Isolation of novel proteins that regulate the Wnt signaling pathway

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We have identified three novel proteins that regulate the Wnt signaling pathway in this project. They are Axin-binding, Dvl-binding, and β-catenin-binding proteins, and we designated them Axam, Idax, and Duplin, respectively. Axam has nuclear localization signal (NLS) at the N-terminus and Axin-binding domain in its central region. Furthermore, Axam shares high homology with the catalytic domain of Senp1, which is a SUMO specific protease. Indeed, Axam showed an desumoylation activity. Axam stimulated degradation of β-catenin in mammalian cells and inhibited axis formation in Xenopus embryos. Catalyticaly inactive mutant of Axam reduced these activity. Therefore, sumoylation may be involved in the Wnt signaling pathway. Idax does not share any homology with other proteins. Idax suppressed Wnt dependent β-catenin accumulation and axis formation by inhibiting the binding of Dvl to Axin. Duplin has NLS and β-catenin-binding domain in its C-treminus. Although Duplin inhibited β-catenin-dependent Tcf activation and axis formation, the Duplin mutant that lacks NLS lost these activities, suggesting that Duplin must be in the nucleus to exert its functions. Taken together, Axam, Idax, and Duplin act as a negative regulator of the Wnt signaling pathway. Screening of mutations of these novel molecules in human cancers remains to be clarified.