%0 Journal Article %A John N. Griffin %A Florencia del Viso %A Anna R. Duncan %A Andrew Robson %A Saurabh Kulkarni %A Karen J. Liu %A Mustafa K. Khokha %T RAPGEF5 regulates nuclear translocation of β-catenin %D 2017 %R 10.1101/152892 %J bioRxiv %P 152892 %X Canonical Wnt signaling coordinates many critical aspects of embryonic development, while dysregulated Wnt signaling contributes to common diseases, including congenital malformations and cancer. The nuclear localization of β-catenin is the defining step in pathway activation. However, despite intensive investigation, the mechanisms regulating β-catenin nuclear transport remain undefined. In a patient with congenital heart disease and heterotaxy, a disorder of left-right patterning, we previously identified the guanine nucleotide exchange factor, RAPGEF5. Here, we demonstrate that RAPGEF5 regulates left-right patterning via Wnt signaling. In particular, RAPGEF5, regulates the nuclear translocation of β-catenin independently of both β-catenin cytoplasmic stabilization and the importin β1/Ran mediated transport system. We propose a model whereby RAPGEF5 activates the nuclear GTPases, Rap1/2, to facilitate the nuclear transport of β-catenin, defining a parallel nuclear transport pathway to Ran. Our results suggest new targets for modulating Wnt signaling in disease states. %U https://www.biorxiv.org/content/biorxiv/early/2017/06/20/152892.full.pdf