Skip to main content

Advertisement

Log in

IK-guided PP2A suppresses Aurora B activity in the interphase of tumor cells

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Aurora B activation is triggered at the mitotic entry and required for proper microtubule-kinetochore attachment at mitotic phase. Therefore, Aurora B should be in inactive form in interphase to prevent aberrant cell cycle progression. However, it is unclear how the inactivation of Aurora B is sustained during interphase. In this study, we find that IK depletion-induced mitotic arrest leads to G2 arrest by Aurora B inhibition, indicating that IK depletion enhances Aurora B activation before mitotic entry. IK binds to Aurora B, and colocalizes on the nuclear foci during interphase. Our data further show that IK inhibits Aurora B activation through recruiting PP2A into IK and Aurora B complex. It is thus believed that IK, as a scaffold protein, guides PP2A into Aurora B to suppress its activity in interphase until mitotic entry.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

IK:

Inhibitor K562

PP2A:

Protein phosphatase 2A

References

  1. Krief P, Augery-Bourget Y, Plaisance S, Merck MF, Assier E, Tanchou V, Billard M, Boucheix C, Jasmin C, Azzarone B (1994) A new cytokine (IK) down-regulating HLA class II: monoclonal antibodies, cloning and chromosome localization. Oncogene 9(12):3449–3456

    CAS  PubMed  Google Scholar 

  2. Willers J, Haffner A, Zepter K, Storz M, Urosevic M, Burg G, Dummer R (2001) The interferon inhibiting cytokine IK is overexpressed in cutaneous T cell lymphoma derived tumor cells that fail to upregulate major histocompatibility complex class II upon interferon-gamma stimulation. J Invest Dermatol 116(6):874–879. doi:10.1046/j.1523-1747.2001.01339.x (jid1339 [pii])

    Article  CAS  PubMed  Google Scholar 

  3. Cao LXLB-KM, Clay D, Oshevski S, Jasmin C, Krief P (1997) Implication of a new molecule IK in CD34+ hematopoietic progenitor cell proliferation and differentiation. Blood 89(10):3615–3623

    CAS  PubMed  Google Scholar 

  4. Muraoka M, Hasegawa H, Kohno M, Inoue A, Miyazaki T, Terada M, Nose M, Yasukawa M (2006) IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice. Arthritis Rheum 54(11):3591–3600. doi:10.1002/art.22172

    Article  CAS  PubMed  Google Scholar 

  5. Shao R, Liu X, Ding Y, Chen X, Gao R, He J, Wang Y (2012) Characterization of IK cytokine expression in mouse endometrium during early pregnancy and its significance on implantation. Int J Mol Med 30(3):615–621. doi:10.3892/ijmm.2012.1019

    CAS  PubMed  Google Scholar 

  6. Lee S, Han S, Jeong AL, Park JS, Yang Y (2014) Depletion of IK causes mitotic arrest through aberrant regulation of mitotic kinases and phosphatases. FEBS Lett 588(17):2844–2850. doi:10.1016/j.febslet.2014.06.046 (S0014-5793(14)00508-0 [pii])

    Article  CAS  PubMed  Google Scholar 

  7. Hu L, Yang F, Liu X, Xu D, Dai W (2013) Nuclear protein IK undergoes dynamic subcellular translocation and forms unique nuclear bodies during the cell cycle. Biomark Res 1(1):1

    Article  Google Scholar 

  8. Assier E, Bouzinba-Segard H, Stolzenberg MC, Stephens R, Bardos J, Freemont P, Charron D, Trowsdale J, Rich T (1999) Isolation, sequencing and expression of RED, a novel human gene encoding an acidic-basic dipeptide repeat. Gene 230(2):145–154 (S0378111999000669 [pii])

    Article  CAS  PubMed  Google Scholar 

  9. Kimura M, Matsuda Y, Yoshioka T, Okano Y (1999) Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem 274(11):7334–7340

    Article  CAS  PubMed  Google Scholar 

  10. Sasai K, Katayama H, Stenoien DL, Fujii S, Honda R, Kimura M, Okano Y, Tatsuka M, Suzuki F, Nigg EA, Earnshaw WC, Brinkley WR, Sen S (2004) Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motil Cytoskelet 59(4):249–263. doi:10.1002/cm.20039

    Article  CAS  Google Scholar 

  11. Tang CJ, Lin CY, Tang TK (2006) Dynamic localization and functional implications of Aurora-C kinase during male mouse meiosis. Dev Biol 290(2):398–410. doi:10.1016/j.ydbio.2005.11.036 (S0012-1606(05)00866-3 [pii])

