Hk2

Summary

Gene Symbol: Hk2
Description: hexokinase 2
Alias: AI642394, HKII, hexokinase-2, HK II, hexokinase type II
Species: mouse
Products:     Hk2

Top Publications

  1. Tracy K, Dibling B, Spike B, Knabb J, Schumacker P, Macleod K. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol. 2007;27:6229-42 pubmed
    ..These studies identify BNIP3 as a key regulator of hypoxia-induced autophagy and suggest a novel role for the RB tumor suppressor in preventing nonapoptotic cell death by limiting the extent of BNIP3 induction in cells. ..
  2. Smeele K, Southworth R, Wu R, Xie C, Nederlof R, Warley A, et al. Disruption of hexokinase II-mitochondrial binding blocks ischemic preconditioning and causes rapid cardiac necrosis. Circ Res. 2011;108:1165-9 pubmed publisher
    Isoforms I and II of the glycolytic enzyme hexokinase (HKI and HKII) are known to associate with mitochondria...
  3. Wu R, Smeele K, Wyatt E, Ichikawa Y, Eerbeek O, Sun L, et al. Reduction in hexokinase II levels results in decreased cardiac function and altered remodeling after ischemia/reperfusion injury. Circ Res. 2011;108:60-9 pubmed publisher
    ..We sought to define how HKII and its binding to mitochondria play a role in cardiac response and remodeling after I/R...
  4. Mergenthaler P, Kahl A, Kamitz A, van Laak V, Stohlmann K, Thomsen S, et al. Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state. Proc Natl Acad Sci U S A. 2012;109:1518-23 pubmed publisher
    ..Here, we show that the hypoxia-inducible factor (HIF)-1-regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of ..
  5. Chiara F, Castellaro D, Marin O, Petronilli V, BRUSILOW W, Juhaszova M, et al. Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels. PLoS ONE. 2008;3:e1852 pubmed publisher
    ..These findings have profound implications for our understanding of the pathways of outer mitochondrial membrane permeabilization and their inactivation in tumors. ..
  6. Heikkinen S, Pietila M, Halmekyto M, Suppola S, Pirinen E, Deeb S, et al. Hexokinase II-deficient mice. Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes. J Biol Chem. 1999;274:22517-23 pubmed
    ..Mice homozygous for hexokinase II deficiency (HKII(-/-)) died at approximately 7...
  7. Fang R, Xiao T, Fang Z, Sun Y, Li F, Gao Y, et al. MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting hexokinase 2 gene. J Biol Chem. 2012;287:23227-35 pubmed publisher
    ..b>Hexokinase 2 (HK2), coding for the first rate-limiting enzyme of glycolysis, is among the top list of genes predicted and ..
  8. Fueger P, Heikkinen S, Bracy D, Malabanan C, Pencek R, Laakso M, et al. Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice. Am J Physiol Endocrinol Metab. 2003;285:E958-63 pubmed
    ..Because HK II overexpression augments exercise-stimulated MGU, it was hypothesized that a reduction in HK II activity would ..
  9. Roberts D, Tan Sah V, Smith J, Miyamoto S. Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes. J Biol Chem. 2013;288:23798-806 pubmed publisher
    ..This increase is, at least in part, due to the decreased sensitivity to G-6P-induced dissociation. Thus, phosphorylation-mediated regulation of mitochondrial HK-II would be a critical component of the protective effect of Akt. ..

More Information

Publications52

  1. Majewski N, Nogueira V, Bhaskar P, Coy P, Skeen J, Gottlob K, et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell. 2004;16:819-30 pubmed
  2. Fueger P, Shearer J, Krueger T, Posey K, Bracy D, Heikkinen S, et al. Hexokinase II protein content is a determinant of exercise endurance capacity in the mouse. J Physiol. 2005;566:533-41 pubmed
    ..In conclusion, adaptations that increase HK protein content and/or functional activity such as regular exercise contribute to increased muscular endurance. ..
