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  • Despite efforts over the past decade to

    2021-11-30

    Despite efforts over the past decade to shed light on the endosomal maturation process and its underlying Rab conversion, the context in which all the involved protein components interact needs to be further elucidated. After defining single components and modules of the machinery important for endocytosis (ESCRT-driven formation of intraluminal vesicles, retromer-dependent recycling, and the basal regulation of the master switches, namely Rab5 and Rab7) the crosstalk of all these modules remains to be explored (see Outstanding Questions). To dissect this process will require a combination of novel time-resolved in vivo assays combined with in vitro analysis of the Rab conversion from Rab5 to Rab7. Given that endosomal and lysosomal biogenesis is tightly linked to metabolism, signaling processes, receptor downregulation, and, thus, cancer progression, a clear understanding of the underlying machinery that controls their biogenesis is critical to evaluate the success and consequences of any medical intervention.
    Acknowledgments
    Introduction RAL GTPases (RALs) are RAS effectors critical for tumor initiation (Lim et al., 2005) and anchorage independent growth of colorectal cancer (CRC) cell lines (Martin et al., 2011). Consequently, RALs are potential therapeutic targets in this setting (Neel et al., 2011, Yan et al., 2014). The mammalian genome encodes for two RALs, RALA and RALB, with non-redundant functions spanning development (Peschard et al., 2012), exocyst formation (Bodemann and White, 2008, Chen et al., 2007, Chien et al., 2006), and endocytosis. Specifically, the RAL Wang Resin RALBP1 drives clathrin-mediated endocytosis (Jullien-Flores et al., 2000), while RALA promotes caveolar endocytosis (Jiang et al., 2016). RAL activity is potentiated by RAL guanine nucleotide exchange factors (RALGEFs) and negatively regulated by RAL GTPase-activating proteins (RALGAPs) (Neel et al., 2011). Multiple RALGEF molecules, such as RALGDS, contain RAS-binding domains and are activated by association with oncogenic RAS (Koyama and Kikuchi, 2001). Indeed, RALGDS has a reported role in tumor initiation and growth (González-García et al., 2005, Rodriguez-Viciana and McCormick, 2005). However, the precise role of RALs or associated effectors in intestinal biology remains unknown. Wnt signaling is critical in intestinal health and disease. Impaired signaling leads to crypt death (Ireland et al., 2004, Kuhnert et al., 2004), while pathway hyperactivation drives cancer (Clevers, 2006). Balanced pathway activity is essential to maintain tissue homeostasis while preventing tumorigenesis. High Wnt signaling is found at the crypt base (Gregorieff et al., 2005), where intestinal stem cells (ISCs) and Paneth cells exhibit nuclear β-catenin and transcriptional signatures associated with Wnt pathway activation. A subset of ISCs also express Lgr5, which potentiates Wnt signaling by binding to the agonist R-Spondin (R-Spo) (Barker et al., 2007, Sato et al., 2009). Lgr5+ ISCs are redundant for homeostasis but required for regeneration following damage (Metcalfe et al., 2014). Wnt ligands are expressed in numerous cell lineages within the intestinal epithelium and its microenvironment, including Paneth and mesenchymal cells (Shoshkes-Carmel et al., 2018, Valenta et al., 2016, Zou et al., 2018). Removal of Paneth cell-derived Wnt affects outgrowth of crypts as organoids, whereas the mesenchymal source is enough to sustain crypts in vivo (Degirmenci et al., 2018, Kim et al., 2012, Sato et al., 2011, Shoshkes-Carmel et al., 2018). The redundant Wnt stem cell niche is conserved in the Drosophila melanogaster intestine. Drosophila Wnt/Wg produced by uncommitted progenitor cells called enteroblasts (EBs) is specifically required for ISC proliferation upon stress and regeneration, while the mesenchyme-derived ligand is sufficient to maintain tissue homeostasis (Cordero et al., 2012b, Lin et al., 2008). The Wnt signalosome is composed of a cluster of Frizzled receptors, Lrp5/6 co-receptors, and Dishevelled (Dvl) at the plasma membrane (Bilic et al., 2007, Chung et al., 2012, Schwarz-Romond et al., 2007). An important step in the assembly of the Wnt signalosome involves polymerization of Dvl and interaction with Frizzled receptors during ligand-induced endocytosis of the receptor complex (Gammons et al., 2016). Once assembled, the Wnt signalosome immobilizes the β-catenin destruction complex and stabilizes β-catenin, activating transcription of Wnt target genes (Kishida et al., 1999, MacDonald et al., 2009). Altogether, evidence suggests that the regulation of Wnt activity through ligand availability and cell-surface receptor internalization is critical in control of ISC proliferation and differentiation states.