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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jiangbin
authors.initials: J
authors.lastname: Ye
authors.forename: Anthony
authors.initials: A
authors.lastname: Mancuso
authors.forename: Xuemei
authors.initials: X
authors.lastname: Tong
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Ward
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006019:Glycolysis; D006801:Humans; D007700:Kinetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000096:biosynthesis*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: C497109:ATF4 protein, human; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D051701:Activating Transcription Factor 4; D012694:Serine; D011770:Pyruvate Kinase; C529271:EIF2AK4 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases