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Dev Cell 2018 Jan 22;442:248-260.e4. doi: 10.1016/j.devcel.2017.12.001.
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RAPGEF5 Regulates Nuclear Translocation of β-Catenin.

Griffin JN , Del Viso F , Duncan AR , Robson A , Hwang W , Kulkarni S , Liu KJ , Khokha MK .

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.

PubMed ID: 29290587
PMC ID: PMC5818985
Article link: Dev Cell
Grant support: [+]

Species referenced: Xenopus
Genes referenced: cep43 chrd.1 ctnnb1 dand5 fgf8 foxj1 foxj1.2 gdf3 gsc gsk3b lrp1 nodal nodal1 nodal3.1 nog not otx2 pitx2 ralgds ran rap1a rap1b rap2a rap2b rapgef5 rpe ventx1
Antibodies: Ctnnb1 Ab1 Ctnnb1 Ab2 H3f3a Ab33 Rap1a Ab1 Rap2a Ab1 Rapgef5 Ab1
Morpholinos: rapgef5 MO1 rapgef5 MO2

Article Images: [+] show captions
References [+] :
Bhanot, A new member of the frizzled family from Drosophila functions as a Wingless receptor. 1996, Pubmed