Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Ye, J., Mancuso, A., Tong, X., Ward, P., S., Fan, J., Rabinowitz, J., D., & Thompson, C., B. Proceedings of the National Academy of Sciences of the United States of America, 109(18):6904-9, 5, 2012.
Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. [link]Website  abstract   bibtex   
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.
@article{
 title = {Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation.},
 type = {article},
 year = {2012},
 identifiers = {[object Object]},
 keywords = {Activating Transcription Factor 4,Activating Transcription Factor 4: metabolism,Animals,Cell Line, Tumor,Cell Proliferation,Glycolysis,Humans,Kinetics,Mice,Models, Biological,Multiprotein Complexes,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: metabolism,Proteins,Proteins: metabolism,Pyruvate Kinase,Pyruvate Kinase: antagonists & inhibitors,Pyruvate Kinase: genetics,Pyruvate Kinase: metabolism,RNA, Small Interfering,RNA, Small Interfering: genetics,Serine,Serine: biosynthesis,Signal Transduction,TOR Serine-Threonine Kinases},
 pages = {6904-9},
 volume = {109},
 websites = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3345000&tool=pmcentrez&rendertype=abstract},
 month = {5},
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 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.},
 bibtype = {article},
 author = {Ye, Jiangbin and Mancuso, Anthony and Tong, Xuemei and Ward, Patrick S and Fan, Jing and Rabinowitz, Joshua D and Thompson, Craig B},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {18}
}

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