Patients with glioblastomas, the most common primary tumors of the central nervous system, have poor prognoses because of uncontrolled tumor cell invasion and proliferation. β-Catenin plays an important role in tumor development. However, whether α-catenin expression contributes to β-catenin transactivation in glioma cells is largely unknown. We report here that α-catenin expression abrogates epidermal growth factor receptor (EGFR)-activation-induced β-catenin nuclear translocation in human glioblastoma cells, thereby attenuating β-catenin transactivation and the expression of its downstream genes CCND1 and c-myc. In addition, ectopic expression of α-catenin or depletion of β-catenin suppresses EGF-promoted glioblastoma cell migration, invasion, and proliferation. In contrast, α-catenin depletion promotes β-catenin nuclear translocation and transactivation, and tumor cell motility and growth. These findings reveal the importance of β-catenin regulation by α-catenin in cellular activities of glioblastoma cells.