Direct contacts between keratinocytes and melanocytes play an important role in conserving the characteristic phenotype and biologic behavior of melanocytic cells. Although the mechanisms involved remain unclear, given the role of adhesion molecules in controlling cellular interactions, disturbances in normal keratinocyte-melanocyte adhesion mediated by cadherin may contribute to malignant transformation by releasing melanocytes from a variety of contact-mediated regulatory controls. To determine the potential clinical relevance of cadherin profiles in melanomas and to study their possible involvement in the phenotypic plasticity of melanocytic cells, we used immunostaining, biochemical, and co-culture techniques. Double immunofluorescence demonstrated expression of cadherins and their associating proteins, alpha- and beta-catenin, in melanocytes in situ. Melanomas were heterogeneous when evaluated immunohistochemically, with positive rates of four of 14, eight of 12, and 12 of 16 to anti-E-, anti-P-, and anti-N-cadherin monoclonal antibodies, respectively. Flow cytometry indicated abundant expression of E-cadherin but marginal P- and N-cadherin in cultured melanocytes. In contrast, only one (WM1232) of 16 melanoma cell lines tested was positive for E-cadherin, none was positive for P-cadherin, and all but one were positive for N-cadherin. Western blot confirmed E-cadherin expression in melanocytic cells. Immunoprecipitation further revealed complexes of E-cadherin with catenins in WM1232 melanoma cells. Co-culture studies indicated that only melanoma cells expressing E-cadherin (WM1232) were susceptible to keratinocyte-mediated control of the expression of the melanoma cell adhesion molecule, Mel-CAM. The results suggest downregulation of E-cadherin but upregulation of N-cadherin in melanoma cells. Such a shift in cadherin profiles may endow melanocytic cells with new adhesive properties and altered spatial relations that favor uncontrolled proliferation, migration, and invasion.