Functional Significance of Aurora Kinase A in Centrosome Amplification and Genomic Instability

  • Subrata Sen
  • Hiroshi Katayama
  • Kaori Sasai
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)

Aurora kinase (Aur) A is the member of a Serine/Threonine protein kinase family that is represented by a single prototypic Ip11 kinase in yeast and additional paralogues in metazoan organisms. Among mammals, this kinase family consists of three members, AurA, AurB, and AurC while in Drosophila, C. elegans and Xenopus, two members, AurA and B have been identified (1). Since its discovery about a decade ago, Aur family of kinases has received significant attention because of frequent over expression of all three kinases detected in human cancers and their roles as critical regulators of mitotic cell proliferation and chromosome segregation processes (2). Ectopic elevated expression of AurA in mammalian cells in vitro was reported to induce oncogenic transformation in cells along with centrosome amplification and chromosomal instability (3). Chromosomal ploidy alterations correlating with AurA over expression has since been detected in several human cancers (4–8), rat (9, 10), and mouse (11) in vivo mammary cancer model systems. These findings suggest that chromosomal instability is a genetically determined mutant phenotype induced due to anomalies in the molecular pathways critical to the development of malignant transformation in cells.


Aurora Kinase Spindle Microtubule Centrosome Amplification Microtubule Nucleation Centrosome Duplication 
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  1. 1.
    Carmena M, Earnshaw WC (2003) The cellular geography of Aurora kinases. Nat Rev of Mol Cell Biol 4:842–854.CrossRefGoogle Scholar
  2. 2.
    Katayama H, Brinkley WR, Sen S (2003) The Aurora kinases: role in cell transformation and tumorigenesis. Cancer Metastasis Rev 22:451–464.PubMedCrossRefGoogle Scholar
  3. 3.
    Zhou H, Kuang J, Zhong L, et al. (1998) Tumor amplified kinase STK 15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193.PubMedCrossRefGoogle Scholar
  4. 4.
    Bischoff JR, Anderson L, Zhu Y, et al. (1988) A homologue of Drosophilia aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17:3052–3065.CrossRefGoogle Scholar
  5. 5.
    Tanaka T, Kimura M, Matsunga K, et al. (1999) Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res 59:2041–2044.PubMedGoogle Scholar
  6. 6.
    Sen S, Zhou H, Zhang RD, et al. (2002) Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 94:1320–1329.PubMedGoogle Scholar
  7. 7.
    Li D, Zhu J, Sen S, et al. (2003) Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin Cancer Res 9:991–997.PubMedGoogle Scholar
  8. 8.
    Tanaka E, Hashimoto Y, Ito T, et al. (2005) The clinical significance of Aurora-A/STK15/BTAK expression in human esophageal squamous cell carcinoma. Clin Cancer Res 11:1827–1834.PubMedCrossRefGoogle Scholar
  9. 9.
    Goepfert TM, Adigun YE, Zhong L, et al. (2002) Centrosome amplification and overexpression of aurora A are early events in rat mammary carcinogenesis. Cancer Res 62:4115–4122.PubMedGoogle Scholar
  10. 10.
    Li JJ, Weroha SJ, Lingle WL, et al. (2004) Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats. Proc Natl Acad Sci USA 101:18123–18128.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang X, Zhou YX, Qiao W, et al. (2006) Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene Adv (online publication).Google Scholar
  12. 12.
    Crosio C, Fimia GM, Sen S, et al. (2002) Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol Cell Biol 22:874–885.PubMedCrossRefGoogle Scholar
  13. 13.
    Dutertre S, Descamps S, Prigent C (2002) On the role of aurora-A in centrosome function. Oncogene 21:6175–6183.PubMedCrossRefGoogle Scholar
  14. 14.
    Littlepage LE, Wu H, Anderson T, et al. (2002) Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A. Proc Natl Acad Sci USA 99:15440–15445.PubMedCrossRefGoogle Scholar
  15. 15.
    Honda K, Mihara H, Kato Y, et al. (2000) Degradation of human Aurora2 protein kinase by the anaphase-promoting complex-ubiquitin-proteasome pathway. Oncogene 19:2812–2819.PubMedCrossRefGoogle Scholar
  16. 16.
    Castro A, Vigneron S, Bennis C, et al. (2002) The D box activating domain (DAD) is a new proteolysis signal that stimulates the silent D-box sequence of Aurora A. EMBO Rep 3:1209–1214.PubMedCrossRefGoogle Scholar
  17. 17.
