title: Identification of TP53-induced glycolysis and apoptosis regulator (TIGAR) as the phosphoglycolate-independent 2,3-bisphosphoglycerate phosphatase.
abstract: The p53-induced protein TIGAR [TP53 (tumour protein 53)-induced glycolysis and apoptosis regulator] is considered to be a F26BPase (fructose-2,6-bisphosphatase) with an important role in cancer cell metabolism. The reported catalytic efficiency of TIGAR as an F26BPase is several orders of magnitude lower than that of the F26BPase component of liver or muscle PFK2 (phosphofructokinase 2), suggesting that F26BP (fructose 2,6-bisphosphate) might not be the physiological substrate of TIGAR. We therefore set out to re-evaluate the biochemical function of TIGAR. Phosphatase activity of recombinant human TIGAR protein was tested on a series of physiological phosphate esters. The best substrate was 23BPG (2,3-bisphosphoglycerate), followed by 2PG (2-phosphoglycerate), 2-phosphoglycolate and PEP (phosphoenolpyruvate). In contrast the catalytic efficiency for F26BP was approximately 400-fold lower than that for 23BPG. Using genetic and shRNA-based cell culture models, we show that loss of TIGAR consistently leads to an up to 5-fold increase in the levels of 23BPG. Increases in F26BP levels were also observed, albeit in a more limited and cell-type dependent manner. The results of the present study challenge the concept that TIGAR acts primarily on F26BP. This has significant implications for our understanding of the metabolic changes downstream of p53 as well as for cancer cell metabolism in general. It also suggests that 23BPG might play an unrecognized function in metabolic control.
authors.affiliation: *WELBIO and the Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Bruxelles, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gerin
authors.affiliation: *WELBIO and the Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Bruxelles, Belgium.
authors.forename: Gaëtane
authors.initials: G
authors.lastname: Noël
authors.affiliation: *WELBIO and the Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Bruxelles, Belgium.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bolsée
authors.affiliation: *WELBIO and the Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Bruxelles, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Haumont
authors.affiliation: *WELBIO and the Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Bruxelles, Belgium.
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
authors.affiliation: *WELBIO and the Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, 1200 Bruxelles, Belgium.
authors.forename: Guido T
authors.initials: GT
authors.lastname: Bommer
mesh_terms: D019794:2,3-Diphosphoglycerate / Q000737:chemistry; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006016:Glycolates / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013379:Substrate Specificity; D014158:Transcription, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; D006016:Glycolates; D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; C019794:bisphosphoglycerate phosphatase; D019794:2,3-Diphosphoglycerate; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; C013193:phosphoglycolate