RAPGEF5 Regulates Nuclear Translocation of β-Catenin

Publication date: Available online 28 December 2017
Source:Developmental Cell
Author(s): John N. Griffin, Florencia del Viso, Anna R. Duncan, Andrew Robson, Woong Hwang, Saurabh Kulkarni, Karen J. Liu, Mustafa K. Khokha
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.

Graphical abstract

Teaser

Griffin et al. demonstrate that the candidate congenital heart disease gene, RAPGEF5, regulates nuclear translocation of β-catenin independently of the importin β1/Ran-mediated transport system. They propose that RAPGEF5 and its target GTPases define a parallel nuclear transport pathway required for Wnt signaling activity in development and disease.


http://ift.tt/2BQSvmK