Amino acids activate mTOR Complex 1 via Ca2+/CaM signaling to hVps34
Amino acids activate mTOR Complex 1 via Ca2+/CaM signaling to hVps34
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DOI：
10.1016/j.cmet.2008.03.002
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发表时间：
2008-05-01
期刊：
影响因子：
29
通讯作者：
Thomas, George
中科院分区：
文献类型：
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作者：
Gulati, Pawan;Gaspers, Lawrence D.;Thomas, George
过量的循环氨基酸（AA）在特定的人类病理学中起着因果作用，包括肥胖和2型糖尿病。此外，肥胖和糖尿病是癌症发展的促成因素，最近的研究表明，这种联系部分是由哺乳动物雷帕霉素靶蛋白（mTOR）复合物1的AA活化介导的。AA似乎通过III类磷脂酰肌醇3-激酶（PI 3 K）或人空泡蛋白分选34（hVps 34）介导这种反应，而不是通过生长因子和激素使用的经典I类PI 3 K途径。在这里，我们表明AA诱导细胞内Ca 2+（[Ca 2 +]（i））的升高，这触发mTOR复合物1和hVps 34活化。我们证明了[Ca 2 +]（i）的升高增加了Ca 2 +/钙调蛋白（CaM）与hVps 34中进化上保守的基序的直接结合，该基序是脂质激酶活性和增加的mTOR复合物1信号传导所需的。这些发现对于将代谢紊乱与癌症进展联系起来的基本信号机制具有重要意义。
Excess levels of circulating amino acids (AAs) play a causal role in specific human pathologies, including obesity and type 2 diabetes. Moreover, obesity and diabetes are contributing factors in the development of cancer, with recent studies suggesting that this link is mediated in part by AA activation of mammalian target of rapamycin (mTOR) Complex 1. AAs appear to mediate this response through class III phosphatidylinositol 3-kinase (PI3K), or human vacuolar protein sorting 34 (hVps34), rather than through the canonical class I PI3K pathway used by growth factors and hormones. Here we show that AAs induce a rise in intracellular Ca2+ ([Ca2+](i)), which triggers mTOR Complex 1 and hVps34 activation. We demonstrate that the rise in [Ca2+](i) increases the direct binding of Ca2+/calmodulin (CaM) to an evolutionarily conserved motif in hVps34 that is required for lipid kinase activity and increased mTOR Complex 1 signaling. These findings have important implications regarding the basic signaling mechanisms linking metabolic disorders with cancer progression.