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Functional specialization of CK2 isoforms and characterization of isoform-specific binding partners

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Abstract

In mammals, protein kinase CK2 has two isozymic forms of its catalytic subunit, designated CK2αgr; and CK2α′. CK2α and CK2α′ exhibit extensive similarity within their catalytic domains but have completely unrelated C-terminal sequences. To systematically examine the cellular functions of each CK2 isoform in mammalian cells, we have generated human osteosarcoma U2-OS cell lines with the expression of active or inactive versions of each CK2 isoform under the control of an inducible promoter [22]. Examination of these cell lines provides evidence for functional specialization of CK2 isoforms at the cellular level in mammals with indications that CK2α′ is involved in the control of proliferation and/or cell survival. To understand the molecular basis for functional differences between CK2α and CK2α′, we have undertaken studies to identify proteins that interact specifically with each isoform of CK2 and could contribute to the regulation of their independent functions. A novel pleckstrin-homology domain containing protein, designated CK2-interacting protein 1 (i.e. CKIP-1) was isolated using the yeast two hybrid system as a protein that interacts with CK2α but not CK2α′ [23]. When expressed in cells as a fusion with green fluorescent protein, CKIP-1 localizes to the cell membrane and to the nucleus. In this study, we present evidence from deletion analysis of CKIP-1 suggesting that a C-terminal region containing a putative leucine zipper has a role in regulating its nuclear localization. Collectively, our data supports a model whereby CKIP-1 is a non-enzymatic regulator of CK2α that regulates the cellular functions of CK2α by targeting or anchoring CK2α to specific cellular localization or by functioning as an adapter to integrate CK2α-mediated signaling events with components of other signal transduction pathways.

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References

  1. Allende JE, Allende CC: Protein kinase CK2: An enzyme with multiple substrates and a puzzling regulation. FASEB J 9: 313–323, 1995

    Google Scholar 

  2. Pinna L, Meggio F: Protein kinase CK2 ('casein kinase-2') and its implication in cell division and proliferation. Prog Cell Cycle Res 3: 77–97, 1997

    Google Scholar 

  3. Glover CV: On the physiological role of casein kinase II in Saccharomyces cerevisiae. Prog Nucleic Acid Res Mol Biol 59: 95–133, 1998

    Google Scholar 

  4. Guerra B, Issinger O-G: Protein kinase CK2 and its role in cellular proliferation, development and pathology. Electrophoresis 20: 391–408, 1999

    Google Scholar 

  5. Tawfic S, Faust RA, Gapany M, Ahmed K: Nuclear matrix as an anchor for protein kinase CK2 nuclear signalling. J Cell Biochem 62:165–171, 1996

    Google Scholar 

  6. Litchfield DW., Lüscher B: Casein kinase II in signal transduction and cell cycle regulation. Mol Cell Biochem 127-128: 187–200, 1993

    Google Scholar 

  7. Litchfield DW, Lozeman FJ, Piening C, Sommercorn J, Takio K, Walsh KA, Krebs EG: Subunit structure of casein kinase II from bovine testis: Demonstration that the α and α′ subunits are distinct polypeptides. J Biol Chem 265: 7638–7644, 1990

    Google Scholar 

  8. Lozeman FJ, Litchfield DW, Piening C, Takio K, Walsh KA, Krebs EG: Isolation and characterization of human cDNA clones encoding the α and α′ subunits of casein kinase II. Biochemistry 29: 8436–8447, 1990

    Google Scholar 

  9. Yang-Feng TL, Naiman T, Kopatz I, Eli D, Dafni N, Canaani D: Assignment of the human casein kinase II alpha′ gene (CSNK2A1) to chromosome 16p13.2-p12.3. Genomics 19: 173, 1994

    Google Scholar 

  10. Wirkner U, Voss H, Lichter P, Ansorge W, Pyerin W: The human gene (CSNK2A1) coding for the casein kinase II subunit alpha is located on chromosome 20 and contains tandemly arranged Alu repeats. Genomics 19: 257–265, 1994

    Google Scholar 

  11. Bodenbach L, Fauss J, Robitzki A, Krehan A, Lorenz P, Lozeman FJ, Pyerin W: Recombinant casein kinase II. Eur J Biochem 220: 263–273, 1994

