Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-beta 2 nuclear import system

doi:10.1371/journal.pbio.2002063

	Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-beta 2 nuclear import system
	Han, Yuhong 1; Xiong, Yue 2; Shi, Xuanming 3; Wu, Jiang 3; Zhao, Yun2 ; Jiang, Jin 1,4
	2017-08
发表期刊	PLOS BIOLOGY (IF:7.8[JCR-2023],8.2[5-Year])
ISSN	1545-7885
卷号	15 期号:8
发表状态	已发表
DOI	10.1371/journal.pbio.2002063
摘要	Hedgehog (Hh) signaling in vertebrates depends on primary cilia. Upon stimulation, Hh pathway components, including Gli transcription factors, accumulate at primary cilia to transduce the Hh signal, but the mechanisms underlying their ciliary targeting remains largely unknown. Here, we show that the PY-type nuclear localization signal (PY-NLS)/karyopherin beta 2 (Kap beta 2) nuclear import system regulates Gli ciliary localization and Hh pathway activation. Mutating the PY-NLS in Gli or knockdown of Kap beta 2 diminished Gli ciliary localization. Kap beta 2 is required for the formation of Gli activator (Gli A) in wild-type but not in Sufu mutant cells. Knockdown of Kap beta 2 affected Hh signaling in zebrafish embryos, as well as in vitro cultured cerebellum granule neuron progenitors (CGNPs) and SmoM2-driven medulloblastoma cells. Furthermore, Kap beta 2 depletion impaired the growth of cultured medulloblastoma cells, which was rescued by Gli overexpression. Interestingly, Kap beta 2 is a transcriptional target of the Hh pathway, thus forming a positive feedback loop for Gli activation. Our study unravels the molecular mechanism and cellular machinery regulating Gli ciliary localization and identifies Kap beta 2 as a critical regulator of the Hh pathway and a potential drug target for Hh-driven cancers.
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收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[31630047] ; National Natural Science Foundation of China[31371492]
WOS研究方向	Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics
WOS类目	Biochemistry & Molecular Biology ; Biology
WOS记录号	WOS:000408756200008
出版者	PUBLIC LIBRARY SCIENCE
WOS关键词	BASAL-CELL CARCINOMA ; PRIMARY CILIUM ; SONIC-HEDGEHOG ; DIFFUSION BARRIER ; PROTEIN FUNCTION ; PATHWAY ; MOUSE ; MEDULLOBLASTOMA ; PROLIFERATION ; CEREBELLUM
原始文献类型	Article
通讯作者	Zhao, Yun ; Jiang, Jin
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/4524
专题	生命科学与技术学院_特聘教授组_赵允组
通讯作者	Zhao, Yun; Jiang, Jin
作者单位	1.Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA 2.ShanghaiTech Univ, State Key Lab Cell Biol,Shanghai Inst Life Sci,CA, CAS,Ctr Excellence Mol Cell Sci,Inst Biochem & Ce, Innovat Ctr Cell Signaling Network,Sch Life Sci &, Shanghai, Peoples R China 3.Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX USA 4.Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
通讯作者单位	上海科技大学
推荐引用方式 GB/T 7714	Han, Yuhong,Xiong, Yue,Shi, Xuanming,et al. Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-beta 2 nuclear import system[J]. PLOS BIOLOGY,2017,15(8).
APA	Han, Yuhong,Xiong, Yue,Shi, Xuanming,Wu, Jiang,Zhao, Yun,&Jiang, Jin.(2017).Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-beta 2 nuclear import system.PLOS BIOLOGY,15(8).
MLA	Han, Yuhong,et al."Regulation of Gli ciliary localization and Hedgehog signaling by the PY-NLS/karyopherin-beta 2 nuclear import system".PLOS BIOLOGY 15.8(2017).