Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake
Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake
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DOI：
10.1091/mbc.01-12-0584
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发表时间：
2002-07-01
影响因子：
3.3
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Edinger, AL;Thompson, CB
在多细胞生物中，组成细胞的生长、增殖和存活依赖于细胞外信号。当细胞失去生长因子时，它们会发生凋亡。丝氨酸/苏氨酸激酶Akt/PKB组成型活性形式的表达能够在生长因子缺失的情况下阻止细胞凋亡。Akt介导的存活部分依赖于葡萄糖代谢的维持，这表明葡萄糖利用的减少有助于生长因子缺失诱导的死亡。然而，尚不清楚仅仅限制细胞获取细胞外葡萄糖是如何导致生长因子缺失后所观察到的代谢崩溃的。我们在此报道，生长因子缺失不仅导致葡萄糖表面转运蛋白的丢失，还导致氨基酸、低密度脂蛋白和铁的表面转运蛋白丢失。细胞外分子的转运蛋白和受体的这种协同下降造成了一种以萎缩和线粒体膜电位下降为特征的分解代谢状态。在缺乏生长因子的情况下，Akt的活化形式通过一种依赖mTOR的机制将这些转运蛋白维持在细胞表面。mTOR抑制剂雷帕霉素减少了Akt介导的细胞大小、线粒体膜电位和细胞存活的增加。这些结果表明，生长因子通过调节Akt和mTOR的活性，部分地通过调控细胞获取细胞外营养物质来控制细胞的生长和存活。
In multicellular organisms, constituent cells depend on extracellular signals for growth, proliferation, and survival. When cells are withdrawn from growth factors, they undergo apoptosis. Expression of constitutively active forms of the serine/threonine kinase Akt/PKB can prevent apoptosis upon growth factor withdrawal. Akt-mediated survival depends in part on the maintenance of glucose metabolism, suggesting that reduced glucose utilization contributes to growth factor withdrawal-induced death. However, it is unclear how restricting access to extracellular glucose alone would lead to the metabolic collapse observed after growth factor withdrawal. We report herein that growth factor withdrawal results in the loss of surface transporters for not only glucose but also amino acids, low-density lipoprotein, and iron. This coordinated decline in transporters and receptors for extracellular molecules creates a catabolic state characterized by atrophy and a decline in the mitochondrial membrane potential. Activated forms of Akt maintained these transporters on the cell surface in the absence of growth factor through an mTOR-dependent mechanism. The mTOR inhibitor rapamycin diminished Akt-mediated increases in cell size, mitochondrial membrane potential, and cell survival. These results suggest that growth factors control cellular growth and survival by regulating cellular access to extracellular nutrients in part by modulating the activity of Akt and mTOR.