Nicklin Paul, Bergman Philip, Zhang Bailin, Triantafellow Ellen, Wang Henry, Nyfeler Beat, Yang Haidi, Hild Marc, Kung Charles, Wilson Christopher, Myer Vic E, MacKeigan Jeffrey P, Porter Jeffrey A, Wang Y Karen, Cantley Lewis C, Finan Peter M, Murphy Leon O
Respiratory Diseases Area, Novartis Institutes for BioMedical Research, Novartis Horsham Research Centre, West Sussex, UK.
Cell. 2009 Feb 6;136(3):521-34. doi: 10.1016/j.cell.2008.11.044.
Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.
氨基酸是激活雷帕霉素哺乳动物靶蛋白（mTOR）激酶所必需的，该激酶调节蛋白质翻译、细胞生长和自噬。目前尚不清楚允许氨基酸进入细胞并向mTOR发出信号的细胞表面转运体。我们发现，L-谷氨酰胺的细胞摄取及其在必需氨基酸（EAA）存在下随后的快速流出是激活mTOR的限速步骤。L-谷氨酰胺的摄取受SLC1A5调节，SLC1A5功能丧失会抑制细胞生长并激活自噬。L-谷氨酰胺敏感性的分子基础归因于SLC7A5/SLC3A2，这是一种双向转运体，可调节L-谷氨酰胺从细胞中同时流出以及L-亮氨酸/EAA进入细胞的转运。某些基础细胞L-谷氨酰胺水平较高的肿瘤细胞系无需摄取L-谷氨酰胺，并已准备好激活mTOR。因此，L-谷氨酰胺通量调节mTOR、翻译和自噬，以协调细胞生长和增殖。
