RAP2 mediates mechanoresponses of the Hippo pathway
| Autor: | Audrey W. Hong, Cun-Yu Wang, Zhipeng Meng, Min Luo, Bing Ren, Shu Chien, Kuei Chun Wang, Shicong Lu, Kun-Liang Guan, Aditya Kumar, Kimberly C. Lin, Zhen Ye, Xiaoqiong Wang, Jesse K. Placone, Yunjiang Qiu, Hyun Woo Park, Adam J. Engler, Yarui Diao, Cao Fang, Fa-Xing Yu, Margaret Pan, Toshiro Moroishi, Steven W. Plouffe |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Nude WWTR1 Mice SCID Cell Transformation Germinal Center Kinases Extracellular matrix Mice Mice Inbred NOD Guanine Nucleotide Exchange Factors Mechanotransduction YAP1 Multidisciplinary Chemistry GTPase-Activating Proteins Intracellular Signaling Peptides and Proteins Adaptor Proteins Protein-Serine-Threonine Kinases Cell biology Extracellular Matrix Cell Transformation Neoplastic Female Signal transduction Signal Transduction General Science & Technology 1.1 Normal biological development and functioning Mice Nude Nerve Tissue Proteins Protein Serine-Threonine Kinases SCID 03 medical and health sciences Underpinning research Animals Humans Hippo Signaling Pathway Transcription factor Adaptor Proteins Signal Transducing Neoplastic Hippo signaling pathway Phospholipase C gamma HEK 293 cells Signal Transducing YAP-Signaling Proteins Phosphoproteins 030104 developmental biology HEK293 Cells rap GTP-Binding Proteins Transcriptional Coactivator with PDZ-Binding Motif Proteins Trans-Activators Inbred NOD Transcriptome Transcription Factors |
| Zdroj: | Nature, vol 560, iss 7720 |
| ISSN: | 1476-4687 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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