RAP2 mediates mechanoresponses of the Hippo pathway

Zhipeng Meng, Yunjiang Qiu, Kimberly C. Lin, Aditya Kumar, Jesse K. Placone, Cao Fang, Kuei-Chun Wang, Shicong Lu, Margaret Pan, Audrey W. Hong, Toshiro Moroishi, Min Luo, Steven W. Plouffe, Yarui Diao, Zhen Ye, Hyun Woo Park, Xiaoqiong Wang, Fa-Xing Yu, Shu Chien, Cun-Yu Wang, Bing Ren, Adam J. Engler and Kun-Liang Guan ()
Additional contact information
Zhipeng Meng: University of California San Diego
Yunjiang Qiu: Ludwig Institute for Cancer Research
Kimberly C. Lin: University of California San Diego
Aditya Kumar: University of California San Diego
Jesse K. Placone: University of California San Diego
Cao Fang: University of California San Diego
Kuei-Chun Wang: University of California San Diego
Shicong Lu: University of California San Diego
Margaret Pan: University of California San Diego
Audrey W. Hong: University of California San Diego
Toshiro Moroishi: University of California San Diego
Min Luo: University of California San Diego
Steven W. Plouffe: University of California San Diego
Yarui Diao: Ludwig Institute for Cancer Research
Zhen Ye: Ludwig Institute for Cancer Research
Hyun Woo Park: University of California San Diego
Xiaoqiong Wang: Cleveland Clinic
Fa-Xing Yu: Fudan University
Shu Chien: University of California San Diego
Cun-Yu Wang: University of California Los Angeles
Bing Ren: Ludwig Institute for Cancer Research
Adam J. Engler: University of California San Diego
Kun-Liang Guan: University of California San Diego

Nature, 2018, vol. 560, issue 7720, 655-660

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0444-0

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