谷氨酰胺分解
mTORC1型
谷氨酰胺
生物
细胞生物学
生物化学
氨基酸
信号转导
PI3K/AKT/mTOR通路
作者
Raúl V. Durán,Wolfgang Oppliger,Aaron M. Robitaille,Lisa Heiserich,Roswitha Skendaj,Eyal Gottlieb,Michael N. Hall
出处
期刊:Molecular Cell
[Elsevier]
日期:2012-08-01
卷期号:47 (3): 349-358
被引量:557
标识
DOI:10.1016/j.molcel.2012.05.043
摘要
Amino acids control cell growth via activation of the highly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth control and metabolism. However, the role of glutamine in TORC1 activation remains poorly defined. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate. We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and α-ketoglutarate production. Inhibition of glutaminolysis prevented GTP loading of RagB and lysosomal translocation and subsequent activation of mTORC1. Constitutively active Rag heterodimer activated mTORC1 in the absence of glutaminolysis. Conversely, enhanced glutaminolysis or a cell-permeable α-ketoglutarate analog stimulated lysosomal translocation and activation of mTORC1. Finally, cell growth and autophagy, two processes controlled by mTORC1, were regulated by glutaminolysis. Thus, mTORC1 senses and is activated by glutamine and leucine via glutaminolysis and α-ketoglutarate production upstream of Rag. This may provide an explanation for glutamine addiction in cancer cells.
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