Transforming mutations of RAC guanosine triphosphatases in human cancers
Transforming mutations of RAC guanosine triphosphatases in human cancers
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DOI：
10.1073/pnas.1216141110
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发表时间：
2013-02-19
影响因子：
11.1
通讯作者：
Mano, Hiroyuki
中科院分区：
文献类型：
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作者：
Kawazu, Masahito;Ueno, Toshihide;Mano, Hiroyuki
小鸟苷三磷酸酶（GTP酶）的RAS超家族的成员在GDP结合的非活性状态和GTP结合的活性状态之间转变，从而在调节各种细胞活性中充当二元开关。尽管HRAS、NRAS和KRAS经常在人类癌症中获得转化错义突变，但对其他小GTP酶的致癌作用知之甚少，包括Ras相关的C3肉毒杆菌毒素底物（RAC）蛋白。我们发现，人肉瘤细胞系HT 1080窝藏NRAS（Q61 K）和RAC 1（N92 I）突变蛋白。尽管这两种突变体都能够转化成纤维细胞，但敲低实验表明RAC 1（N92 I）可能是该细胞系的基本生长驱动因素。在细胞系和公共数据库中筛选RAC 1、RAC 2或RAC 3突变，发现了RAC 1和RAC 2的几种错义突变，其中一些突变蛋白，包括RAC 1（P29 S）、RAC 1（C157 Y）、RAC 2（P29 L）和RAC 2（P29 Q），被发现被激活和转化。P29 S，N92 I，和C157 Y突变体的RAC 1被证明存在优先在GTP结合状态的结果，从GDP结合状态的快速转变，而不是作为一个减少的内在GTdR活性的结果。因此，RAC GTP酶的激活突变在多种人类癌症中以低频率发现;然而，鉴于其显著的转化能力，突变蛋白是开发新治疗剂的潜在靶标。
Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.