Mutationally activated Rho GTPases in cancer.
Mutationally activated Rho GTPases in cancer.
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DOI：
10.4161/sgtp.26530
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Lundquist, Erik A
中科院分区：
文献类型：
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作者：
Alan, Jamie K;Lundquist, Erik A
GTP酶的Rho家族（Ras超家族的成员）最为人所知的是它们在调节细胞骨架动力学中的作用。Rho蛋白的错误调节有助于肿瘤发生和转移，这也是公认的。与Ras蛋白不同，Ras蛋白在癌症中经常发生突变（约30%），Rho蛋白本身通常不会在癌症中发生突变。相反，癌症中Rho活性的误调节被认为是通过这些蛋白质的过表达或通过控制Rho活性的分子的误调节而发生的，例如GEF的激活或过表达以及GAP或GDI的失活或丢失。最近的研究，通过下一代肿瘤外显子组测序，报告了激活Rho GTP酶中的点突变作为黑色素瘤以及乳腺癌和头颈癌中的驱动突变。在这些肿瘤研究中发现的Rac1（P29L）突变先前被我们的实验室鉴定为C. elegans神经元发育，突出了这种突变的保守性。此外，这一发现支持在模式生物如C. elegans来研究致癌的机制。这篇综述将描述最近的研究结果，报告激活Rho突变在各种癌症类型，移动Rho GTPases从分子失调的癌症致突变的目标，驱动肿瘤发生。
The Rho family of GTPases (members of the Ras superfamily) are best known for their roles in regulating cytoskeletal dynamics. It is also well established that misregulation of Rho proteins contributes to tumorigenesis and metastasis. Unlike Ras proteins, which are frequently mutated in cancer (around 30%), Rho proteins themselves are generally not found to be mutated in cancer. Rather, misregulation of Rho activity in cancer was thought to occur by overexpression of these proteins or by misregulation of molecules that control Rho activity, such as activation or overexpression of GEFs and inactivation or loss of GAPs or GDIs. Recent studies, enabled by next-generation tumor exome sequencing, report activating point mutations in Rho GTPases as driver mutations in melanoma, as well as breast, and head and neck cancers. The Rac1(P29L) mutation identified in these tumor studies was previously identified by our lab as an activating Rac mutation in C. elegans neuronal development, highlighting the conserved nature of this mutation. Furthermore, this finding supports the relevance of studying Rho GTPases in model organisms such as C. elegans to study the mechanisms that underlie carcinogenesis. This review will describe the recent findings that report activating Rho mutations in various cancer types, moving Rho GTPases from molecules misregulated in cancer to mutagenic targets that drive tumorigenesis.