The Rsu-1-PINCH1-ILK complex is regulated by Ras activation in tumor cells
The Rsu-1-PINCH1-ILK complex is regulated by Ras activation in tumor cells
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DOI：
10.1016/j.ejcb.2008.02.011
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发表时间：
2008-09-01
影响因子：
6.6
通讯作者：
Cutler, Mary Lou
中科院分区：
文献类型：
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作者：
Dougherty, Gerard W.;Jose, Cynthia;Cutler, Mary Lou
在肿瘤发生中，由于整合素信号的改变，Ras转化和细胞迁移增强之间的联系已经得到了很好的证实，但是我们对其机制的理解仍然存在空白。Ras抑制因子Rsu-1最近通过与PINCH1的LIM 5结构域的相互作用，与IPP（整合素连接激酶{TLK}， PINCH-1/LIMS1, parvin）局灶粘附复合物连接。确定Rsu1-PINCH1-ILK-parvin复合物在肿瘤发生中的作用是很重要的，因为在某些肿瘤中ILK和PINCH1都升高，而Rsu-1的异位表达则阻止肿瘤发生。我们的研究先前在高级别胶质瘤中发现了一种选择性剪接的Rsu-1亚型。我们在此报告了截断（p29）的ru -1蛋白的检测，这与选择性剪接的ru -1 RNA的存在相关。这种RNA和相应的蛋白在含有高水平活化Ras的人类肿瘤细胞系中被检测到，抑制剂研究表明Mek-ERK通路调节这种截断的ru -1产物的表达。我们还发现，在未转化的细胞中，ru -1与ILK在局灶接触处共定位，与ILK- pinch1复合物共免疫沉淀，但在Ras转化后，ru -1与PINCH1-ILK复合物的关联大大降低。利用人乳腺癌细胞系，我们的体外研究表明，Rsu-1全长蛋白的缺失增强了细胞迁移，与Rac-GTP的所有增加一致，而p29 Rsu-1截断蛋白的缺失抑制了迁移。这些发现表明，Rsu-1可能通过稳定IPP粘附复合体来抑制细胞迁移，而Ras激活通过调节Rsu-1剪接和全长Rsu-1与IPP的关联来干扰这种抑制功能。因此，我们的研究结果表明，Rsu-1将Ras通路与IPP复合物和恶性过程中发生的细胞附着依赖性信号的扰动联系起来。(C) 2008爱思唯尔有限公司版权所有。
The link between Ras transformation and enhanced cell migration due to altered integrin signaling is well established in tumorigenesis, however there remain gaps in our understanding of its mechanism. The Ras suppressor, Rsu-1, has recently been linked to the IPP (integrin-linked kinase {TLK}, PINCH-1/LIMS1, parvin) focal adhesion complex based on its interaction with the LIM 5 domain of PINCH1. Defining the role of the Rsu1-PINCH1-ILK-parvin complex in tumorigenesis is important because both ILK and PINCH1 are elevated in certain tumors while ectopic expression of Rsu-1 blocks tumorigenesis. Our Studies previously identified an alternatively spliced isoform of Rsu-1 in high-grade gliomas. We report here the detection of a truncated (p29) Rsu-1 protein, which correlates with the presence of the alternatively spliced Rsu-1 RNA. This RNA and the respective protein were detected in human tumor cell lines that contain high levels of activated Ras, and inhibitor Studies demonstrate that the Mek-ERK pathway regulates expression of this truncated Rsu-1 product. We also show that Rsu-1 co-localizes with ILK at focal contacts and co-immunoprecipitates with the ILK-PINCH1 complex in non-transformed cells, but following Ras transformation the association of Rsu-1 with the PINCH1-ILK complex is greatly reduced. Using a human breast cancer cell line, our in vitro studies demonstrate that the depletion of Rsu-1 full-length protein enhances cell migration coincident with all increase in Rac-GTP while the depletion of the p29 Rsu-1 truncated protein inhibits migration. These findings indicate that Rsu-1 may inhibit cell migration by stabilizing the IPP adhesion complex and that Ras activation perturbs this inhibitory function by modulating both Rsu-1 splicing and association of full-length Rsu-1 with IPP. Hence, Our findings demonstrate that Rsu-1 links the Ras pathway with the IPP complex and the perturbations of cell attachment-dependent signaling that occur in the malignant process. (C) 2008 Elsevier GmbH. All rights reserved.