  3. Fueger P, Lee Young R, Shearer J, Bracy D, Heikkinen S, Laakso M, et al. Phosphorylation barriers to skeletal and cardiac muscle glucose uptakes in high-fat fed mice: studies in mice with a 50% reduction of hexokinase II. Diabetes. 2007;56:2476-84 pubmed
    ..Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK(+/-))...
  4. Wilson G, Thibodeau B, Fortier L, Pruetz B, Galoforo S, Baschnagel A, et al. Glucose metabolism gene expression patterns and tumor uptake of ¹⁸F-fluorodeoxyglucose after radiation treatment. Int J Radiat Oncol Biol Phys. 2014;90:620-7 pubmed publisher
    ..the tumors were harvested for global gene expression analysis and immunohistochemical evaluation of GLUT1 and HK2. Different analytic parameters were used to process the dynamic PET data...
  5. McCommis K, Douglas D, Krenz M, Baines C. Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux. J Am Heart Assoc. 2013;2:e000355 pubmed publisher
    The enzyme hexokinase-2 (HK2) phosphorylates glucose, which is the initiating step in virtually all glucose utilization pathways...
  6. Taneja N, Coy P, Lee I, Bryson J, Robey R. Proinflammatory interleukin-1 cytokines increase mesangial cell hexokinase activity and hexokinase II isoform abundance. Am J Physiol Cell Physiol. 2004;287:C548-57 pubmed
    ..Changes in HK activity were associated with both increased Glc metabolism and selective increases in HKII isoform abundance...
  7. Lai L, Leone T, Zechner C, Schaeffer P, Kelly S, Flanagan D, et al. Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev. 2008;22:1948-61 pubmed publisher
    ..We conclude that PGC-1alpha and PGC-1beta share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT. ..
  8. Zhou H, Hu S, Jin Q, Shi C, Zhang Y, Zhu P, et al. Mff-Dependent Mitochondrial Fission Contributes to the Pathogenesis of Cardiac Microvasculature Ischemia/Reperfusion Injury via Induction of mROS-Mediated Cardiolipin Oxidation and HK2/VDAC1 Disassociation-Involved mPTP Opening. J Am Heart Assoc. 2017;6: pubmed publisher
    ..transition pore opening via blocking the oligomerization of voltage-dependent anion channel 1 and subsequent hexokinase 2 separation from mitochondria...
  9. Zhou H, Zhang Y, Hu S, Shi C, Zhu P, Ma Q, et al. Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis. J Pineal Res. 2017;63: pubmed publisher
    ..mitochondrial fission, which subsequently induced voltage-dependent anion channel 1 (VDAC1) oligomerization, hexokinase 2 (HK2) liberation, mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ..
  10. Lundgaard I, Li B, Xie L, Kang H, Sanggaard S, Haswell J, et al. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat Commun. 2015;6:6807 pubmed publisher
    ..These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identify the neuron as the principal locus of glucose uptake as visualized by functional brain imaging. ..
  11. Smeele K, Eerbeek O, Schaart G, Koeman A, Bezemer R, Nelson J, et al. Reduced hexokinase II impairs muscle function 2 wk after ischemia-reperfusion through increased cell necrosis and fibrosis. J Appl Physiol (1985). 2012;113:608-18 pubmed publisher
    ..Circ Res 108: 1165-1169, 2011; Wu et al. Circ Res 108: 60-69, 2011). However, it is unknown whether HKII also plays a key role in I/R injury and healing thereafter in skeletal muscle, and if so, through which mechanisms...
  12. Bhaskar P, Nogueira V, Patra K, Jeon S, Park Y, Robey R, et al. mTORC1 hyperactivity inhibits serum deprivation-induced apoptosis via increased hexokinase II and GLUT1 expression, sustained Mcl-1 expression, and glycogen synthase kinase 3beta inhibition. Mol Cell Biol. 2009;29:5136-47 pubmed publisher
    ..Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1...
  13. Nakagawa Y, Shimano H, Yoshikawa T, Ide T, Tamura M, Furusawa M, et al. TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes. Nat Med. 2006;12:107-13 pubmed
    ..TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1)...
