Amino Acids

, Volume 40, Issue 4, pp 1091–1106 | Cite as

Regulation of taurine homeostasis by protein kinase CK2 in mouse fibroblasts

  • Daniel Bloch Hansen
  • Barbara Guerra
  • Jack Hummeland Jacobsen
  • Ian Henry LambertEmail author
Original Article


Increased expression of the ubiquitous serine/threonine protein kinase CK2 has been associated with increased proliferative capacity and increased resistance towards apoptosis. Taurine is the primary organic osmolyte involved in cell volume control in mammalian cells, and shift in cell volume is a critical step in cell proliferation, differentiation and induction of apoptosis. In the present study, we use mouse NIH3T3 fibroblasts and Ehrlich Lettré ascites tumour cells with different CK2 expression levels. Taurine uptake via the Na+ dependent transporter TauT and taurine release are increased and reduced, respectively, following pharmacological CK2 inhibition. The effect of CK2 inhibition on TauT involves modulation of transport kinetics, whereas the effect on the taurine release pathway involves reduction in the open-probability of the efflux pathway. Stimulation of PLA2 activity, exposure to exogenous reactive oxygen species as well as inhibition of protein tyrosine phosphotases (PTP) potentiate the swelling-induced taurine loss. Inhibition of PI3K and PTEN reduces and potentiates swelling-induced taurine release, respectively. Inhibition of CK2 has no effect on PLA2 activity and ROS production by NADPH oxidase, whereas it lifts the effect of PTEN and PTP inhibition. It is suggested that CK2 regulates the taurine release downstream to known swelling-induced signal transducers including PLA2, NADPH oxidase and PI3K.


Regulatory volume decrease TBCA DMAT SLC6A6 Volume sensitive organic osmolyte channel 



The present work was supported by The Danish Council for Independent Research/Natural Sciences (Grant 272-07-0530, 272-08-0170, 272-07-0258), The Danish Council for Independent Research/Medical Sciences (Grant 271-08-0520), and The Danish Cancer Society (Grant DP08152). The technical assistance of Dorthe Nielsen is gratefully acknowledged.


