Tyrosine phosphorylation of β-catenin, an intracytoplasmic E-cadherin-binding protein, has been shown to disrupt the cadherin-mediated cell adhesion system in vitro. In order to investigate the relationships of expression and tyrosine phosphorylation of cadherin-catenin molecules and expression of growth factor receptor-tyrosine kinase with loose cell-to-cell adhesion, immunohistochemical staining for E-cadherin, α- and β-catenin, phosphorylated tyrosine residues and tyrosine kinase receptors, including c-erbB-2, epidermal growth factor-receptor (EGF-R), c-met and K-sam, in 17 undifferentiated- and 10 differentiated-type human gastric cancers was performed. Loss or reduced expressions of E-cadherin and α- and β-catenin (11, 11, 10 cancers, respectively) were observed in the former, but not the latter. Diffuse cytoplasmic staining of E-cadherin, α- and β-catenin and phosphotyrosine residues was observed frequently in the undifferentiated-type cancers. The cytoplasmic localization of phosphotyrosine residues in undifferentiated-type cancers was correlated significantly with K-sam expression (P<0.01) and diffuse cytoplasmic staining of E-cadherin (P<0.05) and β-catenin (P<0.05). Expression of K-sam protein was detected significantly more frequently in undifferentiated- (617; P<0.05) than differentiated-type adenocarcinomas whereas the converse applied to c-erbB-2 expression (810 of the latter, P<0.05). Tyrosine phosphorylation of β-catenin was directly confirmed in the protein extracts of one undifferentiated-type gastric cancer. These data indicate that alteration of tyrosine phosphorylation status associated with K-sam expression may cause the cytoplasmic distribution of cadherin-catenin molecules and loose cell-cell adhesion in undifferentiated-type gastric cancers.