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DOI | 10.1038/s41586-018-0222-z |
RAP2 mediates mechanoresponses of the Hippo pathway | |
Meng, Zhipeng1,2; Qiu, Yunjiang3,4; Lin, Kimberly C.1,2; Kumar, Aditya5; Placone, Jesse K.5; Fang, Cao1,2; Wang, Kuei-Chun5,6; Lu, Shicong1,2; Pan, Margaret1,2; Hong, Audrey W.1,2; Moroishi, Toshiro1,2,7,8; Luo, Min1,2,9; Plouffe, Steven W.1,2; Diao, Yarui3; Ye, Zhen3; Park, Hyun Woo1,2,10; Wang, Xiaoqiong11; Yu, Fa-Xing12,13; Chien, Shu5,6; Wang, Cun-Yu14; Ren, Bing3,15; Engler, Adam J.5; Guan, Kun-Liang1,2 | |
2018-08-30 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2018 |
卷号 | 560期号:7720页码:655-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Japan; Peoples R China; South Korea |
英文摘要 | Mammalian cells are surrounded by neighbouring cells and extracellular matrix (ECM), which provide cells with structural support and mechanical cues that influence diverse biological processes(1). The Hippo pathway effectors YAP (also known as YAP1) and TAZ (also known as WWTR1) are regulated by mechanical cues and mediate cellular responses to ECM stiffness(2,3). Here we identified the Ras-related GTPase RAP2 as a key intracellular signal transducer that relays ECM rigidity signals to control mechanosensitive cellular activities through YAP and TAZ. RAP2 is activated by low ECM stiffness, and deletion of RAP2 blocks the regulation of YAP and TAZ by stiffness signals and promotes aberrant cell growth. Mechanistically, matrix stiffness acts through phospholipase C gamma 1 (PLC gamma 1)to influence levels of phosphatidylinositol 4,5-bisphosphate and phosphatidic acid, which activates RAP2 through PDZGEF1 and PDZGEF2 (also known as RAPGEF2 and RAPGEF6). At low stiffness, active RAP2 binds to and stimulates MAP4K4, MAP4K6, MAP4K7 and ARHGAP29, resulting in activation of LATS1 and LATS2 and inhibition of YAP and TAZ. RAP2, YAP and TAZ have pivotal roles in mechanoregulated transcription, as deletion of YAP and TAZ abolishes the ECM stiffness-responsive transcriptome. Our findings show that RAP2 is a molecular switch in mechanotransduction, thereby defining a mechanosignalling pathway from ECM stiffness to the nucleus. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000443218600052 |
WOS关键词 | FOCAL ADHESION KINASE ; MECHANICAL STRAIN ; PUTATIVE EFFECTOR ; MATRIX STIFFNESS ; YAP ; MECHANOTRANSDUCTION ; ACTIVATE ; YAP/TAZ |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/202919 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA; 2.Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA; 3.Ludwig Inst Canc Res, La Jolla, CA USA; 4.Univ Calif San Diego, Bioinformat & Syst Biol Grad Program, La Jolla, CA 92093 USA; 5.Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA; 6.Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA; 7.Kumamoto Univ, Dept Mol Enzymol, Fac Life Sci, Kumamoto, Japan; 8.Kumamoto Univ, Ctr Metab Regulat Hlth Aging, Fac Life Sci, Kumamoto, Japan; 9.Sichuan Univ, West China Hosp Stomatol, Natl Clin Res Ctr Oral Dis, State Key Lab Oral Dis, Chengdu, Sichuan, Peoples R China; 10.Yonsei Univ, Dept Biochem, Coll Life Sci & Biotechnol, Seoul, South Korea; 11.Cleveland Clin, Robert J Tomisch Pathol & Lab Med Inst, Cleveland, OH 44106 USA; 12.Fudan Univ, Childrens Hosp, Shanghai, Peoples R China; 13.Fudan Univ, Inst Biomed Sci, Shanghai, Peoples R China; 14.Univ Calif Los Angeles, Sch Dent, Div Oral Biol & Med, Los Angeles, CA 90024 USA; 15.Univ Calif San Diego, Sch Med, Inst Genom Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA |
推荐引用方式 GB/T 7714 | Meng, Zhipeng,Qiu, Yunjiang,Lin, Kimberly C.,et al. RAP2 mediates mechanoresponses of the Hippo pathway[J]. NATURE,2018,560(7720):655-+. |
APA | Meng, Zhipeng.,Qiu, Yunjiang.,Lin, Kimberly C..,Kumar, Aditya.,Placone, Jesse K..,...&Guan, Kun-Liang.(2018).RAP2 mediates mechanoresponses of the Hippo pathway.NATURE,560(7720),655-+. |
MLA | Meng, Zhipeng,et al."RAP2 mediates mechanoresponses of the Hippo pathway".NATURE 560.7720(2018):655-+. |
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