Advertisement

Role for Protein Kinase CK2 on Cell Proliferation: Assessing CK2 Complex Components in the Nucleus During the Cell Cycle Progression

  • Miwako Kato HommaEmail author
  • Takeshi Shibata
  • Toshiyuki Suzuki
  • Masato Ogura
  • Hiroko Kozuka-Hata
  • Masaaki Oyama
  • Yoshimi Homma
Chapter
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 12)

Abstract

CK2 is one of the serine threonine kinases known to be essential for basic cell viability and survival. Until recently, genetic, biochemical, and cell biological studies have indicated the involvement of this enzyme in the control of cell proliferation and in signal transduction. It has been reported that more than 300 proteins have been identified as CK2 substrates in cells; however, the clarification of the functional relationship between those substrates and CK2 in the aspect of cell proliferation and survival is still required. The identification of the cellular factors involved in CK2 function is important to delineate its molecular mechanism in the cells. We previously demonstrated a significant increase in CK2 activity by growth factor stimulation of quiescent cells and identified eIF5 in the CK2 complex as being a downstream molecule. Also, we described the cell cycle-dependent association of CK2 with an endogenous tumor suppressor adenomatous polyposis coli (APC) protein, which was further investigated to uncover the negative regulation of CK2 activity by the APC-C terminal domain that is lost in more than 60 % of FAP-derived cancer cells. These results established the importance of kinase activity that seems to be non-constitutively active and controlled by unknown cellular mechanisms for properly regulating cell proliferation. We therefore examined the CK2 protein complex in the nucleus in distinct phases of cell proliferation by employing synchronized cells. Cell lysates were made after the stimulation with FBS, and nuclear fractions were extracted and immunoprecipitated with anti-CK2 polyclonal antibodies. Using two-dimensional gel electrophoresis followed by mass spectrometry analysis, we identified 22 proteins, including hnRNP, histone-binding proteins, and lamin-B, which were localized in the nuclear fraction preferentially associated with CK2 in the early G1 phase. In further studies, using nuclear CK2 immunoprecipitates followed by nanoLC mass spectrometry analysis, we identified 140 proteins as CK2-interacting proteins in the nucleus. Intriguingly, more than 20 % of these proteins were constituted by DNA-binding and RNA-binding proteins, suggesting the involvement of CK2 function as a dynamic regulator for gene function associated with cell cycle progression. Our approach can be extended to other cell states and cellular compartments and provide the broad biochemical framework for understanding the role of the kinase.

Keywords

Adenomatous polyposis coli (APC) Cell cycle CK2 Eukaryotic translation initiation factor 5 (eIF5) Mass spectrometry (MS) Nuclear functions Phosphorylation Posttranslational modifications Protein complex Proteomics 

Abbreviations

2D

Two dimensional

Ala

Alanine

APC

Adenomatous polyposis coli

CK2

Casein kinase 2/II

DMEM

Dulbecco’s Modified Eagle’s Medium

eIF5

Eukaryotic translation initiation factor 5

FBS

Fetal bovine serum

FDR

False discovery rate

Glu

Glutamic acid

nanoLC

Nanoscale liquid chromatography

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

Notes

Acknowledgments

The authors acknowledge Drs. Dongxia Li and Tamiko Sueoka for discussions on the manuscript, Ms Junko Yamaki for her technical assistance, and Pete McCann, Roy Cameron, and Naoko Shiota for their critical reading on the manuscript. This work was supported by grants #23570170 from the Ministry of Education, Science, Sports, and Culture of Japan, Research Seeds Quest Program from the Japan Science and Technology Agency, and the Grant for Joint Research Project of the Institute of Medical Science, the University of Tokyo.

