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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cell Transformation, Neoplastic
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Extracellular Matrix / chemistry
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Extracellular Matrix / genetics
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Extracellular Matrix / metabolism
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Female
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GTPase-Activating Proteins / metabolism
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Germinal Center Kinases
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Guanine Nucleotide Exchange Factors / metabolism
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HEK293 Cells
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Hippo Signaling Pathway
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Nerve Tissue Proteins / metabolism
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Phospholipase C gamma / metabolism
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction*
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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Transcriptome
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YAP-Signaling Proteins
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rap GTP-Binding Proteins / genetics
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rap GTP-Binding Proteins / metabolism*
Substances
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ARHGAP29 protein, human
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Adaptor Proteins, Signal Transducing
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GTPase-Activating Proteins
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Germinal Center Kinases
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Guanine Nucleotide Exchange Factors
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Intracellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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Phosphoproteins
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RAPGEF2 protein, human
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RAPGEF6 protein, human
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human
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MAP4K4 protein, human
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MINK1 protein, human
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Protein Serine-Threonine Kinases
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Phospholipase C gamma
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RAP2A protein, human
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rap GTP-Binding Proteins