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丙酮酸激酶M2通过磷酸化AKT1S1激活mTORC1。

Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.

作者信息

He Chang-Liang, Bian Yang-Yang, Xue Yu, Liu Ze-Xian, Zhou Kai-Qiang, Yao Cui-Fang, Lin Yan, Zou Han-Fa, Luo Fang-Xiu, Qu Yuan-Yuan, Zhao Jian-Yuan, Ye Ming-Liang, Zhao Shi-Min, Xu Wei

机构信息

State Key Lab of Genetic Engineering, Obstetrics &Gynecology Hospital of Fudan University and School of Life Sciences, Shanghai 200090, P.R. China.

Institutes of Biomedical Sciences and Collaborative Innovation Center for Genetics and Development Biology, Fudan University, Shanghai 200032, P.R. China.

出版信息

Sci Rep. 2016 Feb 15;6:21524. doi: 10.1038/srep21524.

DOI:10.1038/srep21524
PMID:26876154
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4753445/
Abstract

In cancer cells, the mammalian target of rapamycin complex 1 (mTORC1) that requires hormonal and nutrient signals for its activation, is constitutively activated. We found that overexpression of pyruvate kinase M2 (PKM2) activates mTORC1 signaling through phosphorylating mTORC1 inhibitor AKT1 substrate 1 (AKT1S1). An unbiased quantitative phosphoproteomic survey identified 974 PKM2 substrates, including serine202 and serine203 (S202/203) of AKT1S1, in the proteome of renal cell carcinoma (RCC). Phosphorylation of S202/203 of AKT1S1 by PKM2 released AKT1S1 from raptor and facilitated its binding to 14-3-3, resulted in hormonal- and nutrient-signals independent activation of mTORC1 signaling and led accelerated oncogenic growth and autophagy inhibition in cancer cells. Decreasing S202/203 phosphorylation by TEPP-46 treatment reversed these effects. In RCCs and breast cancers, PKM2 overexpression was correlated with elevated S202/203 phosphorylation, activated mTORC1 and inhibited autophagy. Our results provided the first phosphorylome of PKM2 and revealed a constitutive mTORC1 activating mechanism in cancer cells.

摘要

在癌细胞中，需要激素和营养信号来激活的哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）被组成性激活。我们发现丙酮酸激酶M2（PKM2）的过表达通过磷酸化mTORC1抑制剂AKT1底物1（AKT1S1）来激活mTORC1信号通路。一项无偏向性的定量磷酸化蛋白质组学研究在肾细胞癌（RCC）蛋白质组中鉴定出974个PKM2底物，包括AKT1S1的丝氨酸202和丝氨酸203（S202/203）。PKM2对AKT1S1的S202/203磷酸化使AKT1S1从猛禽蛋白（raptor）上释放，并促进其与14-3-3结合，导致mTORC1信号通路在不依赖激素和营养信号的情况下被激活，并导致癌细胞中致癌生长加速和自噬抑制。用TEPP-46处理降低S202/203磷酸化可逆转这些效应。在肾细胞癌和乳腺癌中，PKM2过表达与S202/203磷酸化升高、mTORC1激活和自噬抑制相关。我们的研究结果提供了PKM2的首个磷酸化蛋白质组，并揭示了癌细胞中一种组成性的mTORC1激活机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/14fce75cecaf/srep21524-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/138b16174130/srep21524-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/cdcb31640666/srep21524-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/fe092ac6e8c7/srep21524-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/689cc7009f09/srep21524-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/fe4c6193d760/srep21524-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/77715efdb4a5/srep21524-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/14fce75cecaf/srep21524-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/138b16174130/srep21524-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/cdcb31640666/srep21524-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/fe092ac6e8c7/srep21524-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/689cc7009f09/srep21524-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/fe4c6193d760/srep21524-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/77715efdb4a5/srep21524-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6b6f/4753445/14fce75cecaf/srep21524-f7.jpg

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