mTORC1型
生物
氨基酸
精氨酸
亮氨酸
生物化学
胞浆
细胞生物学
溶酶体
激活剂(遗传学)
蛋白质水解
氨基酸转运体
信号转导
运输机
酶
基因
PI3K/AKT/mTOR通路
作者
Gregory A. Wyant,Monther Abu-Remaileh,Rachel L. Wolfson,Walter W. Chen,Elizaveta Freinkman,Laura V. Danai,Matthew G. Vander Heiden,David M. Sabatini
出处
期刊:Cell
[Cell Press]
日期:2017-10-01
卷期号:171 (3): 642-654.e12
被引量:409
标识
DOI:10.1016/j.cell.2017.09.046
摘要
The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth.
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