    Article  CAS  PubMed  Google Scholar 

  12. Fu J, Bian M, Jiang Q, Zhang C (2007) Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5(1):1–10. doi:10.1158/1541-7786.MCR-06-0208 (5/1/1 [pii])

    Article  CAS  PubMed  Google Scholar 

  13. Katayama H, Brinkley WR, Sen S (2003) The Aurora kinases: role in cell transformation and tumorigenesis. Cancer Metastasis Rev 22(4):451–464

    Article  PubMed  Google Scholar 

  14. Hannak E, Kirkham M, Hyman AA, Oegema K (2001) Aurora-A kinase is required for centrosome maturation in Caenorhabditis elegans. J Cell Biol 155(7):1109–1116. doi:10.1083/jcb.200108051 (jcb.200108051 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Berdnik D, Knoblich JA (2002) Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis. Curr Biol 12(8):640–647 (S0960982202007662 [pii])

    Article  CAS  PubMed  Google Scholar 

  16. Dodson CA, Bayliss R (2012) Activation of Aurora-A kinase by protein partner binding and phosphorylation are independent and synergistic. J Biol Chem 287(2):1150–1157. doi:10.1074/jbc.M111.312090 (M111.312090 [pii])

    Article  CAS  PubMed  Google Scholar 

  17. Eyers PA, Erikson E, Chen LG, Maller JL (2003) A novel mechanism for activation of the protein kinase Aurora A. Curr Biol 13(8):691–697 (S0960982203001660 [pii])

    Article  CAS  PubMed  Google Scholar 

  18. Eyers PA, Maller JL (2004) Regulation of Xenopus Aurora A activation by TPX2. J Biol Chem 279(10):9008–9015. doi:10.1074/jbc.M312424200 (M312424200 [pii])

    Article  CAS  PubMed  Google Scholar 

  19. Adams RR, Carmena M, Earnshaw WC (2001) Chromosomal passengers and the (aurora) ABCs of mitosis. Trends Cell Biol 11(2):49–54 (S0962-8924(00)01880-8 [pii])

    Article  CAS  PubMed  Google Scholar 

  20. Murata-Hori M, Tatsuka M, Wang YL (2002) Probing the dynamics and functions of aurora B kinase in living cells during mitosis and cytokinesis. Mol Biol Cell 13(4):1099–1108. doi:10.1091/mbc.01-09-0467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bolton MA, Lan W, Powers SE, McCleland ML, Kuang J, Stukenberg PT (2002) Aurora B kinase exists in a complex with survivin and INCENP and its kinase activity is stimulated by survivin binding and phosphorylation. Mol Biol Cell 13(9):3064–3077. doi:10.1091/mbc.E02-02-0092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Honda R, Korner R, Nigg EA (2003) Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis. Mol Biol Cell 14(8):3325–3341. doi:10.1091/mbc.E02-11-0769 (E02-11-0769 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yasui Y, Urano T, Kawajiri A, Nagata K, Tatsuka M, Saya H, Furukawa K, Takahashi T, Izawa I, Inagaki M (2004) Autophosphorylation of a newly identified site of Aurora-B is indispensable for cytokinesis. J Biol Chem 279(13):12997–13003. doi:10.1074/jbc.M311128200 (M311128200 [pii])

    Article  CAS  PubMed  Google Scholar 

  24. Bishop JD, Schumacher JM (2002) Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP) by the Aurora B Kinase stimulates Aurora B kinase activity. J Biol Chem 277(31):27577–27580. doi:10.1074/jbc.C200307200 (C200307200 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sessa F, Mapelli M, Ciferri C, Tarricone C, Areces LB, Schneider TR, Stukenberg PT, Musacchio A (2005) Mechanism of Aurora B activation by INCENP and inhibition by hesperadin. Mol Cell 18(3):379–391. doi:10.1016/j.molcel.2005.03.031 (S1097-2765(05)01224-4 [pii])

    Article  CAS  PubMed  Google Scholar 

  26. Sugiyama K, Sugiura K, Hara T, Sugimoto K, Shima H, Honda K, Furukawa K, Yamashita S, Urano T (2002) Aurora-B associated protein phosphatases as negative regulators of kinase activation. Oncogene 21(20):3103–3111. doi:10.1038/sj.onc.1205432

