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β-Catenin is a critical transducer of the Wnt signal pathway and plays an important role in many developmental and cellular processes. Deregulation of β-catenin signaling has been observed in a broad range of human tumors. In this report, we investigated whether tyrosine kinase inhibitor STI-571 could inhibit the β-catenin signaling activity and hence suppress cell proliferation. Our results demonstrated that STI-571 effectively inhibited the constitutive activity of β-catenin signaling in human colon cancer cells as well as the Wnt1-induced activation of β-catenin signaling in HOS, HTB-94, and HEK 293 cells. Furthermore, STI-571 was shown to effectively suppress the proliferation of human colon cancer cells. Finally, we demonstrated that the Wnt1-mediated activation of a GAL4-β-catenin heterologous transcription system was effectively inhibited by STI-571. Thus, our findings suggest that tyrosine phosphorylation may play an important role in regulating β-catenin signaling activity, and inhibition of this signaling pathway by STI-571 may be further explored as an important target for alternative/adjuvant treatments for a broader range of human cancer. [Copyright &y& Elsevier]