Scrib module proteins: Control of epithelial architecture and planar spindle orientation
Introduction
The Scrib module, consisting of Scribble (Scrib), Discs large (Dlg), and Lethal giant larvae (Lgl), was originally identified as a neoplastic tumor suppressor in the fruit fly Drosophila melanogaster whose loss-of-function mutants exhibit loss of polarity and overgrowth of proliferating tissue, hallmarks of neoplastic tumors (Bilder et al., 2000; Gateff, 1978; Woods and Bryant, 1991). Subsequent studies using mammalian systems have supported the role of these proteins as tumor suppressors as well as controllers of cell polarity (Stephens et al., 2018; Zhan et al., 2008). Especially in the epithelial context, the Scrib module members are localized at the basolateral plasma membrane and function as determinants of basolateral identity (Fig. 1A). During epithelial development and homeostasis, a polarized architecture mediated by apical-basal polarity is established and maintained by mutual antagonism between the apical Par complex and the basolateral Scrib module proteins. Thus, the Scrib module components are recognized as conserved proteins that control epithelial apical-basal polarity, and, upon dysregulation, result in defects in epithelial organization and tumorigenesis.
Scrib module proteins contain multiple protein binding domains that allow interactions with various proteins to modulate cellular behaviors and function as a signaling platform (Bonello and Peifer, 2019; Stephens et al., 2018). Scrib is a LAP protein family scaffold protein that possesses N-terminal 16 leucine-rich repeats (LRR) domains, two LAP-specific domains (LAPSD), and four postsynaptic density-95/Disc-large/ZO1 (PDZ) domains (Fig. 1B). Dlg, a member of the membrane-associated guanylate kinase homology (MAGUK), is another scaffold protein that has an N-terminal L27 domain, three PDZ domains, an Src homology 3 (SH3) domain, a Hook domain, and a C-terminal guanylate kinase-like (GUK) domain (Fig. 1B). Whereas Scrib and Dlg are multiple PDZ domain-containing proteins, Lgl is a cytoskeletal protein that can interact with non-muscle myosin II, consisting of 14 WD40 repeats that enable the structure of two β propellers and a conserved phosphorylatable polybasic region that mediates binding to plasma membrane (Almagor et al., 2019; Dong et al., 2015) (Fig. 1B). Given the presence of known interacting proteins and predicted protein-protein interactions, the Scrib module can influence a multitude of cellular processes related to cell polarity.
During the last two decades, the Scrib module has received strong attention from the field of cell polarity and tissue growth because alterations in the proteins’ gene expression or protein localization are associated with human cancers (Halaoui and McCaffrey, 2015; Stephens et al., 2018). Although much has been learned about genetic links between polarity genes and gross phenotypes, it is still unclear how Scrib module proteins molecularly control epithelial architecture in vivo. In this article, we focus on the impacts of the Scrib module on epithelial organization in both interphase and mitotic phase by reviewing recent updates in the field’s understanding of the components’ dynamics and roles.
Section snippets
Molecular nature of the Scrib module in vivo
Studies using model animals as well as mammalian cultured cells have indicated that Scrib module proteins function within the same machinery. In fact, mutant phenotypes of Scrib module components are comparable in different Drosophila epithelia, and their protein localization are interdependent (Bilder et al., 2000; Bilder and Perrimon, 2000). Moreover, mammalian Scrib and Dlg can interact with Lgl in vitro (Kallay et al., 2006; Zhu et al., 2014). However, despite genetic and biochemical
The role of the Scrib module in polarity establishment
Apical-basal polarization of epithelial cells is achieved by positioning the polarity complexes at specific locations of the plasma membrane, which leads to the formation of distinct apical and basolateral domains that are separated by apical junctional complexes. This establishment of cortical domains has been thought to be a result of complex interactions and networks of polarity proteins including the apical Par and Crumbs complexes, as well as the basolateral Scrib module. Although genetic
The role of the Scrib module in junction formation
Proper assembly of cell-cell junctions is paramount in the maintenance of epithelial integrity. The locations of junctional complexes along the polarized plasma membrane are interconnected with epithelial polarity programs, and indeed basolateral Scrib module proteins can interact with proteins in the junctional network. For example, in mammalian cell culture, Scrib and Dlg are involved in the control of adherens junctions through E-cadherin, while Scrib regulates the assembly of tight
The role of the Scrib module in planar spindle orientation
During development and homeostasis, symmetric cell division, or planar cell division, is essential for the growth and maintenance of epithelial tissue. In dividing epithelial cells, apical-basal polarity and intercellular adhesion are dynamically remodeled to allow cell-shape change upon mitotic entry and re-polarization of daughter cells after cytokinesis (Osswald and Morais-de-Sa, 2019). In between the processes that accompany cortical reorganization, mitotic spindles are oriented parallel to
Conclusions and future perspective
In summary, Scrib module proteins affect distinct steps in epithelial organization including polarity establishment and maintenance, junction assembly, and planar spindle alignment during cell division. Compared to the mammalian system in which multiple orthologs of Dlg and Lgl as well as functionally-overlapping LAP family proteins exist, utilization of the simple Drosophila system can provide an in depth understanding of how Scrib module proteins regulate the cellular processes in epithelia
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
This work was supported by AMED under Grant Number JP20gm611002, and by the JSPS KAKENHI Grant Numbers JP17H05004, 17H06332, and 19K22550.
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