Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling

Fa Xing Yu, Bin Zhao, Nattapon Panupinthu, Jenna L. Jewell, Ian Lian, Lloyd H. Wang, Jiagang Zhao, Haixin Yuan, Karen Tumaneng, Hairi Li, Xiang Dong Fu, Gordon B. Mills, Kun Liang Guan

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    Abstract

    The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR.

    Original languageEnglish (US)
    Pages (from-to)780-791
    Number of pages12
    JournalCell
    Volume150
    Issue number4
    DOIs
    StatePublished - Aug 17 2012

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    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Yu, F. X., Zhao, B., Panupinthu, N., Jewell, J. L., Lian, I., Wang, L. H., Zhao, J., Yuan, H., Tumaneng, K., Li, H., Fu, X. D., Mills, G. B., & Guan, K. L. (2012). Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell, 150(4), 780-791. https://doi.org/10.1016/j.cell.2012.06.037