N-acetylglucosaminyltransferase V (GnT-V) has been reported to be positively associated with tumor progression, but its mechanism still remains unknown. In the present study, we found that GnT-V overexpression not only changed the glycosylation of receptor protein tyrosine phosphatase kappa (RPTPkappa) but also decreased its protein level. Moreover, GnT-V overexpression decreased cell calcium-independent adhesion and increased the tyrosine phosphorylation level of beta-catenin, in which RPTPkappa played an important role. Since RPTPkappa has an RXKR motif, which is a favored cleavage site for furin, we used furin inhibitor to further explore the effect of RPTPkappa on the change of cell adhesion and beta-catenin signaling induced by GnT-V. Our results showed that preventing RPTPkappa cleavage rescued the above effects of GnT-V, suggesting that furin cleavage could be one of the factors for RPTPkappa to regulate cell adhesion and beta-catenin signaling in GnT-V overexpression cell lines. In addition, the increased tyrosine phosphorylation level of beta-catenin was associated with the increased nuclear level of beta-catenin and downstream signaling molecules such as c-myc and cyclin D1 that were associated with cell proliferation. Our results suggest that GnT-V could decrease human hepatoma SMMC-7721 cell adhesion and promote cell proliferation partially through RPTPkappa.