References

  1. 1.
    Burnett G, Kennedy E (1954) The enzymatic phosphorylation of proteins. J Biol Chem 211:969–980PubMedGoogle Scholar
  2. 2.
    Hanna DE, Rethinaswamy A, Glover CV (1995) Casein Kinase II is required for cell cycle progression during G1 and G2/M in S Cerevisiae. J Biol Chem 270:25905–25914CrossRefPubMedGoogle Scholar
  3. 3.
    Filhol O, Martiel J-L, Cochet C (2004) Protein kinase CK2: a new view of an old molecular complex. EMBO Rep 5:351–355CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2. FASEB J 17:349–368CrossRefPubMedGoogle Scholar
  5. 5.
    Lou DY, Dominquez I, Toselli P, Landesman-Bollaq E, O’Brien C, Seldin DC (2008) The alpha catalytic subunit of protein kinase CK2 is required for mouse embryonic development. Mol Cell Biol 28:131–139CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Xu X, Toselli PA, Russell LD, Seldin DC (1999) Globozoospermia in mice lacking the casein kinase II alpha' catalytic subunit. Nat Genet 23:118–121CrossRefPubMedGoogle Scholar
  7. 7.
    Buchou T, Vernet M, Blond O, Jensen HH, Pointu H, Olsen BB, Cochet C, Issinger OG, Boldyreff B (2003) Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23:908–915CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12:226–230CrossRefPubMedGoogle Scholar
  9. 9.
    Litchfield DW (2003) Protein kinase CK2: Structure, regulation and role in cellular decision of life and death. Biochem J 369:1–15CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Haitao J, Wang J, Nika H et al (2009) EGF-induced ERK activation promotes CK2 mediated disassociation of a-catenin from b-catenin and transactivation of b-catenin. Mol Cell 36:547–559CrossRefGoogle Scholar
  11. 11.
    Duncan JS, Litchfield DW (2008) Too much of good things:the role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Biochim Biophys Acta 1784:33–47CrossRefPubMedGoogle Scholar
  12. 12.
    Trembely JH, Wang G, Unger G, Slaton J, Ahmed K (2009) Protein kinase CK2 in health and disease: CK2 a player in cancer biology. Cell Mol Life Sci 66:1858–1867CrossRefGoogle Scholar
  13. 13.
    Litchfield DW, Dobrowolska G, Krebs EG (1994) Regulation of casein kinase II by growth factors: a reevaluation. Cell Mol Biol Res 4:373–381Google Scholar
  14. 14.
    Sommercorn J, Mulligan JA, Lozeman FJ, Krebs EG (1987) Activation of casein kinase II in response to insulin and to epidermal growth factor. Proc Natl Acad Sci U S A 84:8834–8838CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Ahn NG, Weiel JE, Chan CP, Krebs EG (1990) Identification of multiple epidermal growth factor-stimulated protein serine/threonine kinases from Swiss 3T3 cells. J Biol Chem 265:11487–11494PubMedGoogle Scholar
  16. 16.
    Niefind K, Issinger O-G (2010) Conformational plasticity of the catalytic subunit of protein kinase CK2 and its consequences for regulation and drug design. Biochim Biophys Acta 1804:484–492CrossRefPubMedGoogle Scholar
  17. 17.
    Schnitzler A, Olsen BB, Issinger O-G, Niefind K (2014) The protein kinase CK2 Andante holoenzyme structure supports.J. Mol Biol 426:1871–1882CrossRefGoogle Scholar
  18. 18.
    Homma MK, Wada I, Suzuki T, Yamaki J, Krebs EG, Homma Y (2005) CK2 phosphorylation of eukaryotic translation initiation factor 5 potentiates cell cycle progression. Proc Natl Acad Sci U S A 102:15688–15693CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Homma MK, Li D, Krebs EG, Homma Y (2002) Association and regulation of casein kinase 2 activity by adenomatous polyposis coli protein. Proc Natl Acad Sci U S A 99:5959–5964CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Homma MK, Homma Y (2005) Regulatory role of CK2 during the progression of cell cycle. Mol Cell Biochem 274:47–52CrossRefPubMedGoogle Scholar
  21. 21.
    Montenarh M, Gots C (2013) The interactome of protein kinase CK2. In: Pinna EA (ed) CK2 Protein kinase. Wiley, New York, pp 76–116CrossRefGoogle Scholar
  22. 22.
