Epithelia maintain their function as barriers, despite ongoing cell turnover, by squeezing out dying cells in a process that depends on formation and contraction of an actin and myosin ring by the surrounding cells. Cell extrusion occurs either apically (into the lumen) or basally (into the underlying tissue), depending on the respective basal or apical location of the contractile ring, which depends on microtubule reorientation and targeting to the actin cortex. Noting that the tumor suppressor adenomatous polyposis coli (APC) acts as a scaffold for F-actin and microtubules, Marshall et al. investigated its role in epithelial cell extrusion. APC, which was located near the apex of nonextruding cultured human bronchial epithelial (HBE) cells and during basal extrusion, shifted to the base during apical extrusion. Whereas extrusion was predominantly apical in control HBE cells, APC depletion led to predominantly basal extrusion. Forms of APC with C-terminal truncations are common in colorectal cancers, and a colorectal cancer cell line bearing truncated APC (DLD-1 cells) showed predominantly basal extrusion. Similarly, whereas extrusion in wild-type zebrafish epidermis was apical, 66% of extrusions occurred basally in epidermis bearing truncated APC. Experiments with mosaic monolayers revealed that, although microtubule reorientation toward the contractile ring occurred in the surrounding cells, apical extrusion depended on APC in the extruded cell. HBE cells surrounding an APC-depleted extruding cell showed decreased microtubule staining at the contractile ring compared with those surrounding wild-type cells, whereas, with DLD-1 cells, expression of the APC C-terminal fragment (containing regions involved in microtubule interaction) in the extruding cell increased microtubule staining at the contractile ring. Pharmacological analysis indicated that APC relocalization to the base of extruding HBE cells depended on microtubules and that its ability to induce microtubule reorientation in surrounding cells required myosin contraction. The authors proposed a model in which microtubules relocalize APC to the base of the dying cell, eliciting a contraction that stimulates microtubule reorientation in the surrounding cells to determine the location of the contractile ring. Noting that cancer cells can contain survival-enhancing mutations, they further hypothesized that APC may promote the apical elimination of transformed cells and that its loss or mutation facilitates their exit into the underlying tissue.
T. W. Marshall, I. E. Lloyd, J. M. Delalande, I. Näthke, J. Rosenblatt, The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium. Mol. Biol. Cell 22, 3962–3970 (2011). [Abstract] [Full Text]