Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation Journal Article
| Authors: | Ye, J.; Mancuso, A.; Tong, X.; Ward, P. S.; Fan, J.; Rabinowitz, J. D.; Thompson, C. B. |
| Article Title: | Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation |
| 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. |
| Keywords: | signal transduction; controlled study; protein expression; protein phosphorylation; unclassified drug; human cell; nonhuman; cell proliferation; proteins; mouse; metabolism; mammalia; animals; mice; models, biological; cell growth; serine; rna, small interfering; cancer cell culture; in vitro study; enzyme activity; cell line, tumor; carcinogenesis; kinetics; protein-serine-threonine kinases; tumor cell; glucose; upregulation; activating transcription factor 4; glycolysis; enzyme; mammalian target of rapamycin complex 1; amino acid synthesis; initiation factor 2alpha; nucleotide biosynthesis; pyruvate kinase; pyruvate kinase m2; general control nonderepressible kinase 2 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 109 |
| Issue: | 18 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2012-05-01 |
| Start Page: | 6904 |
| End Page: | 6909 |
| Language: | English |
| DOI: | 10.1073/pnas.1204176109 |
| PROVIDER: | scopus |
| PMCID: | PMC3345000 |
| PUBMED: | 22509023 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus" |
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