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RAPGEF5 regulates nuclear translocation of β-catenin

Research output: Contribution to journalArticle

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

Original languageEnglish
JournalDEVELOPMENTAL CELL
Volume44
Issue number2
Early online date28 Dec 2017
DOIs
StatePublished - 22 Jan 2018

King's Authors

Abstract

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.

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