    Dignam JD (1990) Preparation of extracts from higher eukaryotes. In: Deutscher MP (ed) Methods in Enzymology, vol 182, Guide to Protein Purification. Academic, San Diego, pp 203–224Google Scholar
  23. 23.
    Ozlu N, Montigatti F, Renard BY, Field CM et al (2010) Binding partner switching on microtubules and Aurora-B in the mitosis to cytokinesis transition. Mol Cell Proteomics 9:336–350CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Lessard J, Wu JI, Ranish JA et al (2007) An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55:201–205CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Old WM, Shabb JB, Houel S et al (2009) Functional proteomics identifies targets of phosphorylation by B-Raf signaling in melanoma. Mol Cell 34:115–131CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Eric SW, Old WM, Resing KA, Ahn NG (2007) Mapping protein post-translational modifications with mass spectrometry. Nat Methods 3:798–806Google Scholar
  27. 27.
    Oyama M, Kozuka-Hata H et al (2009) Temporal perturbation of tyrosine phosphoproteome dynamics reveals the system-wide regulatory networks. Mol Cell Proteomics 8:226–231CrossRefPubMedGoogle Scholar
  28. 28.
    Homma MK, Oyama M, Kozuka-Hata H, Ogura M and Homma. Y. Nuclear localization and phosphorylation status of protein kinase CK2 during cell cycle progression: switching in the CK2 complex, Manuscript in preparation for publication.Google Scholar
  29. 29.
    Phanstiel DH, Brumbaugh J, Wenger CD et al (2011) Proteomic and phosphoproteomic comparison of human ES and iPS cells. Nat Methods 8:821–827CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Bian Y, Ye M, Wang C et al (2013) Global screening of CK2 kinase substrates by an integrated phosphoproteomics workflow. Sci Rep 3:3460. doi: 10.1038/srep0346 CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Lehnert S, Gotz C, Kartarius S, Schafer B, Montenarh M (2008) Protein kinase CK2 interacts with the splicing factor hPrp3P. Oncogene 27:2390–2400CrossRefPubMedGoogle Scholar
  32. 32.
    Yata K, Lloyd J et al (2012) Plk1 and CK2 act in concert to regulate Rad51 during DNA double strand break repair. Mol Cell 45:371–383CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Khan D, He S, Yu J, Winter S, Cao W et al (2013) Protein kinase CK2 regulates the dimerization of histone deactylase 1(HDAC1) and HDAC2 during mitosis. J Biol Chem 288:16518–16528CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Montaqnoli A, Valsasina B, Brotherton D, Troiani S (2006) Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases. J Biol Chem 281:10281–10290CrossRefGoogle Scholar
  35. 35.
    Panova TB, Panov KI, Russell J, Zomerdijk JCBM (2006) Casein kinase 2 associates with initiation-competent RNA polymerase I and has multiple roles in ribosomal DNA transcription. Mol Cell Biol 26:5957–5968CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Homma MK, Homma Y (2008) Cell cycle and activation of CK2. Mol Cell Biochem 316:49–55CrossRefPubMedGoogle Scholar
  37. 37.
    Tarrant MK, Rho H-S, Xie Z et al (2012) Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis. Nat Chem Biol 8:262–269CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Homma MK, Oyama M, Kozuka-Hata H, Yamaki J, Koshiba S, Homma Y. Essential role for autophosphorylation of CK2α in the N-terminal region at tyrosine residues. Manuscript in preparation for publicationGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Miwako Kato Homma
    • 1
    Email author
  • Takeshi Shibata
    • 2
  • Toshiyuki Suzuki
    • 1
  • Masato Ogura
    • 1
  • Hiroko Kozuka-Hata
    • 3
  • Masaaki Oyama
    • 3
  • Yoshimi Homma
    • 1
  1. 1.Department Biomolecular ScienceFukushima Medical University School of MedicineFukushimaJapan
  2. 2.ABSciex. K.K.TokyoJapan
  3. 3.Medical Proteomics LaboratoryThe Institute of Medical Sciences, The University of TokyoTokyoJapan

Personalised recommendations