TIGAR_MOUSE
ID TIGAR_MOUSE Reviewed; 269 AA.
AC Q8BZA9;
DT 06-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=Fructose-2,6-bisphosphatase TIGAR {ECO:0000305};
DE EC=3.1.3.46 {ECO:0000250|UniProtKB:Q9NQ88};
DE AltName: Full=TP53-induced glycolysis and apoptosis regulator {ECO:0000250|UniProtKB:Q9NQ88};
DE AltName: Full=TP53-induced glycolysis regulatory phosphatase {ECO:0000312|MGI:MGI:2442752};
GN Name=Tigar {ECO:0000312|MGI:MGI:2442752};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Cerebellum, Egg, and Placenta;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=19131326; DOI=10.1074/mcp.m800451-mcp200;
RA Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.;
RT "Large scale localization of protein phosphorylation by use of electron
RT capture dissociation mass spectrometry.";
RL Mol. Cell. Proteomics 8:904-912(2009).
RN [3]
RP INDUCTION.
RX PubMed=20935145; DOI=10.1152/ajpheart.00250.2010;
RA Kimata M., Matoba S., Iwai-Kanai E., Nakamura H., Hoshino A., Nakaoka M.,
RA Katamura M., Okawa Y., Mita Y., Okigaki M., Ikeda K., Tatsumi T.,
RA Matsubara H.;
RT "p53 and TIGAR regulate cardiac myocyte energy homeostasis under hypoxic
RT stress.";
RL Am. J. Physiol. 299:H1908-H1916(2010).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, DISRUPTION PHENOTYPE, AND INDUCTION.
RX PubMed=22044588; DOI=10.1016/j.yjmcc.2011.10.008;
RA Hoshino A., Matoba S., Iwai-Kanai E., Nakamura H., Kimata M., Nakaoka M.,
RA Katamura M., Okawa Y., Ariyoshi M., Mita Y., Ikeda K., Ueyama T.,
RA Okigaki M., Matsubara H.;
RT "p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after
RT ischemia.";
RL J. Mol. Cell. Cardiol. 52:175-184(2012).
RN [6]
RP FUNCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=23726973; DOI=10.1016/j.devcel.2013.05.001;
RA Cheung E.C., Athineos D., Lee P., Ridgway R.A., Lambie W., Nixon C.,
RA Strathdee D., Blyth K., Sansom O.J., Vousden K.H.;
RT "TIGAR is required for efficient intestinal regeneration and
RT tumorigenesis.";
RL Dev. Cell 25:463-477(2013).
RN [7]
RP FUNCTION, INDUCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=24872551; DOI=10.1523/jneurosci.4655-13.2014;
RA Li M., Sun M., Cao L., Gu J.H., Ge J., Chen J., Han R., Qin Y.Y.,
RA Zhou Z.P., Ding Y., Qin Z.H.;
RT "A TIGAR-regulated metabolic pathway is critical for protection of brain
RT ischemia.";
RL J. Neurosci. 34:7458-7471(2014).
CC -!- FUNCTION: Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate
CC as well as fructose-1,6-bisphosphate (By similarity). Acts as a
CC negative regulator of glycolysis by lowering intracellular levels of
CC fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in
CC the pentose phosphate pathway (PPP) activation and NADPH production
CC (PubMed:23726973). Contributes to the generation of reduced glutathione
CC to cause a decrease in intracellular reactive oxygen species (ROS)
CC content, correlating with its ability to protect cells from oxidative
CC or metabolic stress-induced cell death (PubMed:23726973). Plays a role
CC in promoting protection against cell death during hypoxia by decreasing
CC mitochondria ROS levels in a HK2-dependent manner through a mechanism
CC that is independent of its fructose-bisphosphatase activity (By
CC similarity). In response to cardiac damage stress, mediates p53-induced
CC inhibition of myocyte mitophagy through ROS levels reduction and the
CC subsequent inactivation of BNIP3 (PubMed:22044588). Reduced mitophagy
CC results in an enhanced apoptotic myocyte cell death, and exacerbates
CC cardiac damage (PubMed:22044588). Plays a role in adult intestinal
CC regeneration; contributes to the growth, proliferation and survival of
CC intestinal crypts following tissue ablation (PubMed:23726973). Plays a
CC neuroprotective role against ischemic brain damage by enhancing PPP
CC flux and preserving mitochondria functions (PubMed:24872551). Protects
CC glioma cells from hypoxia- and ROS-induced cell death by inhibiting
CC glycolysis and activating mitochondrial energy metabolism and oxygen
CC consumption in a TKTL1-dependent and p53/TP53-independent manner. Plays
CC a role in cancer cell survival by promoting DNA repair through
CC activating PPP flux in a CDK5-ATM-dependent signaling pathway during
CC hypoxia and/or genome stress-induced DNA damage responses (By
CC similarity). Involved in intestinal tumor progression
CC (PubMed:23726973). {ECO:0000250|UniProtKB:Q9NQ88,
CC ECO:0000269|PubMed:22044588, ECO:0000269|PubMed:23726973,
CC ECO:0000269|PubMed:24872551}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=beta-D-fructose 2,6-bisphosphate + H2O = beta-D-fructose 6-
CC phosphate + phosphate; Xref=Rhea:RHEA:17289, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57634, ChEBI:CHEBI:58579; EC=3.1.3.46;
CC Evidence={ECO:0000250|UniProtKB:Q9NQ88};
CC -!- SUBUNIT: Interacts with HK2; the interaction increases hexokinase HK2
CC activity in a hypoxia- and HIF1A-dependent manner, resulting in the
CC regulation of mitochondrial membrane potential, thus increasing NADPH
CC production and decreasing intracellular ROS levels.