    Google Scholar 

  12. Xu X, Toselli PA, Russell LD, Seldin DC: Globozoospermia in mice lacking the casein kinase II alpha′ catalytic subunit. Nat Genet 23: 118–121, 1999

    Google Scholar 

  13. Maridor G, Park W, Krek W, Nigg EA: Casein kinase II. cDNA sequences, developmental expression and tissue distribution of mRNAs for alpha, alpha′ and beta subunits of the chicken enzyme. J Biol Chem 266: 2362–2368, 1991

    Google Scholar 

  14. Hanna DE, Rethinaswamy A, Glover CVC: Casein kinase II is required for cell cycle progression during G1 and G2/M in Saccharomyces cerevisiae. J Biol Chem 270: 25905–25914, 1995

    Google Scholar 

  15. Rethinaswamy A, Birnbaum MJ, Glover CV:Temperature-sensitive mutations of the CKA1 gene reveal a role for casein kinase II in maintenance of cell polarity in Saccharomyces cerevisiae. J Biol Chem 273: 5869–5877, 1998

    Google Scholar 

  16. Yu IJ, Spector DL, Bae YS, Marshak DR: Immunocytochemical localization of casein kinase II during interphase and mitosis. J Cell Biol 114: 1217–1232, 1991

    Google Scholar 

  17. Litchfield DW, Lüscher B, Lozeman FJ, Eisenman RN, Krebs EG: Phosphorylation of casein kinase II by p34cdc2 in vitro and at mitosis. J Biol Chem 267: 13943–13951, 1992

    Google Scholar 

  18. Litchfield DW, Bosc DG, Slominski E: The protein kinase from mitotic human cells that phosphorylates Ser209 on the casein kinase II β subunit is p34cdc2. Biochim Biophys Acta 1269: 69–78, 1995

    Google Scholar 

  19. Bosc DG, Slominski E, Sichler C, Litchfield DW: Phosphorylation of casein kinase II by p34cdc2: Identification of phosphorylation sites using phosphorylation site mutants in vitro. J Biol Chem 270: 25872–25878, 1995

    Google Scholar 

  20. Bosc DG, Luscher B, Litchfield DW: Expression and regulation of protein kinase CK2 during the cell cycle. Mol Cell Biochem 191: 213–222, 1999

    Google Scholar 

  21. Heriche JK, Lebrin F, Rabilloud T, Leroy D, Chambaz EM, Goldberg Y: Regulation of protein phosphatase 2A by direct interaction with casein kinase 2alpha. Science 276: 952–955, 1997

    Google Scholar 

  22. Vilk G, Saulnier RB, St Pierre R, Litchfield DW: Inducible expression of protein kinase CK2 in mammalian cells: Evidence for functional specialization of CK2 isoforms. J Biol Chem 274: 14406–14414, 1999

    Google Scholar 

  23. Bosc DG, Graham KC, Saulnier RB, Zhang C, Prober D, Gietz RD, Litchfield DW: Identification and characterization of CKIP-1, a novel pleckstrin homology domain containing protein that interacts with protein kinase CK2. J Biol Chem 275: 14296–14306, 2000

    Google Scholar 

  24. Litchfield DW, Dobrowolska G, Krebs EG: Regulation of casein kinase II by growth factors: A re-evaluation. Cell Mol Biol Res 40: 373–381, 1994

    Google Scholar 

  25. Penner CG, Wang Z, Litchfield DW: Expression and localization of epitope-tagged protein kinase CK2. J Cell Biochem 64: 525–537, 1997

    Google Scholar 

  26. Heller-Harrison RA, Czech MP: Enhanced casein kinase II activity in COS-1 cells upon overexpression of either its catalytic or noncatalytic subunit. J Biol Chem 266: 14435–14439, 1991

    Google Scholar 

  27. Shen M, Stukenberg PT, Kirschner MW, Lu KP: The essential mitotic peptidyl-prolyl isomerase Pin 1 binds and regulates mitosis-specific phosphoproteins. Genes Dev 12: 706–720, 1998

