The Ezrin Metastatic Phenotype Is Associated with the Initiation of Protein Translation
The Ezrin Metastatic Phenotype Is Associated with the Initiation of Protein Translation
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DOI：
10.1593/neo.11518
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发表时间：
2012-04-01
期刊：
影响因子：
4.8
通讯作者：
Khanna, Chand
中科院分区：
文献类型：
--
作者：
Briggs, Joseph W.;Ren, Ling;Khanna, Chand
我们先前将细胞骨架连接蛋白Ezrin与儿童肉瘤（包括骨肉瘤和横纹肌肉瘤）的转移表型相关联。这些研究表明，Ezrin有助于癌细胞到达继发转移部位后的存活。为了更好地理解这种作用在转移中，我们进行了两个非候选分析Ezrin功能，包括高和低Ezrin表达细胞的微阵列减法和蛋白质组学方法，以确定在肿瘤裂解物中结合Ezrin N-末端的蛋白质。这些数据的功能分析导致了一个新的和统一的假设，Ezrin有助于通过调节蛋白质翻译的转移效率。为了支持这一假设，我们发现Ezrin是核糖核蛋白复合物的一部分，以促进细胞中复合信使RNA的表达，并与多聚腺苷酸结合蛋白1（PABP 1; PABPC 1）结合。这些发现的相关性得到了我们鉴定的埃兹蛋白和组件的翻译机器中的伪足的高转移性细胞在细胞侵袭的过程中。最后，最近显示的两种小分子抑制剂抑制Ezrin转移表型破坏Ezrin/PABP 1协会。总之，这些结果提供了一个新的机制基础，Ezrin可能有助于转移。
We previously associated the cytoskeleton linker protein, Ezrin, with the metastatic phenotype of pediatric sarcomas, including osteosarcoma and rhabdomyosarcoma. These studies have suggested that Ezrin contributes to the survival of cancer cells after their arrival at secondary metastatic locations. To better understand this role in metastasis, we undertook two noncandidate analyses of Ezrin function including a microarray subtraction of high- and low-Ezrin-expressing cells and a proteomic approach to identify proteins that bound the N-terminus of Ezrin in tumor lysates. Functional analyses of these data led to a novel and unifying hypothesis that Ezrin contributes to the efficiency of metastasis through regulation of protein translation. In support of this hypothesis, we found Ezrin to be part of the ribonucleoprotein complex to facilitate the expression of complex messenger RNA in cells and to bind with poly A binding protein 1 (PABP1; PABPC1). The relevance of these findings was supported by our identification of Ezrin and components of the translational machinery in pseudopodia of highly metastatic cells during the process of cell invasion. Finally, two small molecule inhibitors recently shown to inhibit the Ezrin metastatic phenotype disrupted the Ezrin/PABP1 association. Taken together, these results provide a novel mechanistic basis by which Ezrin may contribute to metastasis.