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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells
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Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells

机译：TOR中的点突变赋予裂变酵母Rheb非依赖性生长和哺乳动物细胞中非营养素依赖性哺乳动物TOR信号转导

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摘要

Rheb is a unique member of the Ras superfamily GTP-binding proteins. We as well as others previously have shown that Rheb is a critical component of the TSC/TOR signaling pathway. In fission yeast, Rheb is encoded by the rhb1 gene. Rhb1p is essential for growth and directly interacts with Tor2p. In this article, we report identification of 22 single amino acid changes in the Tor2 protein that enable growth in the absence of Rhb1p. These mutants also exhibit decreased mating efficiency. Interestingly, the mutations are located in the C-terminal half of the Tor2 protein, clustering mainly within the FAT and kinase domains. We noted some differences in the effect of a mutation in the FAT domain (L1310P) and in the kinase domain (E2221K) on growth and mating. Although the Tor2p mutations bypass Rhb1p's requirement for growth, they are incapable of suppressing Rhb1p's requirement for resistance to stress and toxic amino acids, pointing to multiple functions of Rhb1p. In mammalian systems, we find that mammalian target of rapamycin (mTOR) carrying analogous mutations (L1460P or E2419K), although sensitive to rapamycin, exhibits constitutive activation even when the cells are starved for nutrients. These mutations do not show significant difference in their ability to form complexes with Raptor, Rictor, or mLST8. Furthermore, we present evidence that mutant mTOR can complex with wild-type mTOR and that this heterodimer is active in nutrient-starved cells.
机译：Rheb是Ras超家族GTP结合蛋白的独特成员。我们以及其他人以前已经表明，Rheb是TSC / TOR信号通路的关键组成部分。在裂变酵母中，Rheb由rhb1基因编码。 Rhb1p对生长至关重要，并与Tor2p直接相互作用。在本文中，我们报告了Tor2蛋白中22个单个氨基酸变化的鉴定，这些变化使Rhb1p不存在时能够生长。这些突变体还表现出降低的交配效率。有趣的是，这些突变位于Tor2蛋白的C端一半，主要聚集在FAT和激酶结构域内。我们注意到FAT结构域（L1310P）和激酶结构域（E2221K）突变对生长和交配的影响有些差异。尽管Tor2p突变绕过Rhb1p对生长的要求，但它们不能抑制Rhb1p对胁迫和有毒氨基酸的抗性，这表明Rhb1p具有多种功能。在哺乳动物系统中，我们发现带有类似突变（L1460P或E2419K）的雷帕霉素（mTOR）哺乳动物靶标，尽管对雷帕霉素敏感，但即使细胞缺乏营养，也表现出组成型激活。这些突变与Raptor，Rictor或mLST8形成复合物的能力没有显着差异。此外，我们目前提供的证据表明，突变体mTOR可以与野生型mTOR复合，并且这种异二聚体在营养缺乏的细胞中具有活性。

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