G protein-coupled receptors engage the mammalian Hippo pathway through F-actin

F-Actin, assembled in response to Galpha12/13 induced RhoA-GTP, promotes dephosphorylation and activation of the YAP oncogene

Authors

  • Laura Regué,

    1. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
    2. Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
    3. Department of Medicine, Harvard Medical School, Boston, MA, USA
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  • Fan Mou,

    1. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
    2. Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
    3. Department of Medicine, Harvard Medical School, Boston, MA, USA
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  • Joseph Avruch

    Corresponding author
    1. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
    2. Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
    3. Department of Medicine, Harvard Medical School, Boston, MA, USA
    • Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
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Abstract

The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell-cell contact or determine epithelial cell polarity which, in a tissue-specific manner, use intracellular complexes containing FERM domain and actin-binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha12/13 such as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F-)actin. Morever, cell architectures that promote F-actin assembly per se also activate YAP by kinase-dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells.

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