    Article  CAS  PubMed  Google Scholar 

  27. Foley EA, Maldonado M, Kapoor TM (2011) Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase. Nat Cell Biol 13(10):1265–1271. doi:10.1038/ncb2327 (ncb2327 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Espert A, Uluocak P, Bastos RN, Mangat D, Graab P, Gruneberg U (2014) PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing. J Cell Biol 206(7):833–842. doi:10.1083/jcb.201406109 (jcb.201406109 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bastos RN, Cundell MJ, Barr FA (2014) KIF4A and PP2A-B56 form a spatially restricted feedback loop opposing Aurora B at the anaphase central spindle. J Cell Biol 207(6):683–693. doi:10.1083/jcb.201409129 (jcb.201409129 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hayashi-Takanaka Y, Yamagata K, Nozaki N, Kimura H (2009) Visualizing histone modifications in living cells: spatiotemporal dynamics of H3 phosphorylation during interphase. J Cell Biol 187(6):781–790. doi:10.1083/jcb.200904137 (jcb.200904137 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Neumann B, Walter T, Heriche JK, Bulkescher J, Erfle H, Conrad C, Rogers P, Poser I, Held M, Liebel U, Cetin C, Sieckmann F, Pau G, Kabbe R, Wunsche A, Satagopam V, Schmitz MH, Chapuis C, Gerlich DW, Schneider R, Eils R, Huber W, Peters JM, Hyman AA, Durbin R, Pepperkok R, Ellenberg J (2010) Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes. Nature 464(7289):721–727. doi:10.1038/nature08869 (nature08869 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Munoz-Barrera M, Monje-Casas F (2014) Increased Aurora B activity causes continuous disruption of kinetochore-microtubule attachments and spindle instability. Proc Natl Acad Sci USA 111(38):E3996–E4005. doi:10.1073/pnas.1408017111 (1408017111 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ricke RM, Jeganathan KB, van Deursen JM (2011) Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J Cell Biol 193(6):1049–1064. doi:10.1083/jcb.201012035 (jcb.201012035 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sun L, Gao J, Dong X, Liu M, Li D, Shi X, Dong JT, Lu X, Liu C, Zhou J (2008) EB1 promotes Aurora-B kinase activity through blocking its inactivation by protein phosphatase 2A. Proc Natl Acad Sci USA 105(20):7153–7158. doi:10.1073/pnas.0710018105 (0710018105 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yeh PC, Yeh CC, Chen YC, Juang YL (2012) RED, a spindle pole-associated protein, is required for kinetochore localization of MAD1, mitotic progression, and activation of the spindle assembly checkpoint. J Biol Chem 287(15):11704–11716. doi:10.1074/jbc.M111.299131 (M111.299131 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carmena M, Wheelock M, Funabiki H, Earnshaw WC (2012) The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol 13(12):789–803. doi:10.1038/nrm3474 (nrm3474 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Terada Y, Tatsuka M, Suzuki F, Yasuda Y, Fujita S, Otsu M (1998) AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J 17(3):667–676. doi:10.1093/emboj/17.3.667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tatsuka M, Katayama H, Ota T, Tanaka T, Odashima S, Suzuki F, Terada Y (1998) Multinuclearity and increased ploidy caused by overexpression of the aurora- and Ipl1-like midbody-associated protein mitotic kinase in human cancer cells. Cancer Res 58(21):4811–4816

    CAS  PubMed  Google Scholar 

  39. Goto H, Kiyono T, Tomono Y, Kawajiri A, Urano T, Furukawa K, Nigg EA, Inagaki M (2006) Complex formation of Plk1 and INCENP required for metaphase-anaphase transition. Nat Cell Biol 8(2):180–187. doi:10.1038/ncb1350 (ncb1350 [pii])

    Article  CAS  PubMed  Google Scholar 

  40. Ohkura H, Yanagida M (1991) S. pombe gene sds22+ essential for a midmitotic transition encodes a leucine-rich repeat protein that positively modulates protein phosphatase-1. Cell 64(1):149–157 (0092-8674(91)90216-L [pii])

    Article  CAS  PubMed  Google Scholar 

  41. Posch M, Khoudoli GA, Swift S, King EM, Deluca JG, Swedlow JR (2010) Sds22 regulates aurora B activity and microtubule-kinetochore interactions at mitosis. J Cell Biol 191(1):61–74. doi:10.1083/jcb.200912046 (jcb.200912046 [pii])

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ceulemans H, Vulsteke V, De Maeyer M, Tatchell K, Stalmans W, Bollen M (2002) Binding of the concave surface of the Sds22 superhelix to the alpha 4/alpha 5/alpha 6-triangle of protein phosphatase-1. J Biol Chem 277(49):47331–47337. doi:10.1074/jbc.M206838200 (M206838200 [pii])

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2015R1D1A4A01016293) and Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2015016662) and (No. 2011-0030074).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Young Yang.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1415 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, S., Jeong, A.L., Park, J.S. et al. IK-guided PP2A suppresses Aurora B activity in the interphase of tumor cells. Cell. Mol. Life Sci. 73, 3375–3386 (2016). https://doi.org/10.1007/s00018-016-2162-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-016-2162-9

Keywords

Navigation