Skip to main content

Advertisement

SpringerLink
Log in

Regulation of caspase pathways by protein kinase CK2: identification of proteins with overlapping CK2 and caspase consensus motifs

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Apoptosis, or programmed cell death, is a vital cellular process often impaired in diseases such as cancer. Aspartic acid-directed proteases known as caspases cleave a broad spectrum of cellular proteins and are central constituents of the apoptotic machinery. Caspases are regulated by a variety of mechanisms including protein phosphorylation. One intriguing mechanism by which protein kinases can modulate caspase pathways is by blocking substrate cleavage through phosphorylation of residues adjacent to caspase cleavage sites. To explore this mechanism in detail, we recently undertook a systematic investigation using a combination of bioinformatics, peptide arrays, and peptide cleavage assays to identify proteins with overlapping protein kinase and caspase recognition motifs (Duncan et al., Sci Signal 4:ra30, 2011). These studies implicated protein kinase CK2 as a global regulator of apoptotic pathways. In this article, we extend the analysis of proteins with overlapping CK2 and caspase consensus motifs to examine the convergence of CK2 with specific caspases and to identify CK2/caspase substrates known to be phosphorylated or cleaved in cells. Given its constitutive activity and elevated expression in cancer, these observations suggest that the ability of CK2 to modulate caspase pathways may contribute to a role in promoting cancer cell survival and raise interesting prospects for therapeutic targeting of CK2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    Article  PubMed  CAS  Google Scholar 

  2. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  3. Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326(Pt 1):1–16

    PubMed  CAS  Google Scholar 

  4. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316

    Article  PubMed  CAS  Google Scholar 

  5. Pop C, Salvesen GS (2009) Human caspases: activation, specificity, and regulation. J Biol Chem 284:21777–21781

    Article  PubMed  CAS  Google Scholar 

  6. Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM, Ricci JE, Edris WA, Sutherlin DP, Green DR, Salvesen GS (2003) A unified model for apical caspase activation. Mol Cell 11:529–541

    Article  PubMed  CAS  Google Scholar 

  7. Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656

    Article  PubMed  CAS  Google Scholar 

  8. Kitazumi I, Tsukahara M (2011) Regulation of DNA fragmentation: the role of caspases and phosphorylation. FEBS J 278:427–441

    Article  PubMed  CAS  Google Scholar 

  9. Kurokawa M, Kornbluth S (2009) Caspases and kinases in a death grip. Cell 138:838–854

    Article  PubMed  CAS  Google Scholar 

  10. Duncan JS, Turowec JP, Vilk G, Li SS, Gloor GB, Litchfield DW (2010) Regulation of cell proliferation and survival: convergence of protein kinases and caspases. Biochim Biophys Acta 1804:505–510

    PubMed  CAS  Google Scholar 

  11. Tozser J, Bagossi P, Zahuczky G, Specht SI, Majerova E, Copeland TD (2003) Effect of caspase cleavage-site phosphorylation on proteolysis. Biochem J 372:137–143

    Article  PubMed  Google Scholar 

  12. Duncan JS, Turowec JP, Duncan KE, Vilk G, Wu C, Luscher B, Li SS, Gloor GB, Litchfield DW (2011) A peptide-based target screen implicates the protein kinase CK2 in the global regulation of caspase signaling. Sci Signal 4(172):ra30

    Google Scholar 

  13. Shin S, Lee Y, Kim W, Ko H, Choi H, Kim K (2005) Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J 24:3532–3542

    Article  PubMed  CAS  Google Scholar 

  14. McDonnell MA, Abedin MJ, Melendez M, Platikanova TN, Ecklund JR, Ahmed K, Kelekar A (2008) Phosphorylation of murine caspase-9 by the protein kinase casein kinase 2 regulates its cleavage by caspase-8. J Biol Chem 283:20149–20158

    Article  PubMed  CAS  Google Scholar 

  15. Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B, Martinou JC (2001) Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 8:601–611

