Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation

Jiangbin Ye, Anthony Mancuso, Xuemei Tong, Patrick S. Ward, Jing Fan, Joshua D. Rabinowitz, Craig B. Thompson

Research output: Contribution to journalArticlepeer-review

322 Scopus citations

Abstract

Despite the fact that most cancer cells display high glycolytic activity, cancer cells selectively express the less active M2 isoform of pyruvate kinase (PKM2). Here we demonstrate that PKM2 expression makes a critical regulatory contribution to the serine synthetic pathway. In the absence of serine, an allosteric activator of PKM2, glycolytic efflux to lactate is significantly reduced in PKM2-expressing cells. This inhibition of PKM2 results in the accumulation of glycolytic intermediates that feed into serine synthesis. As a consequence, PKM2-expressing cells can maintain mammalian target of rapamycin complex 1 activity and proliferate in serine-depleted medium, but PKM1-expressing cells cannot. Cellular detection of serine depletion depends on general control nonderepressible 2 kinase-activating transcription factor 4 (GCN2-ATF4) pathway activation and results in increased expression of enzymes required for serine synthesis from the accumulating glycolytic precursors. These findings suggest that tumor cells use serine-dependent regulation of PKM2 and GCN2 to modulate the flux of glycolytic intermediates in support of cell proliferation.

Original languageEnglish (US)
Pages (from-to)6904-6909
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number18
DOIs
StatePublished - May 1 2012

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Amino acid synthesis
  • Glucose
  • Metabolism
  • Nucleotide biosynthesis

Fingerprint

Dive into the research topics of 'Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation'. Together they form a unique fingerprint.

Cite this