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Wnt signaling is essential during development while deregulation of this pathway frequently leads to the formation of various tumors including colorectal carcinomas. A key component of the pathway is ␤-catenin that, in association with TCF-4, directly regulates the expression of Wnt-responsive genes. To identify novel binding partners of ␤-catenin that may control its transcriptional activity, we performed a mammalian twohybrid screen and isolated the Tax-interacting protein (TIP-1). The in vivo complex formation between ␤-catenin and TIP-1 was verified by coimmunoprecipitation, and a direct physical association was revealed by glutathione S-transferase pull-down experiments in vitro. By using a panel of deletion mutants of both proteins, we demonstrate that the interaction is mediated by the PDZ (PSD-95/DLG/ZO-1 homology) domain of TIP-1 and requires primarily the last four amino acids of ␤-catenin. TIP-1 overexpression resulted in a dose-dependent decrease in the transcriptional activity of ␤-catenin when tested on the TOP/FOPFLASH reporter system. Conversely, siRNA-mediated knock-down of endogenous TIP-1 slightly increased endogenous ␤-catenin transactivation function. Moreover, we show that overexpression of TIP-1 reduced the proliferation and anchorageindependent growth of colorectal cancer cells. These data suggest that TIP-1 may represent a novel regulatory element in the Wnt/␤-catenin signaling pathway.

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