机构：[1]State Key Lab of Genetic Engineering, Obstetrics & Gynecology Hospital of Fudan University and School of Life Sciences, Shanghai 200090, PR.China[2]Institutes of Biomedical Sciences and Collaborative Innovation Center for Genetics and Development Biology, Fudan University, Shanghai 200032, P R.China[3]Chinese Academy of Sciences, Dalian Institute Chemical Physics, National Chromatography R&A Center, Key Lab Separation Science Analytic Chemistry, Dalian 116023, P R.China[4]Department of Medical Engineering, College of Life Sciences and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR.China[5]Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR.China四川大学华西医院[6]Department of Pathology, Affiliated Ruijin Hospital of Shanghai Jiaotong University, Shanghai, 201821 PR.China[7]Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, PR.China[8]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, PR.China
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.
基金：
This work was supported by the State Key Development Programs (973) of Basic Research of China (Nos.
2012CB910103, 2013CB531200, 2013CB945100, 2013CB911204, 2011CB503902), grants from the National
Science Foundation of China (Nos.31030042, 31330023, 81301717), International Cooperative grant from
Minister of Science and Technology (2014DFA30630) and Science and Technology Municipal Commission of
Shanghai (Nos. 12ZR1440800, 12JC1402700).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2016]版：
大类|2 区综合性期刊
小类|2 区综合性期刊
最新[2023]版：
大类|2 区综合性期刊
小类|2 区综合性期刊
第一作者：
第一作者机构：[1]State Key Lab of Genetic Engineering, Obstetrics & Gynecology Hospital of Fudan University and School of Life Sciences, Shanghai 200090, PR.China[2]Institutes of Biomedical Sciences and Collaborative Innovation Center for Genetics and Development Biology, Fudan University, Shanghai 200032, P R.China[3]Chinese Academy of Sciences, Dalian Institute Chemical Physics, National Chromatography R&A Center, Key Lab Separation Science Analytic Chemistry, Dalian 116023, P R.China
共同第一作者：
通讯作者：
通讯机构：[1]State Key Lab of Genetic Engineering, Obstetrics & Gynecology Hospital of Fudan University and School of Life Sciences, Shanghai 200090, PR.China[2]Institutes of Biomedical Sciences and Collaborative Innovation Center for Genetics and Development Biology, Fudan University, Shanghai 200032, P R.China[3]Chinese Academy of Sciences, Dalian Institute Chemical Physics, National Chromatography R&A Center, Key Lab Separation Science Analytic Chemistry, Dalian 116023, P R.China
推荐引用方式(GB/T 7714)：
He Chang-Liang,Bian Yang-Yang,Xue Yu,et al.Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.[J].Scientific reports.2016,6:21524.doi:10.1038/srep21524.
APA：
He Chang-Liang,Bian Yang-Yang,Xue Yu,Liu Ze-Xian,Zhou Kai-Qiang...&Xu Wei.(2016).Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1..Scientific reports,6,
MLA：
He Chang-Liang,et al."Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.".Scientific reports 6.(2016):21524