    Crane R, Kloepfer A, Ruderman JV (2004) Requirements of the destruction of human Aurora-A. J Cell Sci 117:5975–5983.PubMedCrossRefGoogle Scholar
  18. 18.
    Walter AO, Seqhezzi W, Korner W, et al. (2002) The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. Oncogene 19:4906–4916.CrossRefGoogle Scholar
  19. 19.
    Cheetham GM, Knegtel RM, Coll JT, et al. (2002) Crystal structure of aurora-2, an oncogenic serine/threonine kinase. J Biol Chem 277:42419–42422.PubMedCrossRefGoogle Scholar
  20. 20.
    Bayliss R, Sardon T, Vernos I, et al. (2003) Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol Cell 12:851–862.PubMedCrossRefGoogle Scholar
  21. 21.
    Giet R, Prigent C (2001) The non-catalytic domain of the Xenopus laevis aurora A kinase localises the protein to the centrosome. J Cell Sci 114:2095–2104.PubMedGoogle Scholar
  22. 22.
    Stenoien DL, Sen S, Mancini MA, et al. (2003) Dynamic association of a tumor amplified kinase, aurora A, with the centrosome and mitotic spindle. Cell Motil Cytoskeletin 55:134–146.CrossRefGoogle Scholar
  23. 23.
    Murphy SM, Preble AM, Patel UK, et al. (2001) GCP5 and GCP6: Two new members of the human gamma-tubulin complex. Mol Biol Cell 12:3340–3352.PubMedGoogle Scholar
  24. 24.
    Doxsey S, Zimmerman W, Mikule K (2005) Centrosome control of the cell cycle. Trends Cell Biol 15:303–311.PubMedCrossRefGoogle Scholar
  25. 25.
    Lacey KR, Jackson PK, Stearns T (1999) Cyclin-dependent kinase control of centrosome duplication. Proc Natl Acad Sci USA 96:2817–2822.PubMedCrossRefGoogle Scholar
  26. 26.
    Matsumoto Y, Malles JL (2004) A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science 306:885–888.PubMedCrossRefGoogle Scholar
  27. 27.
    Meraldi P, Honda R, Nigg EA (2002) Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J 21:483–492.PubMedCrossRefGoogle Scholar
  28. 28.
    Habedanck R, Stierhof YD, Wilkinson CJ, et al. (2005) The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 7:1140–1146.PubMedCrossRefGoogle Scholar
  29. 29.
    Eto M, Elliott E, Prinkett TD, et al. (2002) Inhibitor-2 regulates protein phosphatase-1 complexed with NimA-related kinase to induce centrosome separation. J Biol Chem 277:44013–44020.PubMedCrossRefGoogle Scholar
  30. 30.
    Casenghi M, Meraldi P, Weinhart U, et al. (2003) Polo-like kinase 1 regulates Nip, a centrosome protein involved in microtubule nucleation. Dev Cell 5:113–125.PubMedCrossRefGoogle Scholar
  31. 31.
    Fry AM, Mayor T, Meraldi P, et al. (1998a) C-Nap1, a novel centrosomal coiled-coil protein and candidate substrate of the cell cycle-regulated protein kinase Nek2. J Cell Biol 141:1563–1574.PubMedCrossRefGoogle Scholar
  32. 32.
    Fry AM, Meraldi P, Nigg EA (1998b) A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators. EMBO J 17:470–481.PubMedCrossRefGoogle Scholar
  33. 33.
    Katayama H, Zhou H, Li Q, et al. (2001) Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle. J Biol Chem 276:46219–46224.PubMedCrossRefGoogle Scholar
  34. 34.
    Nakayama K, Nagahama H, Minamishima YA, et al. (2000) Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J 19:2069–2081.PubMedCrossRefGoogle Scholar
  35. 35.
    Sharita LM, Machida Y, Sankaran S, et al. (2004) BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number. Mol Cell Biol 24:8457–8566.CrossRefGoogle Scholar
  36. 36.
    Hsu JY, Reimann JD, Sorensen CS, et al. (2002) E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat Cell Biol 4:358–366.PubMedCrossRefGoogle Scholar
  37. 37.
    Meraldi P, Lukas J, Fry AM, et al. (1999) Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat Cell Biol 1:88–93.PubMedCrossRefGoogle Scholar
  38. 38.
    Ouchi M, Fujiuchi N, Sasai K, et al. (2004) BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem 279:19643–19648.PubMedCrossRefGoogle Scholar
  39. 39.
