Abstract
The Hippo signaling pathway plays a crucial role in tissue growth and tumorigenesis. Core components of the Hippo pathway include the MST1/2 and Lats1/2 kinases. Acting downstream from the Hippo pathway are the YAP/TAZ transcription coactivators, which are inhibited through phosphorylation by Lats. However, upstream signals that regulate the Hippo pathway have not been well delineated. Here we report that stimulation of protease-activated receptors (PARs) activates YAP/TAZ by decreasing phosphorylation and increasing nuclear localization. PAR1 acts through G(12/13) and Rho GTPase to inhibit the Lats1/2 kinase. Our observations establish thrombin as a physiological signal for the Hippo pathway and implicate Hippo-YAP as a key downstream signaling branch of PAR activation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actin Cytoskeleton
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Acyltransferases
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Nucleus / enzymology
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Enzyme Activation / physiology
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Gene Expression Regulation
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Gene Knockdown Techniques
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oligopeptides / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport
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RNA, Small Interfering / metabolism
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Receptors, Proteinase-Activated / agonists
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Receptors, Proteinase-Activated / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Cell Cycle Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Oligopeptides
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RNA, Small Interfering
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Receptors, Proteinase-Activated
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Ser-Phe-Phe-Leu-Arg-Asn
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Transcription Factors
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YY1AP1 protein, human
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Acyltransferases
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TAFAZZIN protein, human
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Protein Serine-Threonine Kinases