title: Pyruvate kinase M2 is a phosphotyrosine-binding protein.
abstract: Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.
authors.affiliation: Department of Systems Biology.
authors.forename: Heather R
authors.initials: HR
authors.lastname: Christofk
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D000495:Allosteric Site; D000818:Animals; D002384:Catalysis; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002477:Cells / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D019151:Peptide Library; D019000:Phosphotyrosine / Q000378:metabolism*; D011485:Protein Binding; D040901:Proteomics; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D019151:Peptide Library; D019000:Phosphotyrosine; D011770:Pyruvate Kinase; D008239:Lysine