  14. Chehtane M, Khaled A. Interleukin-7 mediates glucose utilization in lymphocytes through transcriptional regulation of the hexokinase II gene. Am J Physiol Cell Physiol. 2010;298:C1560-71 pubmed publisher
    ..We conclude that IL-7 controls glucose utilization by regulating the gene expression of HXKII, suggesting a mechanism by which IL-7 supports bioenergetics that control cell fate decisions in lymphocytes. ..
  15. Tsao T, Burcelin R, Charron M. Regulation of hexokinase II gene expression by glucose flux in skeletal muscle. J Biol Chem. 1996;271:14959-63 pubmed
    ..MLC-GLUT4 transgenic mice as a model, we investigated the effects of increased glucose flux on hexokinase II (HK II) gene expression in skeletal muscle...
  16. Weber J, Jang W, Simin K, Lu W, Yu J, Meisler M. High-resolution genetic, physical, and transcript map of the mnd2 region of mouse chromosome 6. Genomics. 1998;54:107-15 pubmed
    ..The genes described here are positional candidates for the Parkinson disease susceptibility locus PARK3 that was recently mapped to the corresponding region of human chromosome band 2p13.1. ..
  17. Nederlof R, Denis S, Lauzier B, Rosiers C, Laakso M, Hagen J, et al. Acute detachment of hexokinase II from mitochondria modestly increases oxygen consumption of the intact mouse heart. Metabolism. 2017;72:66-74 pubmed publisher
    Cardiac hexokinase II (HKII) can translocate between cytosol and mitochondria and change its cellular expression with pathologies such as ischemia-reperfusion, diabetes and heart failure...
  18. Smeele K, Ter Horst L, Koeman A, Heikkinen S, Laakso M, Weber N, et al. The effect of standard chow and reduced hexokinase II on growth, cardiac and skeletal muscle hexokinase and low-flow cardiac ischaemia-reperfusion injury. Lab Anim. 2011;45:160-6 pubmed publisher
    ..SDS versus Purina 5001; both low fat, high carbohydrate) and reductions in hexokinase (HK) II (wild-type versus HKII(+/-) mice) affect (1) growth parameters, (2) HK levels in cardiac and skeletal muscle and (3) low-flow cardiac ..
  19. Robey R, Ma J, Santos A, Noboa O, Coy P, Bryson J. Regulation of mesangial cell hexokinase activity and expression by heparin-binding epidermal growth factor-like growth factor: epidermal growth factors and phorbol esters increase glucose metabolism via a common mechanism involving classic mitogen-ac. J Biol Chem. 2002;277:14370-8 pubmed
    ..Both stimuli were associated with increased HK activity, selectively increased HKII isoform expression, and increased Glc metabolism via both the glycolytic-tricarboxylic acid cycle route and the ..
  20. Zaid H, Talior Volodarsky I, Antonescu C, Liu Z, Klip A. GAPDH binds GLUT4 reciprocally to hexokinase-II and regulates glucose transport activity. Biochem J. 2009;419:475-84 pubmed publisher
    ..with Myc-tagged GLUT4 from L6 myotubes, including GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and HKII (hexokinase-II)...
  21. Arzoine L, Zilberberg N, Ben Romano R, Shoshan Barmatz V. Voltage-dependent anion channel 1-based peptides interact with hexokinase to prevent its anti-apoptotic activity. J Biol Chem. 2009;284:3946-55 pubmed publisher
    ..Moreover, VDAC1-based peptides interfering with HK-mediated anti-apoptotic activity may potentiate the efficacy of conventional chemotherapeutic agents. ..
  22. Roberts D, Tan Sah V, Ding E, Smith J, Miyamoto S. Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell. 2014;53:521-33 pubmed publisher
    ..We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy, based on plentiful energy, to one of conservation, under starvation. ..
  23. An M, Li S, Yao H, Li C, Wang J, Sun J, et al. BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells. J Cell Biol. 2017;216:4091-4105 pubmed publisher
    ..Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level...
