Mutated APC and Asef are involved in the migration of colorectal tumour cells
Mutated APC and Asef are involved in the migration of colorectal tumour cells
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DOI：
10.1038/ncb937
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发表时间：
2003-03-01
影响因子：
21.3
通讯作者：
Akiyama, T
中科院分区：
文献类型：
--
作者：
Kawasaki, Y;Sato, R;Akiyama, T
肿瘤抑制基因腺瘤性结肠息肉病（APC）在散发性和家族性结直肠肿瘤中发生突变。APC与Wnt信号通路的关键组分β-连环蛋白结合，并诱导其降解，，，，。APC与微管相互作用，并在其正端聚集在膜突起中，并以肌动蛋白依赖的方式与质膜结合。此外，APC与Rac特异性鸟嘌呤核苷酸交换因子Asef相互作用并刺激其活性，从而调节肌动蛋白细胞骨架网络和细胞形态。在这里，我们表明，Asef的过度表达降低E-钙粘蛋白介导的细胞间粘附，促进上皮Madin-Darby犬肾细胞的迁移。这两种活性都受到结肠直肠肿瘤细胞中表达的截短APC蛋白的刺激。基于RNA干扰和显性阴性突变体的实验表明，Asef和突变的APC都是表达截短APC的结直肠肿瘤细胞迁移所必需的。这些结果表明，APC-Asef复合物在细胞迁移以及E-钙粘蛋白介导的细胞-细胞粘附中起作用，并且结肠直肠肿瘤细胞中存在的截短的APC有助于其异常迁移特性。
The tumour suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumours,. APC binds to β-catenin, a key component of the Wnt signalling pathway, and induces its degradation,,,,. APC interacts with microtubules and accumulates at their plus ends in membrane protrusions,,,, and associates with the plasma membrane in an actin-dependent manner. In addition, APC interacts with the Rac-specific guanine nucleotide exchange factor Asef and stimulates its activity, thereby regulating the actin cytoskeletal network and cell morphology. Here we show that overexpression of Asef decreases E-cadherin-mediated cell–cell adhesion and promotes the migration of epithelial Madin–Darby canine kidney cells. Both of these activities are stimulated by truncated APC proteins expressed in colorectal tumour cells. Experiments based on RNA interference and dominant-negative mutants show that both Asef and mutated APC are required for the migration of colorectal tumour cells expressing truncated APC. These results suggest that the APC–Asef complex functions in cell migration as well as in E-cadherin-mediated cell–cell adhesion, and that truncated APC present in colorectal tumour cells contributes to their aberrant migratory properties.