mTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3β
mTOR complex 1 controls the nuclear localization and function of glycogen synthase kinase 3β
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DOI：
10.1074/jbc.ra118.002800
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发表时间：
2018-09-21
影响因子：
4.8
通讯作者：
Antonescu, Costin N.
中科院分区：
文献类型：
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作者：
Bautista, Stephen J.;Boras, Ivan;Antonescu, Costin N.
糖原合成酶激酶3 β（GSK 3 β）磷酸化，从而调节参与多种细胞功能的多种蛋白质底物。一些GSK 3 β底物，如c-Myc和Snail，是核转录因子，表明GSK 3 β功能可能通过其核定位来控制。在这里，使用ARPE-19和MDA-MB-231人类细胞系，我们发现mTOR复合物1（mTORC 1）的抑制导致GSK 3 β从胞质溶胶到细胞核的部分重新分布，并导致c-Myc和Snail水平的GSK 3 β依赖性降低。已知mTORC 1受代谢信号控制，例如受AMP活化蛋白激酶（AMPK）或氨基酸丰度控制，我们在此观察到AMPK活化或氨基酸缺失以mTORC 1依赖性方式促进GSK 3 β核定位。在几个不同的内膜隔室（包括溶酶体）上检测到GSK 3 β。一致地，通过RAS致癌基因家族成员7（Rab 7）的扰动破坏晚期内体/溶酶体导致GSK 3 β从溶酶体中丢失，并增强GSK 3 β核定位以及GSK 3 β依赖性c-Myc水平降低。这些发现表明，GSK 3 β的核定位和功能受到mTORC 1的抑制，并表明mTORC 1感知的代谢条件与控制细胞生物量产生的转录网络的GSK 3 β依赖性调节之间存在联系。
Glycogen synthase kinase 3 beta (GSK3 beta) phosphorylates and thereby regulates a wide range of protein substrates involved in diverse cellular functions. Some GSK3 beta substrates, such as c-Myc and Snail, are nuclear transcription factors, suggesting the possibility that GSK3 beta function is controlled through its nuclear localization. Here, using ARPE-19 and MDA-MB-231 human cell lines, we found that inhibition of mTOR complex 1 (mTORC1) leads to partial redistribution of GSK3 beta from the cytosol to the nucleus and to a GSK3 beta-dependent reduction of the levels of both c-Myc and Snail. mTORC1 is known to be controlled by metabolic cues, such as by AMP-activated protein kinase (AMPK) or amino acid abundance, and we observed here that AMPK activation or amino acid deprivation promotes GSK3 beta nuclear localization in an mTORC1-dependent manner. GSK3 beta was detected on several distinct endomembrane compartments, including lysosomes. Consistently, disruption of late endosomes/lysosomes through a perturbation of RAS oncogene family member 7 (Rab7) resulted in loss of GSK3 beta from lysosomes and in enhanced GSK3 beta nuclear localization as well as GSK3 beta-dependent reduction of c-Myc levels. These findings indicate that the nuclear localization and function of GSK3 beta is suppressed by mTORC1 and suggest a link between metabolic conditions sensed by mTORC1 and GSK3 beta-dependent regulation of transcriptional networks controlling cellular biomass production.