  24. Gall J, Wong V, Pimental D, Havasi A, Wang Z, Pastorino J, et al. Hexokinase regulates Bax-mediated mitochondrial membrane injury following ischemic stress. Kidney Int. 2011;79:1207-16 pubmed publisher
    ..ATP depletion led to a progressive HK II dissociation from mitochondria, released mitochondrial apoptosis inducing factor and cytochrome c into the cytosol,..
  25. Smeele K, Eerbeek O, Koeman A, Bezemer R, Ince C, Heikkinen S, et al. Partial hexokinase II knockout results in acute ischemia-reperfusion damage in skeletal muscle of male, but not female, mice. Pflugers Arch. 2010;459:705-12 pubmed publisher
    ..Male and female heterozygote knockout HKII (HK(+/-)), heterozygote overexpressed HKII (HK(tg)), and their wild-type (WT) C57Bl/6 littermates mice were ..
  26. Yao M, Wang X, Tang Y, Zhang W, Cui B, Liu Q, et al. Dicer mediating the expression of miR-143 and miR-155 regulates hexokinase II associated cellular response to hypoxia. Am J Physiol Lung Cell Mol Physiol. 2014;307:L829-37 pubmed publisher
    ..It has been shown recently that miR-143, which can directly target the key glycolytic enzyme hexokinase II (HK2), may be regulated by miR-155...
  27. Cinelli P, Casanova E, Uhlig S, Lochmatter P, Matsuda T, Yokota T, et al. Expression profiling in transgenic FVB/N embryonic stem cells overexpressing STAT3. BMC Dev Biol. 2008;8:57 pubmed publisher
    ..Two of them, Pem/Rhox5 and Pramel7, when overexpressed in ES cells are able to maintain the embryonic stem cells in a pluripotent state in a LIF independent manner as STAT3 or Nanog. ..
  28. Leite T, Coelho R, Da Silva D, Coelho W, Marinho Carvalho M, Sola Penna M. Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. FEBS Lett. 2011;585:92-8 pubmed publisher
    ..PK activity was not affected by lactate. The activity of HK and PFK is directly related to glucose metabolism. Thus, it is conceivable that lactate exposure can induce inhibition of glucose consumption in tissues. ..
  29. Lantier L, Williams A, Williams I, Yang K, Bracy D, Goelzer M, et al. SIRT3 Is Crucial for Maintaining Skeletal Muscle Insulin Action and Protects Against Severe Insulin Resistance in High-Fat-Fed Mice. Diabetes. 2015;64:3081-92 pubmed publisher
    ..Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HFD-fed SIRT3 KO mice, suggesting decreased HKII activity...
  30. Peng Q, Zhou Q, Zhou J, Zhong D, Pan F, Liang H. Stable RNA interference of hexokinase II gene inhibits human colon cancer LoVo cell growth in vitro and in vivo. Cancer Biol Ther. 2008;7:1128-35 pubmed
    The purpose of this study is to investigate the effect of silencing hexokinase II (HK II) gene with RNA interference (RNAi) technique on colon cancer LoVo cell proliferation in vitro and in vivo...
  31. Wu R, Wyatt E, Chawla K, Tran M, Ghanefar M, Laakso M, et al. Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS production. EMBO Mol Med. 2012;4:633-46 pubmed publisher
    Hexokinase-II (HKII) is highly expressed in the heart and can bind to the mitochondrial outer membrane...
  32. Mailloux R, Dumouchel T, Aguer C, Dekemp R, Beanlands R, Harper M. Hexokinase II acts through UCP3 to suppress mitochondrial reactive oxygen species production and maintain aerobic respiration. Biochem J. 2011;437:301-11 pubmed publisher
    ..Genetic knockout or inhibition of UCP3 significantly decreased mitochondrial-bound HKII. Furthermore, UCP3 was required for the HKII-mediated decrease in mitochondrial ROS emission...
