Review
Regulation of cellular and PCP signalling by the Scribble polarity module

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Abstract

Since the first identification of the Scribble polarity module proteins as a new class of tumour suppressors that regulate both cell polarity and proliferation, an increasing amount of evidence has uncovered a broader role for Scribble, Dlg and Lgl in the control of fundamental cellular functions and their signalling pathways. Here, we review these findings as well as discuss more specifically the role of the Scribble module in PCP signalling.

Introduction

Directionality, or polarity, is a fundamental cellular property that together with proper coordination of proliferation, survival and differentiation control is essential for the organisation, development and normal function of all living tissues. Cell polarity is established through the asymmetric distribution of proteins, lipids and RNA, creating specialized cell functions (reviewed in Refs. [1], [2]). Several major types of cell polarity states have been described, characterised by their biological context, and the signalling pathway and cell polarity complexes that take part in establishing polarity and cellular function. Apical-Basal Cell Polarity (ABCP) is most commonly associated with the term cell polarity and the best understood. In an epithelial context, it helps generate and maintain the architecture of the cell within the epithelial tissue including defining an apical membrane facing a lumen, lateral adhesions between neighbouring cells, and basal attachment to the extracellular cellular matrix (ECM). Asymmetric cell division (ACD) is a form of cell polarity utilised to regulate the self-renewal of stem cells and differentiation of the progenitor cells, with Front-Rear cell polarity (FRCP) referring to the regulation of directional migration. Although a common phenomenon, and implicated in an array of developmental processes as well as tumorigenesis, much less is known about the molecular mechanisms governing Planar Cell Polarity (PCP) initiation and maintenance. The Scribble module and each of its components Scrib, Dlg and Lgl, have been shown to be highly conserved and to participate in maintaining a variety of cellular polarity states. Here we focus on the role of the Scribble polarity module in cellular and PCP signalling, linking signalling pathways to asymmetric distribution of structural components and ultimately, tissue polarity.

Section snippets

The Scribble polarity module

The Scribble module was first identified in Drosophila melanogaster (reviewed in Refs. [3], [4] and named after the various phenotypes of their respective mutants including disorganized epithelium and abnormal cuticle deposition (scribbled, scrib), overgrowth of larval tissues (discs large, dlg) or overgrowth of the whole larva itself leading to its untimely death (lethal giant larvae, lgl). Scrib was found to function as a genetic and functional module together with Dlg, a membrane-associated

The Scribble polarity module in cellular signalling pathways

Fundamental processes in development such as tissue growth and differentiation are governed by a number of defined signalling pathways. Evidence garnered across species and tissues have linked members of the Scribble polarity module to many of these pathways (see Fig. 2). Here we summarise these findings which highlight the robust and elementary requirement for the Scribble module in controlling tissue morphogenesis.

The Scribble module in PCP signalling

Planar Cell Polarity (PCP) describes the coordinated planar polarization seen across multiple cells within a tissue sheet or organ and contributes positional information governing the cell’s identity and fate [133], [43]. PCP signalling has also been shown to regulate cell division orientation to impact axis determination, specification, cell fate, epithelial sheet migration and ultimately, tissue morphogenesis [134], [135]. The PCP pathway, also known as the non-canonical Wnt signalling

The Scribble module, PCP signalling and tumourigenesis

How PCP signalling components may be involved in cancer initiation and progression has recently been reviewed [138], and includes potential effects on proliferation, stemness, EMT, cell invasion, tumour-microenvironment interactions and chemoresistance. As the PCP components implicated in various cancers such as Fz receptors, Vangl1/2, and Dsh and Fz receptors can bind directly to Scribble module proteins, it is likely that at least some of the described tumour suppressive activity of the

Future challenges

The Scribble module was initially identified as a core component in the regulation of apicobasal polarity and subsequent studies have now firmly established it as a modulator of a variety of other cell polarity states. Accumulating evidence has shown that members of the Scribble module also interact with and bridge components of other fundamental signalling pathways in development and tumorigenesis. As a regulator of these pathways, the Scribble module therefore provides an attractive target

Acknowledgements

The authors would like to thank Helena Richardson for comments and critical reading of the manuscript and Rebecca Stephens for assistance with figure preparation. MMH was supported by funding from the National Health and Medical Research of Australia (APP1103871) and POH by a Senior Research Fellowship of the National Health and Medical Research of Australia (APP1079133).

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