E-Cadherin and APC Compete for the Interaction with -Catenin and the Cytoskeleton

&Catenin is involved in the formation of adherens junctions of mammalian epithelia. It interacts with the cell adhesion molecule E-cadherin and also with the tumor suppressor gene product APC, and the Drosophila homologue of B-catenin, armadillo, mediates morphogenetic signals. We demonstrate here that E-cadherin and APC directly compete for binding to the internal, armadillo-like repeats of/5-catenin; the NH2-terminal domain of/3-catenin mediates the interaction of the alternative E-cadherin and APC complexes to the cytoskeleton by binding to et-catenin. Plakoglobin (7-catenin), which is structurally related to/3-catenin, mediates identical interactions. We thus show that the APC tumor suppressor gene product forms strikingly similar associations as found in cell junctions and suggest that/3-catenin and plakoglobin are central regulators of cell adhesion, cytoskeletal interaction, and tumor suppression. I T recently became evident that the proper formation of intercellular junctions is critical for the maintenance of epithelial differentiation, and that destabilization of junctions allows invasiveness of epithelial cells and the progression of carcinomas (of. for review Tsukita et al., 1993; Birchmeier et al., 1993). Interestingly, various structural components of intercellular junctions have been found to be related to products of tumor suppressor genes. For instance, the adherens junction molecule E-cadberin suppresses invasiveness of carcinoma cells, and the E-cadherin gene is mutated in 50% of the diffuse-type gastric carcinomas (Behrens et al., 1989; Frixen et al., 1991; Vleminckx et al., 1991; Becker et al., 1994). The tumor suppressor gene product APC binds to B-catenin, which is cytoplasmically associated to E-cadherin (Rubinfeld et al., 1993; Suet al., 1993; Nagafuchi and Takeichi, 1988; Ozawa et al., 1989). The tight junction-associated protein ZO-I is related to the dlg tumor suppressor gene product of Drosophila, and the neurofibromatosis-2 tumor suppressor gene product merlin/schwannomin is related to the ezrin/radixin/moesin family of junctional proteins (Woods and Bryant, 1991; Rouleau et al., 1993; Trofatter et al., 1993). Conversely, products of oncogenes have been demonstrated to destabilize intercellular junctions, such as src, ms, fos, or met (Behrens et al., 1993; Hamaguchi et al., 1993; Behrens et al., 1989; Shibamoto et al., 1994; Reichmann et al., 1992; Weidner et al., 1990). Src, the EGF receptor, and met phosphorylate B-catenin on tyrosine residues, which may modulate the adhesive properties of cells. Address all correspondence to W. Birehrneier, Max-Delbriick-Center for Molecular Medicine, Robert-Rtssle-Str. 10, 13122 Berlin, Germany. Ph.: (49) 30 9406 3737. Fax: (49) 30 9406 2656. Adherens junctions of epithelial cells are specialized regions of the plasma membrane where transmembrane E-cadherin molecules on opposing cells make contact with each other (Boiler et al., 1985; Tsukita et al., 1992; for a discussion of the related desmosomes see Garrod, 1993). The cytoplasmic domain of E-cadherin forms complexes with ct-, B-, and 3,-catenin/plakoglobin, which are essential for the adhesive function (Nagafuchi and Takeichi, 1988; Ozawa et al., 1989; Ozawa et al., 1990; Kintner, 1992). ot-Catenin shows sequence similarity to vinculin and interacts with the cytoskeleton (Nagafuchi et al., 1991; Herrenknecht et al., 1991; Hirano et al., 1992). B-Catenin is the vertebrate homologue of the segment polarity gene armadillo of Drosophila and is related to plakoglobin (McCrea et al., 1991; Peifer et al., 1992; Butz et al., 1992). 3,-Catenin is identical to plakoglobin, which is also found in desmosomal junctions (Cowin et al., 1986; Franke et al., 1989; Knudsen and Wheelock, 1992; Peifer et al., 1992; Hinck et al., 1994a,b; Niithke et al., 1994). Recent experimental evidence suggests that any significant change in expression or structure of one of these components leads to adherens junction disassembly and consequently, to non-adhesive and invasive cells. Molecular aberrations which result in such defects have been studied: an E-cadherin deletion mutant lacking its catenin binding region was not functional in cell-cell adhesion when expressed in fibroblasts (Nagafuchi and Takeichi, 1988; Ozawa et al., 1990). Cadherin mutants without the extracellular domain acted in a dominant-negative fashion, i.e., disturbed epithelial cell adhesion (Kintner, 1992). Apparently, these truncated molecules collect catenins, which are thus not available to form proper complexes with intact E-cadherin. The adhesive properties of PC9 lung cancer ceils, which harbor a null mutation in the ct-catenin gene, could be restored by transfection with ct-catenin cDNA (Hirano et al., 1992). © The Rockefeller University Press, 0021-9525/94/12/2061/9 $2.00 The Journal of Cell Biology, Volume 127, Number 6, Part 2, December 1994 2061-2069 2061 on M ay 8, 2017 D ow nladed fom Published December 15, 1994