occurs during normal developmental processes to allow cell types to segregate from one another. Tumor cells often recapitulate this activity and the result is an aggressive tumor cell that gains the ability to leave the site of the tumor and metastasize. At present, we understand some of the mechanisms that promote cadherin switching and some of the pathways downstream of this process that influence cell behavior. Specific cadherin family members influence growthfactor-receptor signaling and Rho GTPases to promote cell motility and invasion. In addition, p120-catenin probably plays multiple roles in cadherin switching, regulating Rho GTPases and stabilizing cadherins. Journal of Cell Science 728cadherin expression has been shown to promote motility and invasion (Hazan et al., 2000; Islam et al., 1996;Nieman et al., 1999). This loss of E-cadherin expression and gain of N-cadherin expression is reminiscent of the cadherin switching that is seen during normal embryonic development and probably underpins many of the phenotypic changes that occur in the participating cells (reviewed in Cavallaro et al., 2002; Christofori, 2003; Gerhart et al., 2004).The term cadherin switching usually refers to a switch from expression of E-cadherin to expression of N-cadherin, but also includes situations in which E-cadherin expression levels do not change significantly but the cells turn on (or increase) expression of N-cadherin. It also includes examples in which other cadherins replace or are co-expressed with E-cadherin, including R-cadherin, cadherin 11, T-cadherin and even P-cadherin, and the expression of the 'inappropriate cadherin' might alter the behavior of the tumor cells (Derycke and Bracke, 2004;Nakajima et al., 2004;Paredes et al., 2005;Patel, I. et al., 2003;Riou et al., 2006;Stefansson et al., 2004;Taniuchi et al., 2005;Tomita et al., 2000). It has even been reported that E-cadherin can influence tumorigenesis in tissues that do not normally express this cadherin. For example, ovarian surface epithelium normally expresses N-cadherin. However, during progression to the neoplastic state, the cells show decreased N-cadherin expression and increased E-cadherin and Pcadherin expression; the E-cadherin might play a role in the initiation of the aberrant differentiation that characterizes ovarian carcinogenesis (Patel, I. et al., 2003;Wong et al., 1999;Wu et al., 2007). Table 1 presents examples of cadherin switching that have been reported during normal developmental processes and during tumorigenesis.One role of cadherin switching is to allow a select population of cells to separate from their neighbors -for example, during processes such as gastrulation, epiblast cell ingression through the primitive streak and neural crest emigration from the neural tube (Edelman et al., 1983; Hatta and Takeichi, 1986;Takeichi, 1988;Takeichi et al., 2000). It is well known that cells expressing different cadherins segregate from one another in in vitro aggregation assays (Nose et al., 1988;Steinberg and Takeichi, 1994) and it is easy...

E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent, homotypic cell–cell adhesion and plays a role in maintaining the normal phenotype of epithelial cells. Decreased expression of E-cadherin has been correlated with increased invasiveness of breast cancer. In other systems, inappropriate expression of a nonepithelial cadherin, such as N-cadherin, by an epithelial cell has been shown to downregulate E-cadherin expression and to contribute to a scattered phenotype. In this study, we explored the possibility that expression of nonepithelial cadherins may be correlated with increased motility and invasion in breast cancer cells. We show that N-cadherin promotes motility and invasion; that decreased expression of E-cadherin does not necessarily correlate with motility or invasion; that N-cadherin expression correlates both with invasion and motility, and likely plays a direct role in promoting motility; that forced expression of E-cadherin in invasive, N-cadherin–positive cells does not reduce their motility or invasive capacity; that forced expression of N-cadherin in noninvasive, E-cadherin–positive cells produces an invasive cell, even though these cells continue to express high levels of E-cadherin; that N-cadherin–dependent motility may be mediated by FGF receptor signaling; and that cadherin-11 promotes epithelial cell motility in a manner similar to N-cadherin.

p120ctn is a catenin whose direct binding to the juxtamembrane domain of classical cadherins suggests a role in regulating cell–cell adhesion. The juxtamembrane domain has been implicated in a variety of roles including cadherin clustering, cell motility, and neuronal outgrowth, raising the possibility that p120 mediates these activities. We have generated minimal mutations in this region that uncouple the E-cadherin–p120 interaction, but do not affect interactions with other catenins. By stable transfection into E-cadherin–deficient cell lines, we show that cadherins are both necessary and sufficient for recruitment of p120 to junctions. Detergent-free subcellular fractionation studies indicated that, in contrast to previous reports, the stoichiometry of the interaction is extremely high. Unlike α- and β-catenins, p120 was metabolically stable in cadherin-deficient cells, and was present at high levels in the cytoplasm. Analysis of cells expressing E-cadherin mutant constructs indicated that p120 is required for the E-cadherin–mediated transition from weak to strong adhesion. In aggregation assays, cells expressing p120-uncoupled E-cadherin formed only weak cell aggregates, which immediately dispersed into single cells upon pipetting. As an apparent consequence, the actin cytoskeleton failed to insert properly into peripheral E-cadherin plaques, resulting in the inability to form a continuous circumferential ring around cell colonies. Our data suggest that p120 directly or indirectly regulates the E-cadherin–mediated transition to tight cell–cell adhesion, possibly blocking subsequent events necessary for reorganization of the actin cytoskeleton and compaction.

Cadherins are transmembrane glycoproteins that mediate calcium-dependent cell-cell adhesion. The cadherin family is large and diverse, and proteins are considered to be members of this family if they have one or more cadherin repeats in their extracellular domain. Cadherin family members are the transmembrane components of a number of cellular junctions, including adherens junctions, desmosomes, cardiac junctions, endothelial junctions, and synaptic junctions. Cadherin function is critical in normal development, and alterations in cadherin function have been implicated in tumorigenesis. The strength of cadherin interactions can be regulated by a number of proteins, including the catenins, which serve to link the cadherin to the cytoskeleton. Cadherins have been implicated in a number of signaling pathways that regulate cellular behavior, and it is becoming increasingly clear that integration of information received from cell-cell signaling, cell-matrix signaling, and growth factor signaling determines ultimate cellular phenotype and behavior.

Abstract. Cadherins are CaZ+-dependent, cell surface glycoproteins involved in cell--cell adhesion. Extracellularly, transmembrane cadherins such as E-, P-, and N-cadherin self-associate, while intracellularly they interact indirectly with the actin-based cytoskeleton. Several intraceUular proteins termed catenins, including a-catenin, B-catenin, and plakoglobin, are tightly associated with these cadherins and serve to link them to the cytoskeleton. Here, we present evidence that in fibroblasts a-actinin, but not vinculin, colocalizes extensively with the N-cadherin/catenin complex. This is in contrast to epithelial cells where both cytoskeletal proteins colocalize extensively with E-cadherin and catenins. We further show that a-actinin, but not vinculin, co-immunoprecipitates specifically with a-and ~3-catenin from N-and E-cadherin--expressing cells, but only if a-catenin is present. Moreover, we show that a-actinin coimmunoprecipitates with the N-cadherin/catenin complex in an actin-independent manner. We therefore propose that cadherin/catenin complexes are linked to the actin cytoskeleton via a direct association between a-actinin and a-catenin.