Buerger Claudia, DeVries Ben, Stambolic Vuk
Division of Signaling Biology, Ontario Cancer Institute, University Health Network, 610 University Ave, Toronto, Ont., Canada M5G 2M9.
Biochem Biophys Res Commun. 2006 Jun 9;344(3):869-80. doi: 10.1016/j.bbrc.2006.03.220. Epub 2006 Apr 19.
Rheb, a small GTPase, has emerged as a key molecular switch that directly regulates the activity of the mammalian target of rapamycin (mTOR). Similar to other members of the Ras superfamily, Rheb has a C-terminal CaaX box that is subject to farnesylation. This study reports that farnesylation is a key determinant of Rheb's subcellular localization and directs its association with the endomembrane. Timed imaging of live cells expressing EGFP-Rheb reveals that following brief association with the ER, Rheb localizes to highly ordered, distinct structures within the cytoplasm that display characteristics of Golgi membranes. Failure of Rheb to localize to the endomembrane impairs its ability to interact with mTOR and activate downstream targets. Consistent with the notion that the endomembrane may serve as a platform for the assembly of a functional Rheb/mTOR complex, treatment of cells with brefeldin A interferes with transmission of Rheb signals to p70S6K.
小GTP酶Rheb已成为直接调节雷帕霉素哺乳动物靶点（mTOR）活性的关键分子开关。与Ras超家族的其他成员类似，Rheb有一个C末端CaaX盒，可进行法尼基化修饰。本研究报告称，法尼基化修饰是Rheb亚细胞定位的关键决定因素，并指导其与内膜的结合。对表达EGFP-Rheb的活细胞进行定时成像显示，在与内质网短暂结合后，Rheb定位于细胞质内高度有序、独特的结构，这些结构具有高尔基体膜的特征。Rheb无法定位于内膜会损害其与mTOR相互作用并激活下游靶点的能力。与内膜可能作为功能性Rheb/mTOR复合物组装平台的观点一致，用布雷菲德菌素A处理细胞会干扰Rheb信号向p70S6K的传递。
