机构：[1]Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA[2]Ludwig Institute for Cancer Research, La Jolla, CA, USA[3]Bioinformatics andSystems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA[4]Department of Bioengineering, University of California San Diego, La Jolla, CA, USA[5]Institute ofEngineering in Medicine, University of California San Diego, La Jolla, CA, USA[6]Department of Molecular Enzymology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan[7]Centerfor Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan[8]State Key Laboratory of Oral Diseases, National Clinical Research Center for OralDiseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China[9]Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul,South Korea[10]Robert J.Tomisch Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA[11]Children’s Hospital and Institutes of Biomedical Sciences, Fudan University,Shanghai, China[12]Division of Oral Biology and Medicine, School of Dentistry, University of California Los Angeles, Los Angeles, CA, USA[13]Department of Cellular and Molecular Medicine, Instituteof Genomic Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
Mammalian cells are surrounded by neighbouring cells and extracellular matrix (ECM), which provide cells with structural support and mechanical cues that influence diverse biological processes1. 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 stiffness2,3. 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 Cγ1 (PLCγ1) 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.
基金：
K.C.L., A.W.H., and S.W.P. are supported by the
T32 GM007752 training grant, A.K. by T32AR060712, and J.K.P. by
F32HL126406. K.-L.G. is supported by grants from the NIH (CA196878,
CA217642, GM51586, DEO15964) as is A.J.E. (R21CA217735,
R01CA206880). A.J.E. is also supported by NSF grant 1463689, and A.K. is
supported by the NSF graduate research fellowship program and an ARCS/
Roche Foundation Scholar Award in Life Science. H.W.P. is supported by KHIDI
grant HI17C1560
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
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最新[2023]版：
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第一作者：
第一作者机构：[1]Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
通讯作者：
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):655-660.doi:10.1038/s41586-018-0444-0.
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)
MLA：
Meng Zhipeng,et al."RAP2 mediates mechanoresponses of the Hippo pathway.".Nature 560..7720(2018):655-660
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