Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1

• Published in: Scientific reports Vol. 6; no. 1; p. 21524
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.02.2016; Nature Publishing Group
• Subjects: 13; 13/109; 13/51; 14; 14-3-3 protein; 14/63; 38; 38/1; 38/70; 38/77; 631/67/2327; 631/80/86; 82; 82/58; 82/80; 82/83; Adaptor Proteins, Signal Transducing - biosynthesis; Adaptor Proteins, Signal Transducing - genetics; AKT1 protein; Autophagy; Autophagy - genetics; Breast cancer; Cancer; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humanities and Social Sciences; Humans; Kidney cancer; Kinases; Mechanistic Target of Rapamycin Complex 1; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; multidisciplinary; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - genetics; Neoplasms - genetics; Neoplasms - pathology; Nutrients; Phagocytosis; Phosphorylation; Proteomes; Proto-Oncogene Proteins c-akt - genetics; Pyruvate kinase; Pyruvic acid; Rapamycin; Renal cell carcinoma; Science; Science (multidisciplinary); Signal Transduction - genetics; Thyroid Hormone-Binding Proteins; Thyroid Hormones - biosynthesis; Thyroid Hormones - genetics; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep21524

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.