    Google Scholar 

  28. Yaffe MB, Schutkowski M, Shen M, Zhou XZ, Stukenberg PT, Rahfeld JU, Xu J, Kuang J, Kirschner MW, Fischer G, Cantley LC, Lu KP: Sequence-specific and phosphorylation-dependent proline isomerization: A potential mitotic regulatory mechanism. Science 278: 1957–1960, 1997

    Google Scholar 

  29. Messenger M, Gilchrist A, Saulnier RB, Gorbsky GJ, Litchfield DW: The peptide-prolyl isomerase Pin-1 interacts with protein kinase CK2 in a phosphorylation dependent manner (submitted for publication)

  30. Lemmon MA, Falasca M, Ferguson KM, Schlessinger J: Regulatory recruitment of signalling molecules to the cell membrane by pleckstrin-homology domains. Trends Cell Biol 7: 237–242, 1997

    Google Scholar 

  31. Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA, Schlessinger J: Activation of phospholipase Cgamma by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J 17: 414–422, 1998

    Google Scholar 

  32. Lorenz P, Pepperkok R, Ansorge W, Pyerin W: Cell biological studies with monoclonal and polyclonal antibodies against human casein kinase II subunit beta demonstrate participation of the kinase in mitogenic signaling. J Biol Chem 268: 2733–2739, 1993

    Google Scholar 

  33. Pepperkok R, Lorenz P, Ansorge W, Pyerin W: Casein kinase II is required for transition of G0/G1, early G1, and G1/S phases of the cell cycle. J Biol Chem 269: 6986, 1994

    Google Scholar 

  34. Gerber DA, Souquere-Besse S, Puvion F, Dubois MF, Bensaude O, Cochet C: Heat-induced relocalization of protein kinase CK2. Implication of CK2 in the context of cellular stress. J Biol Chem 275: 23919–23926, 2000

    Google Scholar 

  35. Sayed M, Kim SO, Salh BS, Issinger OG, Pelech SL: Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase. J Biol Chem 275: 16569–16573, 2000

    Google Scholar 

  36. Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H: A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell 7: 283–292, 2001

    Google Scholar 

  37. Pawson T, Scott JD: Signalling through scaffold, anchoring and adaptor proteins. Science 278: 2075–2080, 1997

    Google Scholar 

  38. Colledge M, Scott JD: AKAPs: From structure to function. Trends Cell Biol 9: 216–221, 1999

    Google Scholar 

  39. Sarrouilhe D, Filhol O, Leroy D, Bonello G, Baudry M, Chambaz E, Cochet C: The tight association of protein kinase CK2 with plasma membrane is mediated by a specific domain of its regulatory β-subunit. Biochim Biophys Acta 1403: 199–210, 1998

    Google Scholar 

  40. Wong HN, Ward MA, Bell AW, Chevet E, Bains S, Blackstock WP, Solari R, Thomas DY, Bergeron JJ: Conserved in vivo phosphorylation of calnexin at casein kinase II sites as well as a protein kinase C/ proline-directed kinase site. J Biol Chem 273: 17227–17235, 1998

    Google Scholar 

  41. Mauxion F, Le Borgne R, Munier-Lehmann H, Hoflack B: A casein kinase II phosphorylation site in the cytoplasmic domain of the cation-dependent mannose 6-phosphate receptor determines the high affinity interaction of the AP-1 Golgi assembly proteins with membranes. J Biol Chem 271: 2171–2178, 1996

    Google Scholar 

  42. Molloy SS, Thomas L, Kamibayashi C, Mumby MC, Thomas G: Regulation of endosome sorting by a specific PP2A isoform. J Cell Biol 142: 1399–1411, 1998

    Google Scholar 

  43. Tawfic S, Davis AT, Faust RA, Gapany M, Ahmed K: Association of protein kinase CK2 with nuclear matrix: Influence of method of preparation of nuclear matrix. J Cell Biochem 64: 499–504, 1997

    Google Scholar 

  44. Krek W, Maridor G, Nigg EA: Casein kinase II is a predominantly nuclear enzyme. J Cell Biol 116: 43–55, 1992

    Google Scholar 

  45. Filhol O, Cochet C, Chambaz EM: Cytoplasmic and nuclear distribution of casein kinase II: Characterization of the enzyme uptake by bovine adrenocortical nuclear preparation. Biochemistry 29: 9928–9936, 1990

