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RAPGEF5 Regulates Nuclear Translocation of ?-Catenin.

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 ?-catenin is the defining step in pathway activation. However, despite intensive investigation, the mechanisms regulating ?-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 ?-catenin independently of both ?-catenin cytoplasmic stabilization and the importin ?1/Ran-mediated transport system. We propose a model whereby RAPGEF5 activates the nuclear GTPases, Rap1a/b, to facilitate the nuclear transport of ?-catenin, defining a parallel nuclear transport pathway to Ran. Our results suggest new targets for modulating Wnt signaling in disease states.

SUBMITTER: Griffin JN 

PROVIDER: S-EPMC5818985 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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RAPGEF5 Regulates Nuclear Translocation of β-Catenin.

Griffin John N JN   Del Viso Florencia F   Duncan Anna R AR   Robson Andrew A   Hwang Woong W   Kulkarni Saurabh S   Liu Karen J KJ   Khokha Mustafa K MK  

Developmental cell 20171228 2

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 previousl  ...[more]

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