Aptamer-Derived Peptides as Potent Inhibitors of the Oncogenic RhoGEF Tgat
Aptamer-Derived Peptides as Potent Inhibitors of the Oncogenic RhoGEF Tgat
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DOI：
10.1016/j.chembiol.2009.02.006
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发表时间：
2009-04-24
影响因子：
--
通讯作者：
Schmidt, Susanne
中科院分区：
文献类型：
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作者：
Bouquier, Nathalie;Fromont, Sylvie;Schmidt, Susanne
鸟嘌呤核苷酸交换因子（GEFs）通过加快其GDP/GTP交换速率来激活Rho GTP酶。一些RhoGEF已基于其致癌潜能被分离出来，因此人们正在积极寻求抑制其活性的策略。在这项研究中，我们设计了一种肽抑制剂筛选策略，以靶向Tgat的GEF活性，Tgat是RhoGEF Trio的一种致癌异构体，该策略基于Trio抑制剂TRIPα的随机突变，我们之前通过肽适体筛选分离出了TRIPα。这鉴定出一种肽，TRIPE32G，它在体外特异性抑制Tgat的GEF活性，并显著降低Tgat诱导的RhoA激活和病灶形成。此外，将表达Tgat和TRIPE32G的细胞皮下注射到裸鼠体内可减少Tgat诱导的肿瘤形成。因此，我们的方法表明肽适体是有效的抑制剂，可用于在体内干扰RhoGEF的功能。
Guanine nucleotide exchange factors (GEFs) activate the Rho GTPases by accelerating their GDP/GTP exchange rate. Some RhoGEFs have been isolated based on their oncogenic potency, and strategies to inhibit their activity are therefore actively being sought. In this study we devise a peptide inhibitor screening strategy to target the GEF activity of Tgat, an oncogenic isoform of the RhoGEF Trio, based on random mutations of the Trio inhibitor TRIP alpha, which we previously isolated using a peptide aptamer screen. This identifies one peptide, TRIPE32G, which specifically inhibits Tgat GEF activity in vitro and significantly reduces Tgat-induced RhoA activation and foci formation. Furthermore, subcutaneous injection of cells expressing Tgat and TRIPE32G into nude mice reduces the formation of Tgat-induced tumors. Our approach thus demonstrates that peptide aptamers are potent inhibitors that can be used to interfere with RhoGEF functions in vivo.