    Google Scholar 

  46. Filhol O, Baudier J, Delphin C, Loue-Mackenbach P, Chambaz E, Cochet C: Casein kinase II and the tumor supressor protein p53 associate in a molecular complex that is negatively regulated upon p53 phosphorylation. J Biol Chem 267: 20577–20583, 1992

    Google Scholar 

  47. Appel K, Wagner P, Boldyreff B, Issinger O-G, Montenarh M: Mapping of the interaction sites of the growth suppressor protein p53 with the regulatory Beta-subunit of protein kinase CK2. Oncogene 11: 1971–1978, 1995

    Google Scholar 

  48. O'Brien KA, Lemke SJ, Cocke KS, Rao RN, Beckmann RP: Casein kinase 2 binds to and phosphorylates BRCA1. Biochem Biophys Res Commun 260: 658–664, 1999

    Google Scholar 

  49. Li D, Dobrowolska G, Krebs EG: The physical association of casein kinase 2 with nucleolin. J Biol Chem 271: 15662–15668, 1996

    Google Scholar 

  50. Li D, Meier T, Dobrowolska G, Krebs EG: Specific interaction between casein kinase 2 and the nucleolar protein Nopp140. J Biol Chem 272: 3773–3779, 1997

    Google Scholar 

  51. Willert K, Brink M, Wodarz A, Varmus H, Nusse R: Casein kinase 2 associates with and phosphorylates dishevelled. EMBO J 16: 3089–3096, 1997

    Google Scholar 

  52. Song DH, Sussman DJ, Seldin DC: Endogenous protein kinase CK2 participates in Wnt signaling in mammary epithelial cells. J Biol Chem 275: 23790–23797, 2000

    Google Scholar 

  53. Boldyreff B, Issinger O-G: A-Raf kinase is a new interacting partner of protein kinase CK2 beta subunit. FEBS Lett 403: 197–199, 1997

    Google Scholar 

  54. Hageman C, Kalmes A, Wixler V, Wixler L, Schuster T, Rapp UR: The regulatory subunit of protein kinase CK2 is a specific A-Raf activator. FEBS Lett 403: 200–202, 1997

    Google Scholar 

  55. Chen M, Li D, Krebs EG, Cooper J: The casein kinase II β subunit binds to Mos and inhibits Mos activity. Mol Cell Biol 17: 1904–1912, 1997

    Google Scholar 

  56. Raman C, Kuo A, Deshane J, Litchfield DW, Kimberly RP: Regulation of casein kinase 2 by direct interaction with cell surface receptor CD5. J Biol Chem 273: 19183–19189, 1998

    Google Scholar 

  57. Miyata Y, Yahara I: Interaction between casein kinase II and the 90-kDa stress protein, HSP90. Biochemistry 34: 8123–8129, 1995

    Google Scholar 

  58. Kimura Y, Rutherford SL, Miyata Y, Yahara I, Freeman BC, Yue L, Morimoto RI, Lindquist S: Cdc37 is a molecular chaperone with specific functions in signal transduction. Genes Dev 11: 1775–1785, 1997

    Google Scholar 

  59. Shi X, Potvin B, Huang T, Hilgard P, Spray DC, Suadicani SO, Wolkoff AW, Stanley P, Stockert RJ: A novel casein kinase 2 alpha-subunit regulates membrane protein traffic in the human hepatoma cell line HuH-7. J Biol Chem 276: 2075–2082, 2001

    Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada E-mail

    David W. Litchfield, Denis G. Bosc, David A. Canton, Ronald B. Saulnier, Greg Vilk & Cunjie Zhang

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  1. David W. Litchfield
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  2. Denis G. Bosc
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  3. David A. Canton
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  4. Ronald B. Saulnier
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  5. Greg Vilk
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  6. Cunjie Zhang
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Correspondence to David W. Litchfield.

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Litchfield, D.W., Bosc, D.G., Canton, D.A. et al. Functional specialization of CK2 isoforms and characterization of isoform-specific binding partners. Mol Cell Biochem 227, 21–29 (2001). https://doi.org/10.1023/A:1013188101465

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