CC {ECO:0000250|UniProtKB:Q9NQ88}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24872551}. Nucleus
CC {ECO:0000250|UniProtKB:Q9NQ88}. Mitochondrion
CC {ECO:0000269|PubMed:24872551}. Note=Translocated to the mitochondria
CC during hypoxia in a HIF1A-dependent manner. Colocalizes with HK2 in the
CC mitochondria during hypoxia. Translocated to the nucleus during hypoxia
CC and/or genome stress-induced DNA damage responses in cancer cells (By
CC similarity). Translocation to the mitochondria is enhanced in ischemic
CC cortex after reperfusion and/or during oxygen and glucose deprivation
CC (OGD)/reoxygenation insult in primary neurons (PubMed:24872551).
CC {ECO:0000250|UniProtKB:Q9NQ88, ECO:0000269|PubMed:24872551}.
CC -!- TISSUE SPECIFICITY: Expressed in olfactory bulb, cerebellum, and cortex
CC (PubMed:24872551). Expressed in neurons and astrocytes
CC (PubMed:24872551) (at protein level). Expressed in intestinal crypt
CC (PubMed:23726973). {ECO:0000269|PubMed:23726973,
CC ECO:0000269|PubMed:24872551}.
CC -!- INDUCTION: Up-regulated by hypoxia in cardiac myocytes in a p53/TP53-
CC dependent manner (PubMed:20935145). Up-regulated in ischemic cortex
CC after reperfusion in a p53/TP5-independent manner (PubMed:24872551).
CC Up-regulated in primary neurons by oxygen and glucose deprivation
CC (OGD)/reoxygenation insult in a p53/TP5-independent manner (at protein
CC level) (PubMed:24872551). Up-regulated in ischemic myocardium in a
CC p53/TP5-dependent manner (PubMed:22044588). Up-regulated in small
CC intestine after gamma irradiation damage (PubMed:23726973).
CC {ECO:0000269|PubMed:20935145, ECO:0000269|PubMed:22044588,
CC ECO:0000269|PubMed:23726973, ECO:0000269|PubMed:24872551}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable and fertile and show no obvious
CC developmental defects (PubMed:23726973). Following intestine ablation
CC by gamma irradiation, adult mice display a reduction in the size and
CC number of proliferating intestinal crypts and an increase in cell death
CC (PubMed:23726973). Mice display reduced intestinal tumor progression
CC compared to wild-type mice (PubMed:23726973). In response to ischemic
CC myocardium injury, display an increase in the ability to stimulate
CC myocyte mitophagy in ischemic border zones through a ROS-induced and
CC BNIP3 activation dependent manner leading to a reduction of defective
CC mitochondria and myocyte cell death, and hence a better recovery of
CC cardiac function (PubMed:22044588). {ECO:0000269|PubMed:22044588,
CC ECO:0000269|PubMed:23726973}.
CC -!- SIMILARITY: Belongs to the phosphoglycerate mutase family.
CC {ECO:0000305}.
CC -!- CAUTION: Not expected to have any kinase activity. {ECO:0000305}.
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DR EMBL; AK036082; BAC29298.1; -; mRNA.
DR EMBL; AK145896; BAE26732.1; -; mRNA.
DR EMBL; AK163290; BAE37278.1; -; mRNA.
DR CCDS; CCDS20563.1; -.
DR RefSeq; NP_795977.1; NM_177003.5.
DR AlphaFoldDB; Q8BZA9; -.
DR SMR; Q8BZA9; -.
DR STRING; 10090.ENSMUSP00000048643; -.
DR iPTMnet; Q8BZA9; -.
DR PhosphoSitePlus; Q8BZA9; -.
DR EPD; Q8BZA9; -.
DR MaxQB; Q8BZA9; -.
DR PaxDb; Q8BZA9; -.
DR PRIDE; Q8BZA9; -.
DR ProteomicsDB; 262782; -.
DR Antibodypedia; 22261; 394 antibodies from 37 providers.
DR DNASU; 319801; -.
DR Ensembl; ENSMUST00000039913; ENSMUSP00000048643; ENSMUSG00000038028.
DR GeneID; 319801; -.
DR KEGG; mmu:319801; -.
DR UCSC; uc009dvq.2; mouse.
DR CTD; 57103; -.
DR MGI; MGI:2442752; Tigar.
DR VEuPathDB; HostDB:ENSMUSG00000038028; -.
DR eggNOG; KOG0235; Eukaryota.
DR GeneTree; ENSGT00390000013224; -.
