Abstract
Hippo pathway controls the organ size by modulating cell proliferation and apoptosis. However, the upstream regulation of hippo signaling by actin cytoskeleton is not clear. To elucidate the role of actin as an upstream regulator of Hippo signaling, the levels of F (filamentous)-actin in cells were elevated using jasplakinolide, an actin-stabilizing drug. Induction of F-actin formation in HeLa cells resulted in decreased phosphorylation of YAP, a key effector molecule for Hippo signaling. The activated YAP is localized to the cell nucleus and YAP increase was associated with increased expression of downstream CCN growth factors CCN1/CYR61 and CCN2/CTGF. The effect of the actin-stabilizing drug was blocked when YAP levels were suppressed in YAP “knock-down” cells. In summary, using an actin-stabilizing drug we show that actin cytoskeleton is one of the upstream regulators of Hippo signaling capable of activating YAP and increasing its downstream CCN growth factors.
Highlights
Tissue growth and organ size are regulated by cell proliferation and cell death controlled by several developmental pathways [1]
Jasplakinolide Induces Actin Polymerization Jasplakinolide (Jasp), a naturally occurring cyclic peptide extracted from the marine sponge, Jaspis johnstoni, is a potent inducer of actin polymerization [22]
Genome-wide screening studies in Drosophila cells demonstrated the important role of actin polymerization in Hippo signaling disruption [14,15], most studies in mammalian cells were based on indirect measurement of F-actin levels
Summary
Tissue growth and organ size are regulated by cell proliferation and cell death controlled by several developmental pathways [1]. Liverspecific deletion of Mst and 2 [8,9,10] or Sav increased liver size [9,11] whereas cardiac-specific deletion of Sav led to enlarged heart [12].The key effector of Hippo pathway is YAP, a transcriptional coactivator whose phosphorylation by LATS kinases effects nuclear localization and increased activity [13]. Recent studies in Drosophila have shown the regulation of Hippo signaling by the actin cytoskeleton. Changes in actin cytoskeleton due to mechanical cues were shown to regulate YAP activity [16,17,18]. LPA (lysophosphatidic acid) and S1P (sphingosine-1-phosphate), ligands for Gprotein-coupled receptors, have been shown to regulate Hippo signaling mediated by changes in F-actin levels [19,20]. Changes in actin polymerization were not shown in the mammalian cells studied and F-actin formation was mostly deduced from phalloidin staining analyses
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