  1. Ahmad KA, Wang G, Unger G, Slaton J, Ahmed K (2008) Protein kinase CK2—a key suppressor of apoptosis. Adv Enzyme Regul 48:179–187PubMedCrossRefGoogle Scholar
  2. Allen D, Fakler B, Maylie J, Adelman JP (2007) Organization and regulation of small conductance Ca2+ -activated K+ channel multiprotein complexes. J Neurosci 27(9):2369–2376PubMedCrossRefGoogle Scholar
  3. Arrigoni G, Marin O, Pagano MA, Settimo L, Paolin B, Meggio F et al (2004) Phosphorylation of calmodulin fragments by protein kinase CK2. Mechanistic aspects and structural consequences. Biochemistry 43(40):12788–12798PubMedCrossRefGoogle Scholar
  4. Bibby AC, Litchfield DW (2005) The multiple personalities of the regulatory subunit of protein kinase CK2: CK2 dependent and CK2 independent roles reveal a secret identity for CK2beta. Int J Biol Sci 1(2):67–79PubMedGoogle Scholar
  5. Bildl W, Strassmaier T, Thurm H, Andersen J, Eble S, Oliver D et al (2004) Protein kinase CK2 is coassembled with small conductance Ca2+ -activated K+ channels and regulates channel gating. Neuron 43(6):847–858PubMedCrossRefGoogle Scholar
  6. Bunney TB, Katan M (2010) Phosphoinositide signaling in cancer: beyond PI3K and PTEN. Nat Rev Cancer 10(5):342–352Google Scholar
  7. Diaz-Elizondo J, Chiong M, Rojas-Rivera D, Olea-Azar C, Kwon HM, Lavandero S (2006) Reactive oxygen species inhibit hyposmotic stress-dependent volume regulation in cultured rat cardiomyocytes. Biochem Biophys Res Commun 350(4):1076–1081PubMedCrossRefGoogle Scholar
  8. Filhol O, Cochet C (2009) Cellular functions of Protein kinase CK2: a dynamic affair. Cell Mol Life Sci 66(11–12):1830–1839PubMedCrossRefGoogle Scholar
  9. Fiol CJ, Mahrenholz AM, Wang Y, Roeske RW, Roach PJ (1987) Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3. J Biol Chem 262(29):14042–14048PubMedGoogle Scholar
  10. Frame S, Cohen P (2001) GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359(Pt 1):1–16PubMedCrossRefGoogle Scholar
  11. Friis MB, Vorum KG, Lambert IH (2008) Volume-sensitive NADPH oxidase activity and taurine efflux in NIH3T3 mouse fibroblasts. Am J Physiol Cell Physiol 294(6):C1552–C1565PubMedCrossRefGoogle Scholar
  12. Guerra B, Issinger OG (1999) Protein kinase CK2 and its role in cellular proliferation, development and pathology. Electrophoresis 20(2):391–408PubMedCrossRefGoogle Scholar
  13. Hoffmann EK, Lambert IH, Pedersen SF (2009) Physiology of cell volume regulation in vertebrates. Physiol Rev 89(1):193–277PubMedCrossRefGoogle Scholar
  14. Huyer G, Liu S, Kelly J, Moffat J, Payette P, Kennedy B et al (1997) Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate. J Biol Chem 272(2):843–851PubMedCrossRefGoogle Scholar
  15. Jacobsen JG, Smith LH (1968) Biochemistry and physiology of taurine and taurine derivatives. Physiol Rev 48(2):424–511PubMedGoogle Scholar
  16. Jacobsen JH, Clement CA, Friis MB, Lambert IH (2008) Casein kinase 2 regulates the active uptake of the organic osmolyte taurine in NIH3T3 mouse fibroblasts. Pflugers Arch 457(2):327–337PubMedCrossRefGoogle Scholar
  17. Jenkins CM, Wolf MJ, Mancuso DJ, Gross RW (2001) Identification of the calmodulin-binding domain of recombinant calcium-independent phospholipase A2beta implications for structure and function. J Biol Chem 276(10):7129–7135PubMedCrossRefGoogle Scholar
  18. Lai JP, Dalton JT, Knoell DL (2007) Phosphatase and tensin homologue deleted on chromosome ten (PTEN) as a molecular target in lung epithelial wound repair. Br J Pharmacol 152(8):1172–1184PubMedCrossRefGoogle Scholar
  19. Lambert IH (1998) Regulation of the taurine content in Ehrlich ascites tumour cells. Adv Exp Med Biol 442:269–276PubMedGoogle Scholar
  20. Lambert IH (2003) Reactive oxygen species regulate swelling-induced taurine efflux in NIH3T3 mouse fibroblasts. J Membr Biol 192(1):19–32PubMedCrossRefGoogle Scholar
  21. Lambert IH (2004) Regulation of the cellular content of the organic osmolyte taurine in mammalian cells. Neurochem Res 29(1):27–63PubMedCrossRefGoogle Scholar
  22. Lambert IH (2007) Activation and inactivation of the volume-sensitive taurine leak pathway in NIH3T3 fibroblasts and ehrlich lettre ascites cells. Am J Physiol Cell Physiol 293(1):C390–C400PubMedCrossRefGoogle Scholar
