Distinct Activities of the α-Catenin Family, α-Catulin and α-Catenin, on β-Catenin-Mediated Signaling

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Abstract
α-Catenin, an integral part of cadherin-catenin adhesion complexes, is a major binding partner of β-catenin, a key component of the Wnt pathway, which activates T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription and is often upregulated in cancers. Recently, we identified an α-catenin-related protein, α-catulin, whose function is poorly understood, as part of a Rho GTPase signaling complex. Here, based on evidence suggesting that α-catulin may associate with a β-catenin fraction, we investigated the role of α-catenin family members in β-catenin-mediated signals. Expression of the full length or a 103-residue region of α-catenin strongly inhibits the induction of the TCF/LEF-responsive TOPFLASH reporter in HEK293T cells expressing activated β-catenin or in cancer cells with constitutively upregulated Wnt signaling, whereas α-catulin expression had no effect. Interestingly, α-catulin expression attenuates the activation of the cyclin D1 promoter, a target of Wnt pathway signals. α-Catulin appears to inhibit Ras-mediated signals to the cyclin D1 promoter, rather than β-catenin signals, and the synergy between Ras and β-catenin required to fully activate this promoter. Data suggesting the involvement of Rho in this response are presented and discussed. These results suggest a novel function for α-catulin and imply that α-catenin and α-catulin have distinct activities that downregulate, respectively, β-catenin and Ras signals converging on the cyclin D1 promoter.