Regulation of mTORC1 signaling by pH.
Regulation of mTORC1 signaling by pH.
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DOI：
10.1371/journal.pone.0021549
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Roberge M
中科院分区：
文献类型：
--
作者：
Balgi AD;Diering GH;Donohue E;Lam KK;Fonseca BD;Zimmerman C;Numata M;Roberge M
细胞质和细胞外环境的酸化与许多生理和病理状况相关，例如剧烈运动、缺氧和肿瘤发生。酸化影响重要的细胞功能，包括蛋白质合成、生长和增殖。这些重要功能中的许多由mTORC1控制，mTORC1是一种主要的调节性蛋白激酶，它被各种生长刺激信号激活，并在饥饿条件下失活。mTORC1是否也能对细胞外或细胞质pH的变化作出反应，并在酸性条件下在限制合成代谢过程中发挥作用尚不清楚。
我们研究了将细胞外培养基的pH从7.4酸化到6.4对人乳腺癌MCF - 7细胞和永生化小鼠胚胎成纤维细胞的影响。通过测量mTORC1底物S6K的磷酸化来评估，降低细胞外pH会导致细胞内酸化以及对mTORC1快速、分级且可逆的抑制。缺失结节性硬化复合物TSC2基因（mTORC1的一个主要负调节因子）的成纤维细胞在酸性细胞外条件下无法抑制mTORC1，这表明TSC1 - TSC2复合物是这种反应所必需的。对汇聚到TSC1 - TSC2复合物的主要上游通路的研究表明，Akt信号不受pH影响，但Raf/MEK/ERK通路受到抑制。用药物抑制MEK仅导致适度的mTORC1抑制，这意味着其他未确定的通路也起主要作用。
这项研究揭示了TSC1/TSC2复合物和mTORC1在感知环境pH变化方面的一种新作用。作为组织灌注低、葡萄糖可利用性低和能量消耗高的一个共同特征，酸性pH可能作为mTORC1的一个信号，下调诸如蛋白质合成等耗能的合成代谢过程，作为对代谢应激条件的一种适应性反应。
Acidification of the cytoplasm and the extracellular environment is associated with many physiological and pathological conditions, such as intense exercise, hypoxia and tumourigenesis. Acidification affects important cellular functions including protein synthesis, growth, and proliferation. Many of these vital functions are controlled by mTORC1, a master regulator protein kinase that is activated by various growth-stimulating signals and inactivated by starvation conditions. Whether mTORC1 can also respond to changes in extracellular or cytoplasmic pH and play a role in limiting anabolic processes in acidic conditions is not known. We examined the effects of acidifying the extracellular medium from pH 7.4 to 6.4 on human breast carcinoma MCF-7 cells and immortalized mouse embryo fibroblasts. Decreasing the extracellular pH caused intracellular acidification and rapid, graded and reversible inhibition of mTORC1, assessed by measuring the phosphorylation of the mTORC1 substrate S6K. Fibroblasts deleted of the tuberous sclerosis complex TSC2 gene, a major negative regulator of mTORC1, were unable to inhibit mTORC1 in acidic extracellular conditions, showing that the TSC1–TSC2 complex is required for this response. Examination of the major upstream pathways converging on the TSC1–TSC2 complex showed that Akt signaling was unaffected by pH but that the Raf/MEK/ERK pathway was inhibited. Inhibition of MEK with drugs caused only modest mTORC1 inhibition, implying that other unidentified pathways also play major roles. This study reveals a novel role for the TSC1/TSC2 complex and mTORC1 in sensing variations in ambient pH. As a common feature of low tissue perfusion, low glucose availability and high energy expenditure, acidic pH may serve as a signal for mTORC1 to downregulate energy-consuming anabolic processes such as protein synthesis as an adaptive response to metabolically stressful conditions.
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影响因子：
0.9
作者：
Hall, M N
通讯作者：
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影响因子：
3.7
作者：
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