    Article  PubMed  CAS  Google Scholar 

  16. Yin X, Gu S, Jiang JX (2001) The development-associated cleavage of lens connexin 45.6 by caspase-3-like protease is regulated by casein kinase II-mediated phosphorylation. J Biol Chem 276:34567–34572

    Article  PubMed  CAS  Google Scholar 

  17. Torres J, Rodriguez J, Myers MP, Valiente M, Graves JD, Tonks NK, Pulido R (2003) Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: implications for the control of protein stability and PTEN-protein interactions. J Biol Chem 278:30652–30660

    Article  PubMed  CAS  Google Scholar 

  18. Krippner-Heidenreich A, Talanian RV, Sekul R, Kraft R, Thole H, Ottleben H, Luscher B (2001) Targeting of the transcription factor Max during apoptosis: phosphorylation-regulated cleavage by caspase-5 at an unusual glutamic acid residue in position P1. Biochem J 358:705–715

    Article  PubMed  CAS  Google Scholar 

  19. Landesman-Bollag E, Romieu-Mourez R, Song DH, Sonenshein GE, Cardiff RD, Seldin DC (2001) Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20:3247–3257

    Article  PubMed  CAS  Google Scholar 

  20. Munstermann U, Fritz G, Seitz G, Lu YP, Schneider HR, Issinger OG (1990) Casein kinase II is elevated in solid human tumours and rapidly proliferating non-neoplastic tissue. Eur J Biochem 189:251–257

    Article  PubMed  CAS  Google Scholar 

  21. Kim JS, Eom JI, Cheong JW, Choi AJ, Lee JK, Yang WI, Min YH (2007) Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res 13:1019–1028

    Article  PubMed  CAS  Google Scholar 

  22. Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes JL, Cochet C (2007) Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer. Eur J Cancer 43:928–934

    Article  PubMed  CAS  Google Scholar 

  23. Wang G, Unger G, Ahmad KA, Slaton JW, Ahmed K (2005) Downregulation of CK2 induces apoptosis in cancer cells—a potential approach to cancer therapy. Mol Cell Biochem 274:77–84

    Article  PubMed  CAS  Google Scholar 

  24. Di Maira G, Brustolon F, Bertacchini J, Tosoni K, Marmiroli S, Pinna LA, Ruzzene M (2007) Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level. Oncogene 26:6915–6926

    Article  PubMed  CAS  Google Scholar 

  25. Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O’Brien SE, Bliesath J, Omori M, Huser N, Ho C, Proffitt C, Schwaebe MK, Ryckman DM, Rice WG, Anderes K (2010) CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 70:10288–10298

    Article  PubMed  CAS  Google Scholar 

  26. Luthi AU, Martin SJ (2007) The CASBAH: a searchable database of caspase substrates. Cell Death Differ 14:641–650

    Article  PubMed  CAS  Google Scholar 

  27. Gnad F, Gunawardena J, Mann M (2011) PHOSIDA 2011: the posttranslational modification database. Nucleic Acids Res 39:D253–D260

    Article  PubMed  Google Scholar 

  28. Pradelli LA, Beneteau M, Ricci JE (2010) Mitochondrial control of caspase-dependent and -independent cell death. Cell Mol Life Sci 67:1589–1597

    Article  PubMed  CAS  Google Scholar 

  29. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687

    Article  PubMed  CAS  Google Scholar 

  30. Abdul-Ghani M, Megeney LA (2008) Rehabilitation of a contract killer: caspase-3 directs stem cell differentiation. Cell Stem Cell 2:515–516

    Article  PubMed  CAS  Google Scholar 

  31. Hashimoto T, Yamauchi L, Hunter T, Kikkawa U, Kamada S (2008) Possible involvement of caspase-7 in cell cycle progression at mitosis. Genes Cells 13:609–621

    Article  PubMed  CAS  Google Scholar 

  32. McComb S, Mulligan R, Sad S (2010) Caspase-3 is transiently activated without cell death during early antigen driven expansion of CD8(+) T cells in vivo. PLoS One 5:e15328

