The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

Abstract

Altered expression of human Scribble is associated with invasive epithelial cancers, however, its role in tumour development remains unclear. Mutations in Drosophila Scribble result in loss of polarity, overproliferation and 3D-tumourous overgrowth of epithelial cells. Using complementation studies in Drosophila we recently demonstrated that expression of human Scribble can also regulate polarity and restrict tissue overgrowth. Here, we have undertaken a detailed study of human Scribble function in the polarized mammary cell line, MCF10A. We show that although Scribble does not seem to be required for apical-basal polarity or proliferation control in MCF10A cells, Scribble is essential for the control of polarity associated with directed epithelial cell migration. Scribble-depleted MCF10A cells show defective in vitro wound closure and chemotactic movement. The cells at the wound edge fail to polarize, show reduced lamellipodia formation and impaired recruitment of Cdc42 and Rac1 to the leading edge. Furthermore, we show that this function is relevant in vivo as Scribble mutant mice show defective epidermal wound healing. This data identifies an essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration.

Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer

“…Thus, the findings potentially contribute to metastatic dissemination and disease progression in humans. 22 This alternative model is consistent with other mechanistic results showing that Scrib overexpression in astrocytes perturbed cellular polarity and induced randomly oriented cellular protrusions 6 ; conversely, depletion of Scrib in breast cancer cells inhibited migration, 4,5 potentially by disrupting the activation of Rac and PAK motility factors at the leading edge. 5 Loss of Scrib at early stages of cellular transformation may disrupt the apical-basal polarity of epithelial cells, 2 which is potentially consistent with a putative role in tumor suppression.…”

“…2 Experimental evidence, first collected in Drosophila melanogaster 3 and later extended to mammalian cells, 4 implicates Scrib as a general regulator of directional cell motility, largely via the assembly of multiprotein complexes and the activation of small GTPase signaling at the leading edge of migrating cells. 5,6 Accordingly, loss-of-function Scrib mutants 7 or depletion of Scrib 4 has disrupted apical-basal polarity 8 and has cooperated with oncogenic signals 9 to enhance tumor cell migration, invasion, and survival.…”

Drosophila melanogaster Guk-holder interacts with the Scribbled PDZ1 domain and regulates epithelial development with Scribbled and Discs Large

“…Whilst the N-terminal LRR domain is critical for Scrib's cortical localization (14), the four PDZ domains are required for cell-cell junction localization (13) and are the major mediators of Scrib interactions with other proteins (15). hScrib (human Scrib) PDZ domains have been shown to bind a diverse set of cellular interactors including b-PIX, MCC, GIT1 and b-catenin (16)(17)(18)(19)(20), enabling Scrib to integrate a range of cellular cues for the establishment of apico-basal polarity, cell migration and cell signalling.…”

Scrib, un gène suppresseur de tumeurs impliqué dans la polarité cellulaire

“…Parmi ceux-ci, Scribble a initialement été identifié comme gène suppresseur de tumeur chez la drosophile et joue un rôle clé dans la polarité des cellules épithéliales [13]. Récemment, Scrib, son orthologue chez les mammifères, a été impliqué dans le contrôle de la polarité des cellules épithéliales et des astrocytes en migration [14,15]. Ces travaux ont aussi permis de mieux caractériser le rôle de Scrib en le reliant à la petite protéine G Cdc42, acteur central du contrôle de la polarité cellulaire.…”

“…Scrib, normalement localisée au niveau des jonctions cellulaires, est recrutée dès l'initiation de la migration au front de migration des cellules épithéliales et des astrocytes [14,15] (Figure 1). La déplétion de la protéine endogène par une approche d'interférence ARN inhibe la réorientation du centrosome et de l'appareil de Golgi vers le front de migration démon-trant le rôle de Scrib dans la polarisation des cellules.…”