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During progression of melanomas, a crucial role has been attributed to alterations of cell-cell adhesions, specifically, to a "cadherin switch" from E- to N-cadherin (cad). We have examined the adhesion of melanoma cells to each other and to keratinocytes. When different human melanoma cell lines were studied by protein analysis and immunofluorescence microscopy, six of eight lines contained N-cad, three E-cad, and five P-cad, and some lines had more than one cad. Surprisingly, two N-cad-positive lines, MeWo and C32, also contained desmoglein 2 (Dsg2), a desmosomal cad previously not reported for melanomas, whereas other desmosome-specific proteins were absent. This finding was confirmed by reverse transcriptase-PCR, immunoprecipitation, and matrix-assisted laser desorption ionization-time of flight analyses. Double-label confocal and immunoelectron microscopy showed N-cad, alpha- and beta-catenin in plaque-bearing puncta adhaerentia, whereas Dsg2 was distributed rather diffusely over the cell surface. In cocultures with HaCaT keratinocytes Dsg2 was found in heterotypic cell contact regions. Correspondingly, immunohistochemistry revealed Dsg2 in five of 10 melanoma metastases. Together, we show that melanoma cell adhesions are more heterogeneous than expected and that certain cells devoid of desmosomes contain Dsg2 in a non-junction-restricted form. Future studies will have to clarify the diagnostic and prognostic significance of these different adhesion protein subtypes.