    Article  PubMed  CAS  Google Scholar 

  33. Demon D, Van Damme P, Vanden Berghe T, Deceuninck A, Van Durme J, Verspurten J, Helsens K, Impens F, Wejda M, Schymkowitz J, Rousseau F, Madder A, Vandekerckhove J, Declercq W, Gevaert K, Vandenabeele P (2009) Proteome-wide substrate analysis indicates substrate exclusion as a mechanism to generate caspase-7 versus caspase-3 specificity. Mol Cell Proteomics 8:2700–2714

    Article  PubMed  CAS  Google Scholar 

  34. McStay GP, Salvesen GS, Green DR (2008) Overlapping cleavage motif selectivity of caspases: implications for analysis of apoptotic pathways. Cell Death Differ 15:322–331

    Article  PubMed  CAS  Google Scholar 

  35. Hunter T (2000) Signaling–2000 and beyond. Cell 100:113–127

    Article  PubMed  CAS  Google Scholar 

  36. Hu Y, Yao J, Liu Z, Liu X, Fu H, Ye K (2005) Akt phosphorylates acinus and inhibits its proteolytic cleavage, preventing chromatin condensation. EMBO J 24:3543–3554

    Article  PubMed  CAS  Google Scholar 

  37. Bredemeyer AJ, Lewis RM, Malone JP, Davis AE, Gross J, Townsend RR, Ley TJ (2004) A proteomic approach for the discovery of protease substrates. Proc Natl Acad Sci USA 101:11785–11790

    Article  PubMed  CAS  Google Scholar 

  38. Hughes MA, Harper N, Butterworth M, Cain K, Cohen GM, MacFarlane M (2009) Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival. Mol Cell 35:265–279

    Article  PubMed  CAS  Google Scholar 

  39. Cursi S, Rufini A, Stagni V, Condo I, Matafora V, Bachi A, Bonifazi AP, Coppola L, Superti-Furga G, Testi R, Barila D (2006) Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression. EMBO J 25:1895–1905

    Article  PubMed  CAS  Google Scholar 

  40. Matthess Y, Raab M, Sanhaji M, Lavrik IN, Strebhardt K (2010) Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-8 activity. Mol Cell Biol 30(24):5726–5740

    Article  PubMed  CAS  Google Scholar 

  41. Su H, Bidere N, Zheng L, Cubre A, Sakai K, Dale J, Salmena L, Hakem R, Straus S, Lenardo M (2005) Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science 307:1465–1468

    Article  PubMed  CAS  Google Scholar 

  42. Seldin DC, Leder P (1995) Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle. Science 267:894–897

    Article  PubMed  CAS  Google Scholar 

  43. Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE (2002) Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Res 62:6770–6778

    PubMed  CAS  Google Scholar 

  44. Ling P, Lu TJ, Yuan CJ, Lai MD (2008) Biosignaling of mammalian Ste20-related kinases. Cell Signal 20:1237–1247

    Article  PubMed  CAS  Google Scholar 

  45. Cheung WL, Ajiro K, Samejima K, Kloc M, Cheung P, Mizzen CA, Beeser A, Etkin LD, Chernoff J, Earnshaw WC, Allis CD (2003) Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113:507–517

    Article  PubMed  CAS  Google Scholar 

  46. Wen W, Zhu F, Zhang J, Keum YS, Zykova T, Yao K, Peng C, Zheng D, Cho YY, Ma WY, Bode AM, Dong Z (2010) MST1 promotes apoptosis through phosphorylation of histone H2AX. J Biol Chem 285(50):39108–39116

    Article  PubMed  CAS  Google Scholar 

  47. Qian Z, Lin C, Espinosa R, LeBeau M, Rosner MR (2001) Cloning and characterization of MST4, a novel Ste20-like kinase. J Biol Chem 276:22439–22445

    Article  PubMed  CAS  Google Scholar 

  48. Lin JL, Chen HC, Fang HI, Robinson D, Kung HJ, Shih HM (2001) MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene 20:6559–6569