  33. Cifuentes D, Martínez Pons C, Garcia Rocha M, Galina A, Ribas De Pouplana L, Guinovart J. Hepatic glycogen synthesis in the absence of glucokinase: the case of embryonic liver. J Biol Chem. 2008;283:5642-9 pubmed publisher
    ..Hexokinase type I or II (HKI, HKII) substitutes for GK in hepatomas and in embryonic livers...
  34. Trollmann R, Rehrauer H, Schneider C, Krischke G, Huemmler N, Keller S, et al. Late-gestational systemic hypoxia leads to a similar early gene response in mouse placenta and developing brain. Am J Physiol Regul Integr Comp Physiol. 2010;299:R1489-99 pubmed publisher
    ..activity of the HIF system was obvious from elevated expression of various known HIF target genes (Adm, Vegf, Hk2, Pdk1, Bnip3, Ier3, Dusp-1), indicating immediate availability among early response to acute hypoxia...
  35. Panasyuk G, Espeillac C, Chauvin C, Pradelli L, Horie Y, Suzuki A, et al. PPAR? contributes to PKM2 and HK2 expression in fatty liver. Nat Commun. 2012;3:672 pubmed publisher
    ..Expression of specific glycolytic enzymes, namely pyruvate kinase M2 and hexokinase 2, concurs to this metabolic adaptation, as their kinetics and intracellular localization favour biosynthetic ..
  36. Gosmain Y, Dif N, Berbe V, Loizon E, Rieusset J, Vidal H, et al. Regulation of SREBP-1 expression and transcriptional action on HKII and FAS genes during fasting and refeeding in rat tissues. J Lipid Res. 2005;46:697-705 pubmed
    ..The regulation of hexokinase-2 (HKII) was investigated as a marker of the glucose metabolic pathway and that of FAS was investigated as a marker of the ..
  37. Tan H, Yang K, Li Y, Shaw T, Wang Y, Blanco D, et al. Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation. Immunity. 2017;46:488-503 pubmed publisher
  38. Ando M, Uehara I, Kogure K, Asano Y, Nakajima W, Abe Y, et al. Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3. J Nippon Med Sch. 2010;77:97-105 pubmed
    ..Moreover, STAT3 activated by IL-6 enhanced the expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3)...
  39. Heikkinen S, Suppola S, Malkki M, Deeb S, Janne J, Laakso M. Mouse hexokinase II gene: structure, cDNA, promoter analysis, and expression pattern. Mamm Genome. 2000;11:91-6 pubmed
    ..Because of the role of HKII as a leading glycolytic enzyme in insulin-sensitive tissues such as skeletal muscle, heart, and adipose tissue, ..
  40. Varanasi S, Jaggi U, Hay N, Rouse B. Hexokinase II may be dispensable for CD4 T cell responses against a virus infection. PLoS ONE. 2018;13:e0191533 pubmed publisher
    ..Studies in some systems indicate that the HK2 isoform is the most up regulated isoform in activated T cells and in this report the relevance of this finding is ..
  41. Smith J, Stallons L, Schnellmann R. Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury. Am J Physiol Renal Physiol. 2014;307:F435-44 pubmed publisher
    ..Our findings reveal LPS rapidly increases renal cortical HK activity in an EGFR- and Akt-dependent manner and that HK activation is linked to increased pentose phosphate pathway activity. ..
  42. Wang L, Xiong H, Wu F, Zhang Y, Wang J, Zhao L, et al. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 2014;8:1461-74 pubmed publisher
    ..gained from our studies with Pten-/p53-deficient mouse embryonic fibroblasts (MEFs), we report here that hexokinase 2 (HK2) is selectively upregulated by the combined loss of Pten and p53 in prostate cancer cells...
  43. Hotfilder M, Baxendale S, Cross M, Sablitzky F. Def-2, -3, -6 and -8, novel mouse genes differentially expressed in the haemopoietic system. Br J Haematol. 1999;106:335-44 pubmed
    ..Def-3, which is down-regulated upon differentiation into granulocytes but expressed in progenitor cells and macrophages, defines a novel family of RNA binding proteins. ..