Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. Although the integrity of cell-cell contacts, such as adherens junctions, is essential for the maintenance of functional epithelia, they need to be rapidly disassembled during migration. The transmembrane cell adhesion protein E-cadherin and the cytoplasmic catenins are molecular elements of these structures. Here we demonstrate that epithelial cell migration is accompanied by tyrosine phosphorylation of -catenin and an increase of its free cytoplasmic pool. We show further that the protein-tyrosine phosphatase LAR (leukocyte common antigen related) colocalizes with the cadherincatenin complex in epithelial cells and associates with -catenin and plakoglobin. Interestingly, ectopic expression of protein-tyrosine phosphatase (PTP) LAR inhibits epithelial cell migration by preventing phosphorylation and the increase in the free pool of -catenin; moreover, it inhibits tumor formation in nude mice. These data support a function for PTP LAR in the regulation of epithelial cell-cell contacts at adherens junctions as well as in the control of -catenin signaling functions. Thus PTP-LAR appears to play an important role in the maintenance of epithelial integrity, and a loss of its regulatory function may contribute to malignant progression and metastasis.The cadherins represent a family of transmembrane receptors that mediate homophilic, Ca 2ϩ -dependent cell-cell adhesion. In epithelial cells, the members of this family, such as the classical E-, N-, and P-cadherins, are primarily found at the adherens junctions of adjacent cells (1). -Catenin as well as plakoglobin (␥-catenin) associate directly with the highly conserved cytoplasmic domain of classical cadherins in a mutually exclusive manner (2, 3). The cadherin-catenin complex is linked via ␣-catenin either directly (4) or indirectly to the actin filament network via the actin-binding proteins ␣-actinin or vinculin (5, 6). The association of the cadherin-catenin complex with the cytoskeleton is essential for tight cell-cell interaction.Nevertheless, cadherin/catenin-mediated cell-cell contacts have to be highly dynamic because, particularly during embryonic development or wound healing, adherens junctions have to be rapidly disassembled and reassembled (7). Down-regulation of cadherins results in the separation of neighboring cells, a phenomenon that is observed during embryonic development at the epithelial-mesenchymal transition (EMT) 1 of forming mesoderm (8) as well as in tumor cells, allowing their invasion and dissemination throughout the body (9). During epithelialmesenchymal transition, cells transiently lose their epithelial features and acquire a fibroblastoid morphology (10). The critical importance of an intact cadherin-catenin complex is underscored by the observation that down-regulation of any of its components resulting in the loss of the tumor-suppressive actions of adherens junctions correlates with tumor invasion and metastasis (11...