidermal growth factor receptor (EGFr),32 the oncogene 33 phocytes, but on only a minority of circulating lym- c-erb2 and the adenomatous polyposis coli (APC) protein phocytes, and this interaction is therefore suggested to be product.34 35 Leading articles express the views of the author and not those of the editor and editorial board. 582 Jawhari, Pignatelli, Farthing duodenal-ileal axis. The transfected cells were then introduced into mouse B6 blastocysts resulting in chimae- ric mice, which express two populations of monoclonal Gut: first published as 10.1136/gut.41.5.581 on 1 November 1997. Downloaded from crypts—normal or transgenic. The authors demonstrated that expression of a dominant negative N-cadherin mutant in the crypt-villus axis resulted in disruption of intercellu- lar and cell-matrix contacts, with an increased cell migration rate up the villus, loss of cell diVerentiation and polarisation, and precocious apoptosis, confirming the importance of intact E-cadherin mediated adhesion in regulating cell fate and maintenance of normal epithelial homoeostasis. An intact cadherin-catenin complex has been shown to be important in the development of functional tight junctions38 which are necessary for the maintenance of the selective permeability and barrier function of the intestinal epithelium. It is therefore perhaps not surprising that by 6 weeks of life, all chimaeric mice demonstrated increased inflammatory cell infiltration in the transgenic areas of intestinal epithelium, which showed evidence of epithelial barrier disruption. Transmural inflammation with a clinical picture analogous to Crohn’s disease was seen by 3 months of age. A hyperproliferative state was noted in the crypts with early development of adenomas and dysplastic change, although progression to carcinoma was not observed in the first 19 months of life. A role in epithelial cell migration The importance of cell-matrix adhesive interactions in controlling cell migration has been extensively studied.39 The extending lamellipodium of the migrating cell binds to the substratum through integrin receptors. These adhesive interactions are then used to generate the traction force required for cell movement, followed by release of adhesions at the rear of the cell. Less is known, however, about the role of the E-cadherin-catenin complex in this process. In both families of cell adhesion molecules, http://gut.bmj.com/ control of cell migration is thought to involve intimate interactions between the transmembrane adhesion recep- tors and the cytoskeletal motility apparatus. Recent data have demonstrated binding of â-catenin to 40 41 Figure 1: Multimolecular complexes formed by catenins. E-cadherin is a fascin, and of á-catenin to á-actinin, both of which are transmembrane protein which binds to â-orã-catenin in a mutually actin bundling proteins.42 These proteins are known to be exclusive interaction. á-catenin links this complex to the actin cytoskeleton. p120cas binds to the cytoplasmic domain of E-cadherin without any link to important in the dynamic assembly and organisation of the cytoskeleton. Other complexes formed by â-catenin include an actin bundles and networks necessary for the extension of on September 28, 2021 by guest. Protected copyright. interaction with the actin bundling protein fascin (top left), a complex with lamellipodia, the first step in cell migration. This the adenomatous polyposis coli (APC) protein, and in turn to the tublin interaction between proteins involved in intercellular microfilament network (bottom left), and another with the epidermal growth factor receptor (EGFr) (bottom right). TGF-á, tumour growth adhesion and those controlling motility, supports the factor á. notion of co-ordinate regulation of cadherin mediated adhesive interactions and cell motility. Such regulatory The role of the E-cadherin-catenin complex in co-ordination is particularly important under certain maintenance of epithelial morphology and physiological circumstances such as mucosal repair by epi- homoeostasis thelial restitution.43 Downregulation of E-cadherin expres- In vitro cell culture studies have suggested an important sion or function to permit motility of regenerative role for the cadherin-catenin complex in many processes epithelium over ulcers is one potential mechanism44 which including regulation of cell polarity, formation of junc- may be facilitated by factors influencing binding of tional complexes, cell migration and proliferation. Further E-cadherin to â-catenin. Phosphorylation of â-catenin by understanding of the its
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