Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells.
Cell proliferation only proceeds when metabolism is capable of providing a budget of metabolic intermediates that is adequate to ensure both energy regeneration and the synthesis of cell building blocks in sufficient amounts. In tumor cells, the glycolytic pyruvate kinase isoenzyme M2 (PKM2, M2-PK) determines whether glucose is converted to lactate for regeneration of energy (active tetrameric form, Warburg effect) or used for the synthesis of cell building blocks (nearly inactive dimeric form). This review discusses the regulation mechanisms of pyruvate kinase M2 expression by different transcription factors as well as the regulation of pyruvate kinase M2 activity by direct interaction with certain oncoproteins, tyrosine and serine phosphorylation, binding of phosphotyrosine peptides, association with other glycolytic and non glycolytic enzymes, the promyelocytic leukemia tumor suppressor protein, as well as metabolic intermediates. An intervention in the regulation mechanisms of the expression, activity and tetramer to dimer ratio of pyruvate kinase M2 has severe consequences for metabolism as well as proliferation and tumorigenic capacity of the cells which makes this enzyme a promising target for potential therapeutic approaches. The quantification of the dimeric form of pyruvate kinase M2 (Tumor M2-PK) in plasma and stool allows early detection of tumors and therapy control. Several different mechanisms may induce a translocation of pyruvate kinase M2 into the nucleus. The role of pyruvate kinase M2 in the nucleus is complex as witnessed by evidence of its effect both as pro-proliferative as well as pro-apoptotic stimuli.
Institute of Biochemistry & Endocrinology, Veterinary Medicine, University of Giessen, Giessen, Germany. Sybille.Mazurek@vetmed.uni-giessen.de
Sybille
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Mazurek
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism*; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; D007527:Isoenzymes; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; D015513:Oncogene Proteins; C494173:POU5F1 protein, human; D025521:Tumor Suppressor Proteins; D005973:Glutamine; D011770:Pyruvate Kinase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose