Activating ROCK1 somatic mutations in human cancer
Activating ROCK1 somatic mutations in human cancer
复制标题
DOI：
10.1038/onc.2010.3
复制
发表时间：
2010-04-01
期刊：
影响因子：
8
通讯作者：
Olson, M. F.
中科院分区：
文献类型：
--
作者：
Lochhead, P. A.;Wickman, G.;Olson, M. F.
癌细胞具有无调控生长、存活和增加转移潜能的特点。通过促进这些特征而提供选择优势的基因突变被称为“驱动因素”，而不会导致疾病发生/发展的基因突变则被称为“乘客”。高通量方法的出现促进了癌症基因组的大规模筛选和随后新的体细胞突变的鉴定。尽管这种方法产生了有价值的结果，但在确定这些突变的功能后果以区分潜在司机和乘客之前，数据仍然不完整。ROCK1是Rho GTP酶下游的重要效应蛋白，是细胞迁移的重要途径。癌症基因组计划确定了ROCK1基因中的三个非同义突变。我们现在证明，这些体细胞ROCK1突变会导致激酶活性升高，并驱动肌动蛋白细胞骨架重排，从而促进运动性增加和粘附性减少，这是癌症进展的特征。绘制羧基末端的激酶相互作用区域图，结合结构建模，可以深入了解这些突变可能如何影响ROCK1的调控。这些结果与人类癌症中ROCK1突变的频率一致，支持了这样的结论，即ROCK1基因存在选择性压力，以获得导致激酶激活的“驱动”突变。Oncogene(2010)29,2591-2598；doi：10.1038/onc.2010.3；2010年2月8日在线发布
Cancer cells acquire characteristics of deregulated growth, survival and increased metastatic potential. Genetic mutations that provide a selective advantage by promoting these characteristics have been termed 'drivers,' whereas mutations that do not contribute to disease initiation/progression are termed 'passengers.' The advent of high-throughput methodologies has facilitated large-scale screening of cancer genomes and the subsequent identification of novel somatic mutations. Although this approach has generated valuable results, the data remain incomplete until the functional consequences of these mutations are determined to differentiate potential drivers from passengers. ROCK1 is an essential effector kinase downstream of Rho GTPases, an important pathway involved in cell migration. The Cancer Genome Project identified three nonsynonymous mutations in the ROCK1 gene. We now show that these somatic ROCK1 mutations lead to elevated kinase activity and drive actin cytoskeleton rearrangements that promote increased motility and decreased adhesion, characteristics of cancer progression. Mapping of the kinase-interacting regions of the carboxy terminus combined with structural modeling provides an insight into how these mutations likely affect the regulation of ROCK1. Consistent with the frequency of ROCK1 mutations in human cancer, these results support the conclusion that there is selective pressure for the ROCK1 gene to acquire 'driver' mutations that result in kinase activation. Oncogene (2010) 29, 2591-2598; doi:10.1038/onc.2010.3; published online 8 February 2010