Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
J Biol Chem. 2010 Jun 25;285(26):19705-9. doi: 10.1074/jbc.C110.102483. Epub 2010 May 10.
The mammalian target of rapamycin (mTOR) is a key cell growth regulator, which forms two distinct functional complexes (mTORC1 and mTORC2). mTORC1, which is directly inhibited by rapamycin, promotes cell growth by stimulating protein synthesis and inhibiting autophagy. mTORC1 is regulated by a wide range of extra- and intracellular signals, including growth factors, nutrients, and energy levels. Precise regulation of mTORC1 is important for normal cellular physiology and development, and dysregulation of mTORC1 contributes to hypertrophy and tumorigenesis. In this study, we screened Drosophila small GTPases for their function in TORC1 regulation and found that TORC1 activity is regulated by members of the Rab and Arf family GTPases, which are key regulators of intracellular vesicle trafficking. In mammalian cells, uncontrolled activation of Rab5 and Arf1 strongly inhibit mTORC1 activity. Interestingly, the effect of Rab5 and Arf1 on mTORC1 is specific to amino acid stimulation, whereas glucose-induced mTORC1 activation is not blocked by Rab5 or Arf1. Similarly, active Rab5 selectively inhibits mTORC1 activation by Rag GTPases, which are involved in amino acid signaling, but does not inhibit the effect of Rheb, which directly binds and activates mTORC1. Our data demonstrate a key role of Rab and Arf family small GTPases and intracellular trafficking in mTORC1 activation, particularly in response to amino acids.
哺乳动物雷帕霉素靶蛋白（mTOR）是一种关键的细胞生长调节剂，它形成两个不同的功能复合物（mTORC1 和 mTORC2）。mTORC1 可被雷帕霉素直接抑制，通过刺激蛋白质合成和抑制自噬来促进细胞生长。mTORC1 受到多种细胞外和细胞内信号的调节，包括生长因子、营养物质和能量水平。mTORC1 的精确调节对正常细胞生理和发育至关重要，而 mTORC1 的失调导致肥大和肿瘤发生。在这项研究中，我们筛选了果蝇小 GTPases 在 TORC1 调节中的功能，发现 TORC1 活性受到 Rab 和 Arf 家族 GTPases 成员的调节，这些 GTPases 是细胞内囊泡运输的关键调节剂。在哺乳动物细胞中，Rab5 和 Arf1 的失控激活强烈抑制 mTORC1 活性。有趣的是，Rab5 和 Arf1 对 mTORC1 的影响是特定于氨基酸刺激的，而葡萄糖诱导的 mTORC1 激活不受 Rab5 或 Arf1 阻断。同样，活性 Rab5 选择性抑制 Rag GTPases 激活的 mTORC1，Rag GTPases 参与氨基酸信号转导，但不抑制直接结合并激活 mTORC1 的 Rheb 的作用。我们的数据表明 Rab 和 Arf 家族小 GTPases 和细胞内运输在 mTORC1 激活中起着关键作用，特别是在对氨基酸的反应中。
