Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, USA.
J Biol Chem. 2011 Jul 22;286(29):25477-86. doi: 10.1074/jbc.M111.249631. Epub 2011 May 28.
The mammalian target of rapamycin (mTOR) is a critical sensor of nutritional sufficiency. Although much is known about the regulation of mTOR in response to growth factors, much less is known about the regulation of mTOR in response to nutrients. Amino acids have no impact on the signals that regulate Rheb, a GTPase required for the activation of mTOR complex 1 (mTORC1). Phospholipase D (PLD) generates a metabolite, phosphatidic acid, that facilitates association between mTOR and the mTORC1 co-factor Raptor. We report here that elevated PLD activity in human cancer cells is dependent on both amino acids and glucose and that amino acid- and glucose-induced increases in mTORC1 activity are dependent on PLD. Amino acid- and glucose-induced PLD and mTORC1 activity were also dependent on the GTPases RalA and ARF6 and the type III phosphatidylinositol-3-kinase hVps34. Thus, a key stimulatory event for mTORC1 activation in response to nutrients is the generation of phosphatidic acid by PLD.
哺乳动物雷帕霉素靶蛋白（mTOR）是营养充足的关键传感器。尽管人们已经了解了 mTOR 对生长因子的反应调节，但对其对营养物质的反应调节知之甚少。氨基酸对调节雷帕霉素靶蛋白复合物 1（mTORC1）激活所需的 GTP 酶 Rheb 的信号没有影响。磷脂酶 D（PLD）产生代谢产物磷脂酸，促进 mTOR 与 mTORC1 共因子 Raptor 之间的结合。我们在这里报告，人癌细胞中升高的 PLD 活性既依赖于氨基酸又依赖于葡萄糖，并且氨基酸和葡萄糖诱导的 mTORC1 活性增加依赖于 PLD。氨基酸和葡萄糖诱导的 PLD 和 mTORC1 活性也依赖于 GTPases RalA 和 ARF6 以及 III 型磷脂酰肌醇-3-激酶 hVps34。因此，PLD 产生磷脂酸是 mTORC1 对营养物质激活的关键刺激事件。
