Pyruvate Kinase M2 Activates mTORC1 by Phosphorylating AKT1S1

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis*
  • Adaptor Proteins, Signal Transducing / genetics
  • Autophagy / genetics
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics*
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics*
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / genetics*
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics*
  • Thyroid Hormones / biosynthesis
  • Thyroid Hormones / genetics*

Substances

  • AKT1S1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt