Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1
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. The mTORC1 complex integrates growth factor signals with the nutrients signals to control cell growth and proliferation 1 . The availability of growth factors, free essential amino acids and glucose determines cell growth and proliferation. In cancer cells, mTORC1 is constitutively activated regardless the fluctuation of growth factors and nutrients 2,3 . This suggests that cancer cells may employ unique mechanism to activate mTORC1 and provide survival, and growth and proliferation advantages over normal cells. The mTORC1 is a major anabolic regulator that controls an array of macromolecule biosynthetic processes, such as protein translation, mRNA transcription, ribosome biogenesis, lipid biogenesis, autophagy, mitochondrial function and the immune response 4 . The activity of mTORC1 is sensitive to rapamycin, insulin, insulin like growth factor 1 (IGF1), oxygen and amino acids signals and is suppressed by AKT1 substrate 1 (AKT1S1) through binding to regulatory-associated protein of mTOR (raptor), a component of mTORC1 5,6 . Constitutively activation of mTORC1 in cancer cells not only ensure their switches from catabolic metabolism to anabolic metabolism that is required to sustain their unconstrained growth 7 , but also acquire other cancer-promoting consequences such as autophagy inhibition 8 . Oncogene mutations, such as in PI3K, Ras, Raf, growth factor receptor kinases and autocrine growth factors 9-11 , or inactivation of tumor suppressors such as PTEN, AMPK, TSC2, LKB1, NF1 12,13 are all found to be able to activate mTORC1. However, unique common mTORC1 activating mechanisms may exist since these mutations may not always exist in one type of cancers.