The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1
The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1
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DOI：
10.1126/science.1157535
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发表时间：
2008-06-13
期刊：
影响因子：
56.9
通讯作者：
Sabatini, David M.
中科院分区：
文献类型：
--
作者：
Sancak, Yasemin;Peterson, Timothy R.;Sabatini, David M.
多蛋白 mTORC1 蛋白激酶复合物是响应胰岛素、能量水平和氨基酸而促进生长的通路的核心组成部分，并且在常见癌症中不受调节。我们发现 Rag 蛋白 - 四个相关的小鸟苷三磷酸酶 (GTPase) 家族 - 以氨基酸敏感的方式与 mTORC1 相互作用，并且是氨基酸激活 mTORC1 途径所必需的。与三磷酸鸟苷组成型结合的 Rag 突变体与 mTORC1 强烈相互作用，其在细胞内的表达使 mTORC1 途径对氨基酸剥夺具有抵抗力。相反，鸟苷二磷酸结合的 Rag 突变体的表达阻止了氨基酸对 mTORC1 的刺激。 Rag 蛋白不会直接刺激 mTORC1 的激酶活性，但像氨基酸一样，促进 mTOR 的细胞内定位到也包含其激活剂 Rheb 的隔室。
The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins - a family of four related small guanosine triphosphatases (GTPases)-interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.