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      Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs).

      Genes & development
      Actin Cytoskeleton, Cell Line, Tumor, Cell Nucleus, enzymology, Enzyme Activation, physiology, Gene Expression Regulation, Gene Knockdown Techniques, HEK293 Cells, Humans, Intracellular Signaling Peptides and Proteins, genetics, metabolism, Nuclear Proteins, Oligopeptides, Phosphorylation, Protein Transport, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Receptors, Proteinase-Activated, agonists, Transcription Factors

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          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.

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