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WW 结构域形成一种折叠型核定位信号，以指导 YAP1 的核输入。

WW domains form a folded type of nuclear localization signal to guide YAP1 nuclear import.

机构信息

Department of Biochemistry and Molecular Biology, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, PR China.

出版信息

J Cell Biol. 2024 Jun 3;223(6). doi: 10.1083/jcb.202308013. Epub 2024 Mar 15.

DOI:10.1083/jcb.202308013
PMID:38488622
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10942854/
Abstract

The nuclear translocation of YAP1 is significantly implicated in the proliferation, stemness, and metastasis of cancer cells. Although the molecular basis underlying YAP1 subcellular distribution has been extensively explored, it remains to be elucidated how the nuclear localization signal guides YAP1 to pass through the nuclear pore complex. Here, we define a globular type of nuclear localization signal composed of folded WW domains, named as WW-NLS. It directs YAP1 nuclear import through the heterodimeric nuclear transport receptors KPNA-KPNB1, bypassing the canonical nuclear localization signal that has been well documented in KPNA/KPNB1-mediated nuclear import. Strikingly, competitive interference with the function of the WW-NLS significantly attenuates YAP1 nuclear translocation and damages stemness gene activation and sphere formation in malignant breast cancer cells. Our findings elucidate a novel globular type of nuclear localization signal to facilitate nuclear entry of WW-containing proteins including YAP1.

摘要

YAP1 的核转位在癌细胞的增殖、干性和转移中起着重要作用。尽管已经广泛研究了 YAP1 亚细胞分布的分子基础，但核定位信号如何引导 YAP1 通过核孔复合体仍有待阐明。在这里，我们定义了一种由折叠 WW 结构域组成的球形核定位信号，称为 WW-NLS。它通过异二聚体核转运受体 KPNA-KPNB1 指导 YAP1 的核内输入，绕过了 KPNA/KPNB1 介导的核内输入中已经很好地记录的经典核定位信号。引人注目的是，与 WW-NLS 的功能竞争干扰会显著减弱 YAP1 的核转位，并损害恶性乳腺癌细胞中干性基因的激活和球体形成。我们的研究结果阐明了一种新的球形核定位信号，以促进包括 YAP1 在内的含有 WW 结构域的蛋白质进入细胞核。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/8e8e389b050f/JCB_202308013_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/61a66c164276/JCB_202308013_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/bde74ec955b6/JCB_202308013_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/31cbd86c1148/JCB_202308013_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/f1d3d7bfaf42/JCB_202308013_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/ea37b6417998/JCB_202308013_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/87f40591277b/JCB_202308013_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/35dc4278c457/JCB_202308013_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/7be74a8afb12/JCB_202308013_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/89edb5caa9bb/JCB_202308013_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/61f6fb467858/JCB_202308013_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/a89bd0992e6c/JCB_202308013_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/4096e08a0316/JCB_202308013_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/8e8e389b050f/JCB_202308013_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/61a66c164276/JCB_202308013_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/bde74ec955b6/JCB_202308013_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/31cbd86c1148/JCB_202308013_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/f1d3d7bfaf42/JCB_202308013_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/ea37b6417998/JCB_202308013_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/87f40591277b/JCB_202308013_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/35dc4278c457/JCB_202308013_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/7be74a8afb12/JCB_202308013_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/89edb5caa9bb/JCB_202308013_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/61f6fb467858/JCB_202308013_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/a89bd0992e6c/JCB_202308013_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/4096e08a0316/JCB_202308013_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc6f/10942854/8e8e389b050f/JCB_202308013_Fig8.jpg

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