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

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.

We thank L. Bullions, H. Clevers, B. Geiger, A. Hall, C. Marshall, F. McCormick, and B. Vogelstein for plasmids.

Funding for this study was provided by grant NCI CA62029, a Howard Hughes Medical Institute bridge support grant, the Hershey Family Fund for Prostate Cancer Research, grant NIHT32 DK07542, and in part by the Center for Gastroenterology Research on Absorptive and Secretory Processes (GRASP) (grant NIDDK 1 P30 DK39428).