  23. Lambert IH, Hoffmann EK (1993) Regulation of taurine transport in Ehrlich ascites tumor cells. J Membr Biol 131(1):67–79PubMedCrossRefGoogle Scholar
  24. Lambert IH, Pedersen SF (2006) Multiple PLA2 isoforms regulate taurine release in NIH3T3 mouse fibroblasts. Adv Exp Med Biol 583:99–108PubMedCrossRefGoogle Scholar
  25. Lambert IH, Sepulveda FV (2000) Swelling-induced taurine efflux from HeLa cells: cell volume regulation. Adv Exp Med Biol 483:487–495PubMedCrossRefGoogle Scholar
  26. Lambert IH, Nielsen JH, Andersen HJ, Ortenblad N (2001) Cellular model for induction of drip loss in meat. J Agric Food Chem 49(10):4876–4883PubMedCrossRefGoogle Scholar
  27. Lambert IH, Pedersen SF, Poulsen KA (2006) Activation of PLA2 isoforms by cell swelling and ischaemia/hypoxia. Acta Physiol (Oxf) 187(1–2):75–85CrossRefGoogle Scholar
  28. Lambert IH, Hoffmann EK, Pedersen SF (2008) Cell volume regulation: physiology and pathophysiology. Acta Physiol Scand 194:255–282Google Scholar
  29. Lang F (2007) Mechanisms and significance of cell volume regulation. J Am Coll Nutr 26(5):613S–623SPubMedGoogle Scholar
  30. Lang F, Strutz-Seebohm N, Seebohm G, Lang UE (2010) Significance of SGK1 in the regulation of neuronal function. J PhysiolGoogle Scholar
  31. Lee SR, Kwon KS, Kim SR, Rhee SG (1998) Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem 273(25):15366–15372PubMedCrossRefGoogle Scholar
  32. Lourenço R, Camilo ME (2002) Taurine: a conditionally essential amino acid in humans? An overview in health and disease. Nutrición Hospitalaria 17(6):262–270PubMedGoogle Scholar
  33. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193(1):265–275PubMedGoogle Scholar
  34. Mancuso DJ, Jenkins CM, Gross RW (2000) The genomic organization, complete mRNA sequence, cloning, and expression of a novel human intracellular membrane-associated calcium-independent phospholipase A(2). J Biol Chem 275(14):9937–9945PubMedCrossRefGoogle Scholar
  35. Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? Faseb J 17(3):349–368PubMedCrossRefGoogle Scholar
  36. Meng TC, Fukada T, Tonks NK (2002) Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 9(2):387–399PubMedCrossRefGoogle Scholar
  37. Moran J, Miranda D, Pena-Segura C, Pasantes-Morales H (1997) Volume regulation in NIH/3T3 cells not expressing P-glycoprotein. II. Chloride and amino acid fluxes. Am J Physiol 272(6 Pt 1):C1804–C1809PubMedGoogle Scholar
  38. Nielsen MB, Christensen ST, Hoffmann EK (2008) Effects of osmotic stress on the activity of MAPKs and PDGFR-beta-mediated signal transduction in NIH-3T3 fibroblasts. Am J Physiol Cell Physiol 294(4):C1046–C1055PubMedCrossRefGoogle Scholar
  39. Ortenblad N, Young JF, Oksbjerg N, Nielsen JH, Lambert IH (2003) Reactive oxygen species are important mediators of taurine release from skeletal muscle cells. Am J Physiol Cell Physiol 284(6):C1362–C1373PubMedGoogle Scholar
  40. Pagano MA, Poletto G, Di MG, Cozza G, Ruzzene M, Sarno S et al (2007) Tetrabromocinnamic acid (TBCA) and related compounds represent a new class of specific protein kinase CK2 inhibitors. Chembiochem 8(1):129–139PubMedCrossRefGoogle Scholar
  41. Pagano MA, Bain J, Kazimierczuk Z, Sarno S, Ruzzene M, Di MG et al (2008) The selectivity of inhibitors of protein kinase CK2: an update. Biochem J 415(3):353–365PubMedCrossRefGoogle Scholar
  42. Park HS, Lee SM, Lee JH, Kim YS, Bae YS, Park JW (2001) Phosphorylation of the leucocyte NADPH oxidase subunit p47(phox) by casein kinase 2: conformation-dependent phosphorylation and modulation of oxidase activity. Biochem J 358:783–790PubMedCrossRefGoogle Scholar
  43. Pedersen SF, Poulsen KA, Lambert IH (2006) Roles of phospholipase A2 isoforms in swelling- and melittin-induced arachidonic acid release and taurine efflux in NIH3T3 fibroblasts. Am J Physiol Cell Physiol 291(6):C1286–C1296PubMedCrossRefGoogle Scholar
  44. Poulsen KA, Litman T, Eriksen J, Mollerup J, Lambert IH (2002) Downregulation of taurine uptake in multidrug resistant Ehrlich ascites tumor cells. Amino Acids 22(4):333–350PubMedCrossRefGoogle Scholar
  45. Poulsen KA, Andersen EC, Hansen CF, Klausen TK, Hougaard C, Lambert IH et al (2010) Deregulation of apoptotic volume decrease and ionic movements in multidrug-resistant tumor cells: role of chloride channels. Am J Physiol Cell Physiol 298(1):C14–C25PubMedCrossRefGoogle Scholar
