The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium

Abstract

Adenomatous polyposis coli (APC) controls the direction in which cells extrude from epithelia. APC acts in the dying cell to control where microtubules target actomyosin contraction in neighboring cells that squeeze out the dying cell. APC mutations that frequently occur in colon cancer cause cells to extrude aberrantly beneath epithelia, which could enable tumor cell invasion.

Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton

“…This localized contraction enables apical constriction during invagination [73] or defines the topography of cell extrusion (apical or basal side of the epithelial monolayer). At the molecular level, cell extrusion directionality is driven by specific oncogenes (Ras, APC) [74,75] and the engagement of N-WASP or crosslinking proteins such as filamins or EPLIN [45,76,77].…”

Interactions and functions of the adenomatous polyposis coli (APC) protein at a glance

“…For instance, the binding of APC to itself via N-terminal and C-terminal domains affects its interaction with proteins that bind to the armadillo region (Li and Näthke, 2005). Heterozygous expression of such truncated fragments causes measurable changes in cell migration, and changes the ability of cells to extrude from epithelial tissue normally during homeostasis (Marshall et al, 2011;Nelson et al, 2012). However, the detailed molecular mechanisms that underpin these changes are not known.…”

“…Similarly, the contribution of APC to the regulation of cytoskeletal proteins, particularly microtubules and actin, is well established (Moseley et al, 2007;Munemitsu et al, 1994;Näthke et al, 1996;Okada et al, 2010;Smith et al, 1994). The changes in cytoskeletal organization and processes associated with microtubules and actin, including migration and cell division that accompany APC loss, have been described by many research groups (Caldwell et al, 2007;Dikovskaya et al, 2010;Dikovskaya et al, 2004;Dikovskaya et al, 2007;Green et al, 2005;Green and Kaplan, 2003;Kita et al, 2006;Kroboth et al, 2007;Marshall et al, 2011). In the context of cancer, changes in these interactions of APC cause cells to migrate less efficiently and to increase their residence time in the challenging environment of the intestinal tract (Nelson (See poster insert) et al, 2012).…”

“…Moreover, changes in microtubules in cells with mutant APC contribute to changes in how cells extrude during the process of their elimination from epithelia. Instead of extruding apically, which ensures the removal from the body, cells with mutant APC tend to extrude basally, which could cause their inappropriate retention (Marshall et al, 2011). Whether the interactions between APC and microtubules or other cytoskeletal proteins also have a role in the increased compaction of mitotic chromatin in APC-deficient systems is not clear (Dikovskaya et al, 2012).…”

A toolbox to study epidermal cell types in zebrafish

“…For example, our Gal4 enhancer trap lines can be used to manipulate gene expression within specific epithelial cell types, as well as follow their movements and behaviors under physiological conditions and during pathogenesis or carcinogenesis. Recent studies have demonstrated that mutations in conserved tumor suppressor genes or the sphingosine-1-phosphate signaling pathway lead to altered epithelial cell behaviors and hallmarks seen in aggressive tumors (Gu et al, 2015;Marshall et al, 2011;Reischauer et al, 2009), highlighting the utility of the zebrafish epidermis to model the earliest events of carcinoma formation and progression. Our toolset now provides new strategies for loss-of-function studies for the zebrafish epidermis (Fig.…”