title: Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1.
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.
authors.affiliation: 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.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Chang-Liang
authors.initials: CL
authors.lastname: He
authors.affiliation: Chinese Academy of Sciences, Dalian Institute Chemical Physics, National Chromatography R&A Center, Key Lab Separation Science Analytic Chemistry, Dalian 116023, P.R. China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Bian
authors.affiliation: Department of Medical Engineering, College of Life Sciences and Technology, Huazhong University of Science and Technology, Wuhan 430074, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Medical Engineering, College of Life Sciences and Technology, Huazhong University of Science and Technology, Wuhan 430074, P.R. China.
authors.forename: Ze-Xian
authors.initials: ZX
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Kai-Qiang
authors.initials: KQ
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Cui-Fang
authors.initials: CF
authors.lastname: Yao
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Chinese Academy of Sciences, Dalian Institute Chemical Physics, National Chromatography R&A Center, Key Lab Separation Science Analytic Chemistry, Dalian 116023, P.R. China.
authors.forename: Han-Fa
authors.initials: HF
authors.lastname: Zou
authors.affiliation: Department of Pathology, Affiliated Ruijin Hospital of Shanghai Jiaotong University, Shanghai, 201821 P.R. China.
authors.forename: Fang-Xiu
authors.initials: FX
authors.lastname: Luo
authors.affiliation: Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China.|Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Qu
authors.affiliation: State Key Lab of Genetic Engineering, Obstetrics &Gynecology Hospital of Fudan University and School of Life Sciences, Shanghai 200090, P.R. China.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Jian-Yuan
authors.initials: JY
authors.lastname: Zhao
authors.affiliation: Chinese Academy of Sciences, Dalian Institute Chemical Physics, National Chromatography R&A Center, Key Lab Separation Science Analytic Chemistry, Dalian 116023, P.R. China.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: Ye
authors.affiliation: 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.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Shi-Min
authors.initials: SM
authors.lastname: Zhao
authors.affiliation: 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.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D001343:Autophagy / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D013963:Thyroid Hormones / Q000096:biosynthesis / Q000235:genetics*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C484523:AKT1S1 protein, human