Scrib module proteins: Control of epithelial architecture and planar spindle orientation

Abstract

The Scrib module proteins, Scrib, Dlg, and Lgl, are conserved regulators of cell polarity in diverse biological contexts. Originally discovered as neoplastic tumor suppressors in the fruit fly Drosophila melanogaster, disruption of Scrib module components leads to tumorigenesis in mammalian epithelia and is associated with human cancers. With multiple protein interacting domains, Scrib module proteins function as determinants of basolateral identity in epithelial cells with apical-basal polarity while acting as signaling platform scaffold proteins. Recent studies have further revealed novel roles of the Scrib module in the control of epithelial architecture, ranging from polarity establishment and tricellular junction formation to planar spindle orientation during cell division. This review updates the current understanding of the molecular nature and physiological functions of the Scrib module with a focus on in vivo studies, providing a framework for how these protein dynamics affect the processes of epithelial organization.

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.