Phosphatase Subfamily TIGAR
TIGAR inhibits glycolysis and negatively modulates the level of intracellular reactive oxygen species (ROS), therefore regulating autophagy and apoptosis. TIGAR is found in chordates some basal eumetazoan, but is absent from nematodes and arthropoda.
TIGAR is found in chordates and some basal eumetazoa, but is absent from nematodes and arthropods.
TIGAR has a single domain: HP1 phosphatase domain.
TIGAR stands for TP53 Induced Glycolysis and Apoptosis Regulatory phosphatase . It inhibits glycolysis, resulting in higher intracellular NADPH, lower reactive oxygen species (ROS) and therefore autophagic response [1, 2]. It also inhibits apoptosis . It is not surprising that TIGAR is implicated in cancer, such as intestinal cancer .
TIGAR inhibits glycolysis by functioning as fructose- 2,6-bisphosphatase (Fru-2,6-BPase) [1, 5] and/or 23BPG (2,3-bisphosphoglycerate) . It is worthy pointing out that Fru-2,6-BP and 23BPG are the substrates of other HP genes. PFK2 (phosphofructokinase 2) of PFKFB subfamily, HP1 family functions as Fru-2,6-BPase, and the reported catalytic efficiency of TIGAR as an Fru-2,6-BPase is several orders of magnitude lower than that of PFK2. MINPP1 of HP2 family dephosphorylates 23BPG .
Under hypoxia, a fraction of TIGAR protein relocalized to mitochondria and formed a complex with hexokinase 2 (HK2), resulting in an increase in HK2 activity. The ability of TIGAR to function as a Fru-2,6-BPase was independent of HK2 binding and mitochondrial localization, although both of these activities can contribute to the full activity of TIGAR in limiting mitochondrial ROS levels and protecting from cell death .
- Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, and Vousden KH. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006 Jul 14;126(1):107-20. DOI:10.1016/j.cell.2006.05.036 |
- Bensaad K, Cheung EC, and Vousden KH. Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J. 2009 Oct 7;28(19):3015-26. DOI:10.1038/emboj.2009.242 |
- Xie JM, Li B, Yu HP, Gao QG, Li W, Wu HR, and Qin ZH. TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy. Cancer Res. 2014 Sep 15;74(18):5127-38. DOI:10.1158/0008-5472.CAN-13-3517 |
- Li H and Jogl G. Structural and biochemical studies of TIGAR (TP53-induced glycolysis and apoptosis regulator). J Biol Chem. 2009 Jan 16;284(3):1748-54. DOI:10.1074/jbc.M807821200 |
- Gerin I, Noël G, Bolsée J, Haumont O, Van Schaftingen E, and Bommer GT. Identification of TP53-induced glycolysis and apoptosis regulator (TIGAR) as the phosphoglycolate-independent 2,3-bisphosphoglycerate phosphatase. Biochem J. 2014 Mar 15;458(3):439-48. DOI:10.1042/BJ20130841 |
- Cho J, King JS, Qian X, Harwood AJ, and Shears SB. Dephosphorylation of 2,3-bisphosphoglycerate by MIPP expands the regulatory capacity of the Rapoport-Luebering glycolytic shunt. Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):5998-6003. DOI:10.1073/pnas.0710980105 |
- Cheung EC, Ludwig RL, and Vousden KH. Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20491-6. DOI:10.1073/pnas.1206530109 |
- Cheung EC, Athineos D, Lee P, Ridgway RA, Lambie W, Nixon C, Strathdee D, Blyth K, Sansom OJ, and Vousden KH. TIGAR is required for efficient intestinal regeneration and tumorigenesis. Dev Cell. 2013 Jun 10;25(5):463-77. DOI:10.1016/j.devcel.2013.05.001 |