The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium.
The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium.
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DOI：
10.1091/mbc.e11-05-0469
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发表时间：
2011-11
影响因子：
3.3
通讯作者：
Rosenblatt J
中科院分区：
文献类型：
--
作者：
Marshall TW;Lloyd IE;Delalande JM;Näthke I;Rosenblatt J
腺瘤性结肠息肉病（APC）控制细胞从上皮中挤出的方向。APC在垂死细胞中起作用，控制微管靶向邻近细胞中的肌动球蛋白收缩，从而挤出垂死细胞。APC突变经常发生在结肠癌中，导致细胞在上皮下异常突出，这可能使肿瘤细胞侵入。尽管细胞死亡率很高，但上皮细胞通过使用称为细胞挤出的过程将死亡细胞挤出而保持完整的屏障。细胞可以从顶端挤入管腔，也可以从底部挤入上皮包裹的组织，这取决于肌动蛋白和肌球蛋白是分别在细胞底部还是顶端收缩。我们以前发现，微管周围的细胞死亡细胞的目标p115 RhoGEF的肌动蛋白皮质控制收缩发生的地方。然而，是什么控制微管靶向皮层，以及垂死的细胞是否也控制挤出方向尚不清楚。在这里，我们发现，肿瘤抑制腺瘤性结肠息肉病（APC）控制微管靶向细胞的基础，以推动顶端挤出。而野生型细胞优先挤出顶部，细胞缺乏APC或表达致癌APC突变突出主要是在培养的单层和斑马鱼表皮基底。因此，APC是必要的驱动挤出顶部。令人惊讶的是，尽管APC控制微管的重新定向和附着到垂死细胞周围的细胞中的肌动蛋白皮质，但它是通过控制垂死细胞内的肌动蛋白和微管来实现的。在结肠癌和乳腺癌中常见的APC破坏可能会促进肿瘤细胞的基底挤出，这可能使它们能够退出和随后的迁移。
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. 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.