期刊
DEVELOPMENTAL CELL
卷 44, 期 2, 页码 248-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2017.12.001
关键词
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资金
- NIH [R01HD081379, R01HL124402]
- BBSRC [BB/1021922/1, BB/E013872/1]
- BBSRC [BB/E013872/1] Funding Source: UKRI
- MRC [MR/R014302/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E013872/1] Funding Source: researchfish
- British Heart Foundation [PG/17/79/33313] Funding Source: researchfish
- Medical Research Council [MR/R014302/1] Funding Source: researchfish
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, Rap1a/b, 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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