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  • br Concluding Remarks One of the

    2022-09-08


    Concluding Remarks One of the remarkable features of Hippo signaling is its sensitivity to the cytoskeleton and mechanical forces. Progress has been made recently in identifying molecular mechanisms by which the cytoskeleton can influence Hippo signaling, but among the many outstanding questions that remain to be answered (see Outstanding Questions) a key challenge for the future will be to define the respective contributions of these different mechanisms in vivo and understand how these contributions vary in different contexts to control cell fate decisions and regulate organ growth.
    Introduction Precise regulation of stem cell activity is crucial for tissue turnover and necessary to prevent hyperplasia. The digestive epithelium is an excellent system to study the activity of stem Octreotide acetate and how their proliferation and differentiation are regulated, especially in the context of damage. In the intestine, intestinal stem cells (ISCs) give rise to new Octreotide acetate ISCs and daughter cells known as enteroblasts (EBs), which are primed for differentiation toward either absorptive ECs (∼90%) or secretory enteroendocrine cells (EEs; ∼10%), depending on the activity of Notch signaling (He et al., 2018, Micchelli and Perrimon, 2006, Ohlstein and Spradling, 2006). Strikingly, ISCs/EBs dramatically accelerate proliferation and differentiation in order to replenish lost cells when tissue damage causes massive EC death (Amcheslavsky et al., 2009). A number of studies have demonstrated the conserved roles of core pathways, such as epidermal growth factor receptor (EGFR)-Ras-mitogen-activated protein kinase (MAPK) signaling (Jiang et al., 2011, Powell et al., 2012), Janus kinase-signal transducer and activator of transcription (JAK-Stat) signaling (Grivennikov et al., 2009, Jiang et al., 2009), and Hippo signaling (Cai et al., 2010, Karpowicz et al., 2010, Ren et al., 2010, Shaw et al., 2010), in regulating ISCs. Although the role of these pathways in proliferation and differentiation of ISCs/EBs has been characterized, less is known about the signals modulating their activities. The Hippo signaling pathway is particularly essential for tissue homeostasis and cancer prevention. The core components of the Hippo pathway are conserved from Drosophila to mammals. In Drosophila, the kinase Hippo (Hpo) phosphorylates and activates the kinase Warts (Wts), with the aid of the scaffold proteins Mob as tumor suppressor (Mats) and Salvador (Sav). Activated Wts phosphorylates Yki, resulting in the cytoplasmic retention and inhibition of Yki. The mammalian Hippo network is similar but more complex, with two Hpo orthologs (MST1/2), two Wts orthologs (LATS1 or LATS2), two Mats orthologs (MOB1A or MOB1B), one Sav ortholog (SAV1), and two Yki orthologs (YAP or TAZ). When Hippo signaling is inhibited, Yki or YAP or TAZ is activated and induces transcriptional programs promoting tissue growth and inhibiting cell death (Hong and Guan, 2012, Huang et al., 2005, Zhao et al., 2008). In the digestive epithelium of both Drosophila (Karpowicz et al., 2010, Ren et al., 2010, Shaw et al., 2010) and mice (Cai et al., 2010, Gregorieff et al., 2015), the activity of Yki or YAP is induced to facilitate accelerated ISC proliferation following tissue damage. However, it is unclear how Yki or YAP activity is downregulated when tissue repair is complete. Many components of the Hippo pathway are localized near cell junctions, and their activities are regulated by subcellular localization (Sun and Irvine, 2016). Most notably, recruitment of Hpo to the subapical region close to adherens junctions (AJs) by Expanded (Ex), Merlin (Mer), and Kibra facilitates Hpo dimerization and activation (Deng et al., 2013). Moreover, the cell polarity determinant protein atypical protein kinase C (aPKC) antagonizes Hippo signaling by causing Hpo delocalization from the membrane and subsequent Hpo inactivation in both Drosophila and mammals (Archibald et al., 2015, Grzeschik et al., 2010). Interestingly, junction proteins often exhibit differential expression between stem cells and their differentiated progenies. For example, AJs are enriched among Drosophila ISCs/EBs (Choi et al., 2011, Ohlstein and Spradling, 2006), Drosophila germline stem cells (Song et al., 2002), mouse hematopoietic stem cells (Zhang et al., 2003), and mammalian epidermal basal or stem cells (Green et al., 2010). In contrast, septate junctions (SJs) are mainly distributed between ECs in the Drosophila midgut (Resnik-Docampo et al., 2017), and tight junctions (TJs; analogous to Drosophila SJs) are localized between differentiated epithelial cell types in the mouse epidermis (Green et al., 2010) and trachea (Gao et al., 2015). Therefore, the AJ-SJ transition and de novo production of SJs might provide a pivotal link between Hippo signaling and stem cell differentiation.