Scrib regulates PAK activity during the cell migration process

Abstract

Genetic studies have highlighted the key role of Scrib in the development of Metazoans. Deficiency in Scrib impairs many aspects of cell polarity and cell movement although the mechanisms involved remain unclear. In mammals, Scrib belongs to a protein complex containing betaPIX, an exchange factor for Rac/Cdc42, and GIT1, a GTPase activating protein for ARF6 implicated in receptor recycling and exocytosis. Here we show that the Scrib complex associates with PAK, a serine-threonine kinase family crucial for cell migration. PAK colocalizes with members of the Scrib complex at the leading edge of heregulin-treated T47D breast cancer cells. We demonstrate that the Scrib complex is required for epithelial cells and primary mouse embryonic fibroblasts to efficiently respond to chemoattractant cues. In Scrib-deficient cells, the pool of cortical PAK is decreased, thereby precluding its proper activation by Rac. Loss of Scrib also impairs the polarized distribution of active Rac at the leading edge and compromises the regulated activation of the GTPase in T47D cells and mouse embryonic fibroblasts. These data underscore the role of Scrib in cell migration and show the strong impact of Scrib in the function of PAK and Rac, two key molecules implicated in this process.

Aberrant Overexpression of the Cell Polarity Module Scribble in Human Cancer

“…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. 1,3 Future investigations should address whether Scrib mutations are common events in human cancers or whether mutations are responsible for Scrib delocalization into the cytosol.…”

“…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. 10 Although these data have prompted a model that Scrib may function in an evolutionary-conserved pathway of tumor suppression, 1,3 its role in human cancer, in vivo, has remained vehemently debated.…”

The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction

“…Most interestingly, loss of hScrib expression is accompanied by a marked accumulation of active phospho-ERK in the Golgi apparatus and in the nucleus. Although nuclear localized ERK is most likely involved in the regulation of gene expression related to cell cycle progression, Golgi accumulation may be related to the control of cell survival and cell migration, both of which have also been shown to be regulated by hScrib (Qin et al, 2005;Dow et al, 2008;Nola et al, 2008).…”

Involvement of βPIX in angiotensin II-induced migration of vascular smooth muscle cells

“…βPIX isoforms may play important roles in migration of neuronal cells during embryonic development (Kim et al, 2000). Moreover, βPIX controls motility of fibroblasts (Cau and Hall, 2005;Za et al, 2006), epithelial cells (Nola et al, 2008) and T cells (Volinsky et al, 2006). We determined whether βPIX contributes to Ang II-induced VSMC migration.…”