title: The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium.
abstract: Despite high rates of cell death, epithelia maintain intact barriers by squeezing dying cells out using a process termed cell extrusion. Cells can extrude apically into the lumen or basally into the tissue the epithelium encases, depending on whether actin and myosin contract at the cell base or apex, respectively. We previously found that microtubules in cells surrounding a dying cell target p115 RhoGEF to the actin cortex to control where contraction occurs. However, what controls microtubule targeting to the cortex and whether the dying cell also controls the extrusion direction were unclear. Here we find that the tumor suppressor adenomatous polyposis coli (APC) controls microtubule targeting to the cell base to drive apical extrusion. Whereas wild-type cells preferentially extrude apically, cells lacking APC or expressing an oncogenic APC mutation extrude predominantly basally in cultured monolayers and zebrafish epidermis. Thus APC is essential for driving extrusion apically. Surprisingly, although APC controls microtubule reorientation and attachment to the actin cortex in cells surrounding the dying cell, it does so by controlling actin and microtubules within the dying cell. APC disruptions that are common in colon and breast cancer may promote basal extrusion of tumor cells, which could enable their exit and subsequent migration.
authors: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors: Thomas W
authors: TW
authors: Marshall
authors: Isaac E
authors: IE
authors: Lloyd
authors: Jean Marie
authors: JM
authors: Delalande
authors: Inke
authors: I
authors: Näthke
authors: Jody
authors: J
authors: Rosenblatt
mesh_terms: D000199:Actins / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D002460:Cell Line; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000502:physiology; D059010:Single-Cell Analysis; D014404:Tubulin / Q000378:metabolism; D015027:Zebrafish
chemical_list: C555337:APC protein, human; D000199:Actins; D025601:Adenomatous Polyposis Coli Protein; D015513:Oncogene Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014404:Tubulin