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  • Recent studies have also identified


    Recent studies have also identified additional proteins that could act as scaffolds and promote the interaction of core Hippo pathway components. APC, which is best known as a key component of the β-catenin destruction complex, was observed in mammalian topoisomerase i to have an additional function as a scaffold that promotes association of LATS and SAV [38]. In Drosophila, βPix and Git form a scaffold that promotes activation of Hpo [39]. In mammalian cells, βPix was identified as interacting with LATS and YAP/TAZ to stimulate YAP/TAZ phosphorylation [40]. Schip1 was recently identified in Drosophila as a protein that promotes Hpo activation by binding to both Expanded (Ex) and Tao-1 [41], a kinase that activates Hpo 42, 43.
    Cellular Organization of the Hippo Network and Regulation at Cell Junctions The first decade of Hippo pathway research was characterized by tremendous progress in genetic and biochemical characterization of the pathway. More recently, our understanding of the cell biology of Hippo signaling has advanced significantly: where pathway components localize, where key events occur inside the cell, and how changes in protein localization modulate pathway activity. Many Hippo pathway components localize to cell–cell junctions, such that in addition to their role in maintaining tissue integrity and polarity, these junctions effectively provide a platform for regulation of Hippo signaling. The links between cell junctions and Hippo pathway components can help explain how cell contacts and cell polarity modulate Hippo pathway activity. In both Drosophila and mammalian cells, cadherin-mediated cell–cell adhesion occurs at adherens junctions, and these sites of cell attachment are connected to the actin–myosin cytoskeleton through catenins and associated proteins. Apical to the adherens junctions, mammalian epithelial cells have tight junctions, which form a paracellular diffusion barrier. In Drosophila, the paracellular diffusion barrier is formed by septate junctions, which are basal to the adherens junctions. Nonetheless, many proteins that are found at tight junctions in mammals, such as Crumbs, are conserved in Drosophila and as in mammalian cells they localize to cell junctions just apical to adherens junctions [44]; in Drosophila epithelia this region is referred to as the marginal zone, or subapical region. Several of the proteins first identified as upstream activators of Hippo signaling, including Dachsous (Ds), Fat, Ex, and Merlin (Mer), localize near the marginal zone 18, 45, 46, suggesting that this could be a site of pathway activation. The concept that activation of core components occurs at the membrane was further supported by observations that forced membrane localization of overexpressed Hpo could increase Hpo activity [47] and forced membrane localization of overexpressed Mats or Wts, or their mammalian homologs, could increase Wts/LATS activity 19, 48, 49. More recently, progress has been made in visualizing the endogenous localization of components in Drosophila and in characterizing mechanisms that contribute to their localization (Figure 2A). Sav localizes to cell membranes through interaction with the transmembrane immunoglobulin-domain protein echinoid (Ed) [50], which localizes to the membrane overlapping adherens junctions and the marginal zone. Ed participates in homophilic binding to Ed in neighboring cells [51], which serves as a mechanism linking cell–cell contacts to Hippo pathway regulation. Sav, in turn, can recruit Hpo to apical cell–cell junctions, although Hpo is normally found predominantly in the cytoplasm 18, 19, 52. Crumbs localizes to the marginal zone and this depends on homophilic binding between Crumbs proteins in neighboring cells, which serves as another mechanism linking cell contact and polarity to Hippo signaling [53]. Cell contact-dependent regulation of Hippo signaling through Ed and Crb has recently been implicated in maintaining quiescence of neural stem cells in the larval brain [54]. Crumbs, in turn, is required for membrane localization of Ex 53, 55, 56. By contrast, Wts localizes to adherens junctions, where it is recruited by the Drosophila Ajuba LIM family protein Jub [20]. Jub is an inhibitor of Wts 21, 22, implying that in this context Wts localization to cell–cell junctions is associated with Wts inhibition rather than activation. Consistent with this role, disruption of adherens junctions in Drosophila epithelia can be associated with increased Hippo pathway activity [57]. Wts can also be downregulated by a signaling pathway initiated by the large cadherin family proteins Ds and Fat, which localize to the marginal zone and regulate Hippo signaling through the myosin family protein Dachs [1]. Earlier studies identified an influence of Dachs on Wts protein levels [17] and a more recent study identified an ability of Dachs to inhibit Wts association with Mats [24].