  46. Prasad N, Topping RS, Zhou D, Decker SJ (2000) Oxidative stress and vanadate induce tyrosine phosphorylation of phosphoinositide-dependent kinase 1 (PDK1). Biochemistry 39(23):6929–6935PubMedCrossRefGoogle Scholar
  47. Rao RK, Clayton LW (2002) Regulation of protein phosphatase 2A by hydrogen peroxide and glutathionylation. Biochem Biophys Res Commun 293(1):610–616PubMedCrossRefGoogle Scholar
  48. Ruzzene M, Pinna LA (2010) Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta 1804(3):499–504PubMedGoogle Scholar
  49. Sarkadi B, Attisano L, Grinstein S, Buchwald M, Rothstein A (1984) Volume regulation of Chinese hamster ovary cells in anisoosmotic media. Biochim Biophys Acta 774(2):159–168PubMedCrossRefGoogle Scholar
  50. Sarno S, Pinna LA (2008) Protein kinase CK2 as a druggable target. Mol Biosyst 4(9):889–894PubMedCrossRefGoogle Scholar
  51. Schmid AC, Byrne RD, Vilar R, Woscholski R (2004) Bisperoxovanadium compounds are potent PTEN inhibitors. FEBS Lett 566(1–3):35–38PubMedCrossRefGoogle Scholar
  52. Shimoyama Y, Sakamoto R, Akaboshi T, Tanaka M, Ohtsuki K (2001) Characterization of secretory type IIA phospholipase A2 (sPLA2-IIA) as a glycyrrhizin (GL)-binding protein and the GL-induced inhibition of the CK-II-mediated stimulation of sPLA2-IIA activity in vitro. Biol Pharm Bull 24(9):1004–1008PubMedCrossRefGoogle Scholar
  53. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M et al (2008) PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 118(11):3762–3774PubMedCrossRefGoogle Scholar
  54. St-Denis NA, Litchfield DW (2009) From birth to death: the role of protein kinase CK2 in the regulation of cell proliferation and survival. Cell Mol Life Sci 66(11–12):1817–1829PubMedCrossRefGoogle Scholar
  55. Thornburg W, Lindell TJ (1977) Purification of rat liver nuclear protein kinase NII. J Biol Chem 252(19):6660–6665PubMedGoogle Scholar
  56. Trembley JH, Wang G, Unger G, Slaton J, Ahmed K (2009) CK2: a key player in cancer biology. Cell Mol Life Sci 66(11–12):1858–1867PubMedCrossRefGoogle Scholar
  57. van Diepen MT, Parsons M, Downes CP, Leslie NR, Hindges R, Eickholt BJ (2009) MyosinV controls PTEN function and neuronal cell size. Nat Cell Biol 11(10):1191–1196PubMedCrossRefGoogle Scholar
  58. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD (1997) Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22(7):267–272PubMedCrossRefGoogle Scholar
  59. Villumsen KR, Duelund L, Lambert IH (2010) Acute cholesterol depletion leads to net loss of the organic osmolyte taurine in Ehrlich Lettre tumor cells. Amino Acids. doi: 10.1007/s00726-010-0621-4
  60. Voss JW, Pedersen SF, Christensen ST, Lambert IH (2004a) Regulation of the expression and subcellular localisation of the taurine transporter TauT in mouse NIH3T3 fibroblasts. Eur J Biochem 271:4646–4658PubMedCrossRefGoogle Scholar
  61. Voss JW, Pedersen SF, Christensen ST, Lambert IH (2004b) Regulation of the expression and subcellular localization of the taurine transporter TauT in mouse NIH3T3 fibroblasts. Eur J Biochem 271(23–24):4646–4658PubMedCrossRefGoogle Scholar
  62. Wang GX, McCrudden C, Dai YP, Horowitz B, Hume JR, Yamboliev IA (2004) Hypotonic activation of volume-sensitive outwardly rectifying chloride channels in cultured PASMCs is modulated by SGK. Am J Physiol Heart Circ Physiol 287(2):H533–H544PubMedCrossRefGoogle Scholar
  63. Weston CR, Davis RJ (2001) Signal transduction: signaling specificity—a complex affair. Science 292(5526):2439–2440PubMedCrossRefGoogle Scholar
  64. Zhu D, Hensel J, Hilgraf R, Abbasian M, Pornillos O, Deyanat-Yazdi G et al (2009) Inhibition of protein kinase CK2 expression and activity blocks tumor cell growth. Mol Cell BiochemGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Daniel Bloch Hansen
    • 1
  • Barbara Guerra
    • 2
  • Jack Hummeland Jacobsen
    • 1
  • Ian Henry Lambert
    • 1
    Email author
  1. 1.Department of Biology, Section for Cell and Developmental BiologyUniversity of CopenhagenCopenhagen ØDenmark
  2. 2.Institute of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdense MDenmark

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