RAPGEF5 Regulates Nuclear Translocation of β-Catenin

被引：77

作者：

Griffin, John N. ^{[1
,2
,3
]}

del Viso, Florencia ^{[1
,2
]}

Duncan, Anna R. ^{[1
,2
]}

Robson, Andrew ^{[1
,2
]}

Hwang, Woong ^{[1
,2
]}

Kulkarni, Saurabh ^{[1
,2
]}

Liu, Karen J. ^{[3
]}

Khokha, Mustafa K. ^{[1
,2
]}

机构：

[1] Yale Univ, Sch Med, Pediat Genom Discovery Program, Dept Pediat, 333 Cedar St, New Haven, CT 06510 USA

[2] Yale Univ, Sch Med, Pediat Genom Discovery Program, Dept Genet, 333 Cedar St, New Haven, CT 06510 USA

[3] Kings Coll London, Ctr Craniofacial & Regenerat Biol, London SE1 9RT, England

来源：

DEVELOPMENTAL CELL | 2018年 / 44卷 / 02期

基金：

英国生物技术与生命科学研究理事会;

关键词：

CONGENITAL HEART-DISEASE; LEFT-RIGHT ASYMMETRY; LEFT-RIGHT AXIS; NUCLEOTIDE EXCHANGE FACTORS; COPY NUMBER VARIATIONS; NODAL-RELATED GENE; TRANSCRIPTION FACTOR; SPEMANNS ORGANIZER; SIGNALING PATHWAY; FOXJ1; EXPRESSION;

D O I：

10.1016/j.devcel.2017.12.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：248 / +

页数：17

共 80 条

[31]

Left-right asymmetry in the level of active Nodal protein produced in the node is translated into left-right asymmetry in the lateral plate of mouse embryos [J].