    Article  PubMed  CAS  Google Scholar 

  49. Dan I, Ong SE, Watanabe NM, Blagoev B, Nielsen MM, Kajikawa E, Kristiansen TZ, Mann M, Pandey A (2002) Cloning of MASK, a novel member of the mammalian germinal center kinase III subfamily, with apoptosis-inducing properties. J Biol Chem 277:5929–5939

    Article  PubMed  CAS  Google Scholar 

  50. Lee KK, Murakawa M, Nishida E, Tsubuki S, Kawashima S, Sakamaki K, Yonehara S (1998) Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis. Oncogene 16:3029–3037

    Article  PubMed  CAS  Google Scholar 

  51. Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M, Chernoff J, Clark EA, Krebs EG (1998) Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 17:2224–2234

    Article  PubMed  CAS  Google Scholar 

  52. Timmer JC, Zhu W, Pop C, Regan T, Snipas SJ, Eroshkin AM, Riedl SJ, Salvesen GS (2009) Structural and kinetic determinants of protease substrates. Nat Struct Mol Biol 16:1101–1108

    Article  PubMed  CAS  Google Scholar 

  53. Tadokoro D, Takahama S, Shimizu K, Hayashi S, Endo Y, Sawasaki T (2010) Characterization of a caspase-3-substrate kinome using an N- and C-terminally tagged protein kinase library produced by a cell-free system. Cell Death Dis 1:e89

    Article  PubMed  CAS  Google Scholar 

  54. Emoto Y, Manome Y, Meinhardt G, Kisaki H, Kharbanda S, Robertson M, Ghayur T, Wong WW, Kamen R, Weichselbaum R (1995) Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells. EMBO J 14:6148–6156

    PubMed  CAS  Google Scholar 

  55. Mizuno K, Noda K, Araki T, Imaoka T, Kobayashi Y, Akita Y, Shimonaka M, Kishi S, Ohno S (1997) The proteolytic cleavage of protein kinase C isotypes, which generates kinase and regulatory fragments, correlates with Fas-mediated and 12-O-tetradecanoyl-phorbol-13-acetate-induced apoptosis. Eur J Biochem 250:7–18

    Article  PubMed  CAS  Google Scholar 

  56. Haussermann S, Kittstein W, Rincke G, Johannes FJ, Marks F, Gschwendt M (1999) Proteolytic cleavage of protein kinase Cmu upon induction of apoptosis in U937 cells. FEBS Lett 462:442–446

    Article  PubMed  CAS  Google Scholar 

  57. Bordeaux MC, Forcet C, Granger L, Corset V, Bidaud C, Billaud M, Bredesen DE, Edery P, Mehlen P (2000) The RET proto-oncogene induces apoptosis: a novel mechanism for Hirschsprung disease. EMBO J 19:4056–4063

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study has been funded by an operating grant from the Canadian Institute of Health Research (to DWL). JPT has been supported by scholarships from the Ontario Graduate Scholarship and Ontario Graduate Scholarship Science and Technology programs; JSD was supported by the Canadian Institute of Health Research—Canadian Graduate Scholarship and the Canadian Institute of Health Research—UWO Strategic Training Initiative in Cancer Research and Technology Transfer scholarship. The authors thank all the members of the Litchfield laboratory for holding helpful discussions.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada

    Jacob P. Turowec, James S. Duncan, Greg B. Gloor & David W. Litchfield

  2. Department of Oncology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada

    David W. Litchfield

Authors
  1. Jacob P. Turowec
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James S. Duncan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Greg B. Gloor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David W. Litchfield
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David W. Litchfield.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Turowec, J.P., Duncan, J.S., Gloor, G.B. et al. Regulation of caspase pathways by protein kinase CK2: identification of proteins with overlapping CK2 and caspase consensus motifs. Mol Cell Biochem 356, 159–167 (2011). https://doi.org/10.1007/s11010-011-0972-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0972-5

Keywords

Search

Navigation