Zyxin Links Fat Signaling to the Hippo Pathway

Howard Hughes Medical Institute, Waksman Institute, and Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
PLoS Biology (Impact Factor: 9.34). 06/2011; 9(6):e1000624. DOI: 10.1371/journal.pbio.1000624
Source: PubMed


The Hippo signaling pathway has a conserved role in growth control and is of fundamental importance during both normal development and oncogenesis. Despite rapid progress in recent years, key steps in the pathway remain poorly understood, in part due to the incomplete identification of components. Through a genetic screen, we identified the Drosophila Zyxin family gene, Zyx102 (Zyx), as a component of the Hippo pathway. Zyx positively regulates the Hippo pathway transcriptional co-activator Yorkie, as its loss reduces Yorkie activity and organ growth. Through epistasis tests, we position the requirement for Zyx within the Fat branch of Hippo signaling, downstream of Fat and Dco, and upstream of the Yorkie kinase Warts, and we find that Zyx is required for the influence of Fat on Warts protein levels. Zyx localizes to the sub-apical membrane, with distinctive peaks of accumulation at intercellular vertices. This partially overlaps the membrane localization of the myosin Dachs, which has similar effects on Fat-Hippo signaling. Co-immunoprecipitation experiments show that Zyx can bind to Dachs and that Dachs stimulates binding of Zyx to Warts. We also extend characterization of the Ajuba LIM protein Jub and determine that although Jub and Zyx share C-terminal LIM domains, they regulate Hippo signaling in distinct ways. Our results identify a role for Zyx in the Hippo pathway and suggest a mechanism for the role of Dachs: because Fat regulates the localization of Dachs to the membrane, where it can overlap with Zyx, we propose that the regulated localization of Dachs influences downstream signaling by modulating Zyx-Warts binding. Mammalian Zyxin proteins have been implicated in linking effects of mechanical strain to cell behavior. Our identification of Zyx as a regulator of Hippo signaling thus also raises the possibility that mechanical strain could be linked to the regulation of gene expression and growth through Hippo signaling.

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    • "The UAS.Kib (Genevet et al., 2010), UAS.Mer, and UAS.Ex (Udan et al., 2003) transgenes were expressed in border cells using the slbo GAL4 driver (Rørth et al., 1998). UAS.mycWts, UAS.ZyxinV5 (Rauskolb et al., 2011), and UAS.HA-Cpa (Fernández et al., 2011) have been previously described and were expressed with the c306.Gal4 driver (Bloomington). "
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    ABSTRACT: Collective migration of Drosophila border cells depends on a dynamic actin cytoskeleton that is highly polarized such that it concentrates around the outer rim of the migrating cluster of cells. How the actin cytoskeleton becomes polarized in these cells to enable collective movement remains unknown. Here we show that the Hippo signaling pathway links determinants of cell polarity to polarization of the actin cytoskeleton in border cells. Upstream Hippo pathway components localize to contacts between border cells inside the cluster and signal through the Hippo and Warts kinases to polarize actin and promote border cell migration. Phosphorylation of the transcriptional coactivator Yorkie (Yki)/YAP by Warts does not mediate the function of this pathway in promoting border cell migration, but rather provides negative feedback to limit the speed of migration. Instead, Warts phosphorylates and inhibits the actin regulator Ena to activate F-actin Capping protein activity on inner membranes and thereby restricts F-actin polymerization mainly to the outer rim of the migrating cluster.
    The Journal of Cell Biology 06/2013; 201(6). DOI:10.1083/jcb.201210073 · 9.83 Impact Factor
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    • "Fat and Ds are found planar polarized in specific domains of the fj and ds tissue-wide expression gradients and are necessary to polarize the distribution of the Myosin Dachs (Bosveld et al., 2012; Brittle et al., 2012; Ambegaonkar et al., 2012). Whereas Fat excludes the Dachs from the cell cortex to regulate Hippo signaling (Mao et al., 2006; Rauskolb et al., 2011), Ds intracellular domain interacts with the Dachs to polarize Dachs distribution and to define lines of Dachs planar polarization (Bosveld et al., 2012). Once polarized , Dachs locally increases cortical tension along the lines of its polarized localization, leading to oriented cell rearrangements that shape the Drosophila dorsal thorax epithelium (Bosveld et al., 2012). "
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    ABSTRACT: During development, mechanical forces cause changes in size, shape, number, position, and gene expression of cells. They are therefore integral to any morphogenetic processes. Force generation by actin-myosin networks and force transmission through adhesive complexes are two self-organizing phenomena driving tissue morphogenesis. Coordination and integration of forces by long-range force transmission and mechanosensing of cells within tissues produce large-scale tissue shape changes. Extrinsic mechanical forces also control tissue patterning by modulating cell fate specification and differentiation. Thus, the interplay between tissue mechanics and biochemical signaling orchestrates tissue morphogenesis and patterning in development.
    Cell 05/2013; 153(5):948-962. DOI:10.1016/j.cell.2013.05.008 · 32.24 Impact Factor
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    • "We next tested if the ft scrib interaction affects the Ft-Ex interaction. Earlier studies have shown that Ex is mislocalized from the apical membrane in ft mutant cells (Fig. 5a–c) suggesting that ft affects the stability and localization of Ex at the plasma membrane [21], [50], [51], [52], [53]. Loss of scrib in mutant clones does not cause loss of apical-basal polarity (Fig. 5g) and Ex is not mislocalized from the membrane (Fig. 5h). "
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    ABSTRACT: Epithelial cells are the major cell-type for all organs in multicellular organisms. In order to achieve correct organ size, epithelial tissues need mechanisms that limit their proliferation, and protect tissues from damage caused by defective epithelial cells. Recently, the Hippo signaling pathway has emerged as a major mechanism that orchestrates epithelial development. Hippo signaling is required for cells to stop proliferation as in the absence of Hippo signaling tissues continue to proliferate and produce overgrown organs or tumors. Studies in Drosophila have led the way in providing a framework for how Hippo alters the pattern of gene transcription in target cells, leading to changes in cell proliferation, survival, and other behaviors. Scribble (Scrib) belongs to a class of neoplastic tumor suppressor genes that are required to establish apical-basal cell polarity. The disruption of apical-basal polarity leads to uncontrolled cell proliferation of epithelial cells. The interaction of apical basal polarity genes with the Hippo pathway has been an area of intense investigation. Loss of scrib has been known to affect Hippo pathway targets, however, its functions in the Hippo pathway still remain largely unknown. We investigated the interactions of Scrib with the Hippo pathway. We present data suggesting that Drosophila scrib acts downstream of the Fat (Ft) receptor, and requires Hippo signaling for its growth regulatory functions. We show that Ft requires Scrib to interact with Expanded (Ex) and Dachs (D), and for regulating Warts (Wts) levels and stability, thus placing Scrib in the Hippo pathway network.
    PLoS ONE 11/2012; 7(11):e47173. DOI:10.1371/journal.pone.0047173 · 3.23 Impact Factor
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