RAPGEF5 regulates nuclear translocation of β-catenin

John N. Griffin, Florencia del Viso, Anna Duncan, Andrew Robson, Woong Hwang, Saurabh Kulkarni, Karen J. Liu, Mustafa K. Khokha

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60 Citations (Scopus)
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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, Rap1a/b, 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.
Original languageEnglish
Pages (from-to)P248-260.E4
JournalDevelopmental Cell
Issue number2
Early online date28 Dec 2017
Publication statusPublished - 22 Jan 2018


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