Journal of Molecular Biology
Volume 430, Issue 19, 28 September 2018, Pages 3585-3612
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Review
The Scribble Cell Polarity Module in the Regulation of Cell Signaling in Tissue Development and Tumorigenesis

https://doi.org/10.1016/j.jmb.2018.01.011Get rights and content

Highlights

  • The Scribble cell polarity module has a tumor suppressive role in mammalian epithelial cancers

  • Scribble module proteins interact with many signaling proteins

  • Scribble module proteins control signaling pathways, which are linked to the control of tissue growth, differentiation and cell migration

  • Understanding the molecular interactions between Scribble module proteins and their interacting partners will increase our understanding of their role in tumorigenesis

Abstract

The Scribble cell polarity module, comprising Scribbled (Scrib), Discs-large (Dlg) and Lethal-2-giant larvae (Lgl), has a tumor suppressive role in mammalian epithelial cancers. The Scribble module proteins play key functions in the establishment and maintenance of different modes of cell polarity, as well as in the control of tissue growth, differentiation and directed cell migration, and therefore are major regulators of tissue development and homeostasis. Whilst molecular details are known regarding the roles of Scribble module proteins in cell polarity regulation, their precise mode of action in the regulation of other key cellular processes remains enigmatic. An accumulating body of evidence indicates that Scribble module proteins play scaffolding roles in the control of various signaling pathways, which are linked to the control of tissue growth, differentiation and cell migration. Multiple Scrib, Dlg and Lgl interacting proteins have been discovered, which are involved in diverse processes, however many function in the regulation of cellular signaling. Herein, we review the components of the Scrib, Dlg and Lgl protein interactomes, and focus on the mechanism by which they regulate cellular signaling pathways in metazoans, and how their disruption leads to cancer.

Section snippets

Introduction: Cell polarity regulation and tumorigenesis

Cell polarity involves the asymmetric distribution of macromolecules to specific membrane domains, which is essential for normal cellular function and morphogenesis during development in multicellular organisms [1], [2], [3], [4], [5], [6], [7]. There are four main types of cell polarity: 1) apico-basal cell polarity (ABCP, epithelial polarity) [1], [6], [7], [8], 2) planar cell polarity (PCP, polarity across the plane of an epithelium) [9], [10], [11], 3) asymmetric cell division (ACD, which

Scribble module protein structure and function

Although the Scrib, Dlg and Lgl proteins do not have intrinsic enzymatic activity, they all contain a number of well-characterized protein–protein interaction domains (described in more detail below) that enables them to bind to signaling proteins, such as kinases and phosphatases. Importantly, their function appears to be absolutely dependent on their cellular sublocalization. Hence, much of the currently known functions of the Scribble module proteins can be attributed to their role as

Scribble module protein interactors

In addition to their roles in cell polarity, the Scribble module proteins interact with many proteins involved in different cellular processes, such as cell adhesion, membrane trafficking, cell migration and cellular signaling (see Fig. 1, Fig. 2, Fig. 3, Table 1, Table 2, Table 3). Despite their common role in regulating cell polarity, Scrib, Dlg and Lgl interact with mostly distinct protein interactors. We will highlight below some examples of interacting proteins and the motifs within the

Scribble module proteins in the regulation of cell signaling pathways

Since Scrib and Dlg are similar in structure and function, whilst Lgl is structurally and functionally different, with its function tightly linked to aPKC and the Par complex function, we will consider Scrib and Dlg separately to Lgl and aPKC/Par in discussing their regulation of cell signaling pathways.

Conclusions and Perspectives

We have highlighted in this review, the myriad of Scribble module interacting proteins and how they are involved in cell signaling pathways. It is clear that there is considerably complexity in the protein interactions that have been documented to occur with Scribble module proteins and in the regulation of signaling pathways. Although Scrib, Dlg and Lgl play a common function in cell polarity regulation, they interact with distinct proteins in the regulation of various signaling pathways, and

Acknowledgements

This work was supported by an National Health and Medical Research Council Australia (NHMRC) Project Grant (APP1103871) to MK, POH and HER, an NHMRC Fellowship (APP1020056) to PH, an Australian Research Council Fellowship (FT130101349) to MK, a Juan de la Cierva-Incorporacion postdoctoral fellowship (IJCI-2014-19272) from the Spanish Ministerio de Ciencia e Innovacion (MICINN) to MP, a Australian Government RTP Scholarship to RS, and funds from La Trobe University and the La Trobe Institute of

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