DR HOGENOM; CLU_033323_16_0_1; -.
DR InParanoid; Q8BZA9; -.
DR OMA; YMRNWIG; -.
DR OrthoDB; 1112626at2759; -.
DR PhylomeDB; Q8BZA9; -.
DR TreeFam; TF329053; -.
DR BRENDA; 3.1.3.46; 3474.
DR Reactome; R-MMU-5628897; TP53 Regulates Metabolic Genes.
DR BioGRID-ORCS; 319801; 4 hits in 109 CRISPR screens.
DR PRO; PR:Q8BZA9; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q8BZA9; protein.
DR Bgee; ENSMUSG00000038028; Expressed in knee joint and 212 other tissues.
DR ExpressionAtlas; Q8BZA9; baseline and differential.
DR Genevisible; Q8BZA9; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0004083; F:bisphosphoglycerate 2-phosphatase activity; ISS:UniProtKB.
DR GO; GO:0004331; F:fructose-2,6-bisphosphate 2-phosphatase activity; IMP:MGI.
DR GO; GO:0010659; P:cardiac muscle cell apoptotic process; IMP:MGI.
DR GO; GO:0071279; P:cellular response to cobalt ion; ISO:MGI.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; ISS:UniProtKB.
DR GO; GO:0030388; P:fructose 1,6-bisphosphate metabolic process; ISS:UniProtKB.
DR GO; GO:0006003; P:fructose 2,6-bisphosphate metabolic process; IMP:MGI.
DR GO; GO:0019661; P:glucose catabolic process to lactate via pyruvate; IMP:MGI.
DR GO; GO:0006096; P:glycolytic process; IDA:MGI.
DR GO; GO:0060576; P:intestinal epithelial cell development; IMP:MGI.
DR GO; GO:0000423; P:mitophagy; IMP:MGI.
DR GO; GO:1904024; P:negative regulation of glucose catabolic process to lactate via pyruvate; IMP:MGI.
DR GO; GO:0045820; P:negative regulation of glycolytic process; IDA:MGI.
DR GO; GO:0033673; P:negative regulation of kinase activity; IC:MGI.
DR GO; GO:1901525; P:negative regulation of mitophagy; IMP:MGI.
DR GO; GO:1901215; P:negative regulation of neuron death; IDA:UniProtKB.
DR GO; GO:0043069; P:negative regulation of programmed cell death; ISS:UniProtKB.
DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IMP:MGI.
DR GO; GO:0010666; P:positive regulation of cardiac muscle cell apoptotic process; IMP:MGI.
DR GO; GO:0045739; P:positive regulation of DNA repair; ISS:UniProtKB.
DR GO; GO:1903301; P:positive regulation of hexokinase activity; ISS:UniProtKB.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IMP:MGI.
DR GO; GO:0043456; P:regulation of pentose-phosphate shunt; ISS:UniProtKB.
DR GO; GO:1902153; P:regulation of response to DNA damage checkpoint signaling; ISS:UniProtKB.
DR GO; GO:0010332; P:response to gamma radiation; IMP:MGI.
DR GO; GO:0002931; P:response to ischemia; IDA:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IMP:MGI.
DR CDD; cd07067; HP_PGM_like; 1.
DR Gene3D; 3.40.50.1240; -; 1.
DR InterPro; IPR013078; His_Pase_superF_clade-1.
DR InterPro; IPR029033; His_PPase_superfam.
DR InterPro; IPR001345; PG/BPGM_mutase_AS.
DR Pfam; PF00300; His_Phos_1; 1.
DR SMART; SM00855; PGAM; 1.
DR SUPFAM; SSF53254; SSF53254; 1.
DR PROSITE; PS00175; PG_MUTASE; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Autophagy; Cytoplasm; Hydrolase; Mitochondrion; Nucleus;
KW Reference proteome.
FT CHAIN 1..269
FT /note="Fructose-2,6-bisphosphatase TIGAR"
FT /id="PRO_0000179958"
FT ACT_SITE 11
FT /note="Tele-phosphohistidine intermediate"
FT /evidence="ECO:0000250|UniProtKB:Q7ZVE3"
FT ACT_SITE 89
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q7ZVE3"
FT SITE 198
FT /note="Transition state stabilizer"
FT /evidence="ECO:0000250|UniProtKB:Q7ZVE3"
SQ SEQUENCE 269 AA; 29191 MW; D029B6E34226FE0E CRC64;
MPRFALTVIR HGETRLNKEK IIQGQGVDAP LSETGFRQAA AAGQFLSNVQ FTHAFSSDLT
RTKQTIHGIL EKSRFCKDMA VKYDSRLRER MYGVAEGKPL SELRAMAKAA GEECPMFTPP
GGETVEQVKM RGKDFFDFIC QLILGKAGQR ESVLPGAPGS GLESSLAEVF PVGKHGSLGA
NPKGGTLGLA ASILVVSHGA YMRSLFGYFL SDLRCSLPGA RDKLELSSIT PNTGISVFII
DCEEARQPSI QCVCMNLQEH LNGVTEKQH
