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bioRxiv · 10.1101/152892

RAPGEF5 regulates nuclear transport of β-catenin

Griffin, J. N.·del Viso, F.·Duncan, A. R.·Robson, A.·Kulkarni, S.·Liu, K. J.·Khokha, M. K.
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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 {beta}-catenin is the defining step in pathway activation. However, despite intensive investigation, the mechanisms regulating {beta}-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 {beta}-catenin independently of both {beta}-catenin cytoplasmic stabilization and the importin {beta}1/Ran mediated transport system. We propose a model whereby RAPGEF5 activates the nuclear GTPases, Rap1/2, to facilitate the nuclear transport of {beta}-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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Griffin, J. N., del Viso, F., Duncan, A. R., Robson, A., Kulkarni, S., Liu, K. J., Khokha, M. K.. 2017-06-20. RAPGEF5 regulates nuclear transport of β-catenin. https://doi.org/10.1101/152892

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