    Littlepage LE, Rudeman JV (2002) Identification of a new APC/C recognition domain, the A box, which is required for the Cdh1-dependent destruction of the kinase Aurora-A during mitotic exit. Genes Dev 16:2272–2285.CrossRefGoogle Scholar
  40. 40.
    Tsou MF, Stearns T (2006) Mechanism limiting centrosome duplication to once per cell cycle. Nature 442:947–951.PubMedCrossRefGoogle Scholar
  41. 41.
    Marumoto T, Honda S, Hara T, et al. (2003) Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 278:51786–51795.PubMedCrossRefGoogle Scholar
  42. 42.
    Hirota T, Kunitoku N, Sasayama T, et al. (2003) Aurora-A and in interacting activator, the LIM protein Ajuba, are required in mitotic commitment in human cells. Cell 114:585–598.PubMedCrossRefGoogle Scholar
  43. 43.
    Hannak E, Kirkham M, Hyman AA, et al. (2001) Aurora-A kinase is required for centrosome maturation in Caenorhabditis elegans. J Cell Biol 155:1109–1116.Google Scholar
  44. 44.
    Roghi C, Geit R, Uzebekov R, et al. (1998) The Xenopus protein kinase pEg2 associates with the centrosome in a cell cycle-dependent manner, binds to the spindle microtubules and is involoved in bipolar mitotic spindle assembly. J Cell Sci 111:557–572.PubMedGoogle Scholar
  45. 45.
    Glover DM, Leibowitz MH, McLean DA, et al. (1995) Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81:95–105.PubMedCrossRefGoogle Scholar
  46. 46.
    Geit R, McLean D, Descamps S, et al. (2002) Drosophila Aurora A kinase is required to localize D-TACC to centrosomes and to regulate astral microtubules. J Cell Biol 156:437–451.CrossRefGoogle Scholar
  47. 47.
    Dutertre S, Cazales M, Quaranta M, et al. (2004) Phosphorylation of CDC25B by Aurora-A at the centrosome contributes to the G2-M transition. J Cell Sci 117:2523–2531.PubMedCrossRefGoogle Scholar
  48. 48.
    Pugacheva EN, Golemis EA (2005) The focal adhesion scaffolding protein HEF1 regulates activation of the Aurora-A and Nek2 kinsases at the centrosome. Nat Cell Biol 7:937–946.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhao ZS, Lim JP, Ng YW, et al. (2005) The GIT associated kinase PAK target to the centrosome and regulates Aurora-A. Mol Cell 20:237–249.PubMedCrossRefGoogle Scholar
  50. 50.
    Hutterer A, Berdnik D, Weitz-Peitz F, et al. (2006) Mitotic activation of the kinase Aurora-A requires its binding partner Bora. Dev Cell 11:147–157.PubMedCrossRefGoogle Scholar
  51. 51.
    Tsai MY, Wiese C, Cao K, et al. (2003) A Ran signaling pathway mediated by the mediated by the mitotic kinase Aurora A in spindle assembly. Nat Cell Biol 5:242–248.PubMedCrossRefGoogle Scholar
  52. 52.
    Kufer TA, Sillje HH, Korner R, et al. (2002) Human TPX2 is required for targeting Aurora-A kinase to the spindle. J Cell Biol 158:617–623.PubMedCrossRefGoogle Scholar
  53. 53.
    Koffa MD, Casanova CM, Santarella R, et al. (2006) HURP (Hepatocarcinoma-Upregulated) is part of a Ran-dependent complex involved in spindle formation. Curr Biol 16:743–754.PubMedCrossRefGoogle Scholar
  54. 54.
    Sillje HH, Nagel S, Komer R, et al. (2006) HURP is a Ran-importin beta-regulated protein that stabilizes kinetochore microtubules in the vicinity of chromosomes. Curr Biol 16:731–742.PubMedCrossRefGoogle Scholar
  55. 55.
    Kunitoku N, Sasayama T, Marumoto T, et al. (2003) CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora-B at inner centromeres and for kinetochore function. Dev Cell 5:853–864.PubMedCrossRefGoogle Scholar
  56. 56.
    Katayama H, Sasai K, Kawai H, et al. (2004) Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 36:55–62.PubMedCrossRefGoogle Scholar
  57. 57.
    Furukawa T, Kanai N, Shiwaker HO (2006) AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer. Oncogene Adv (online publication).Google Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Subrata Sen
    • 1
  • Hiroshi Katayama
  • Kaori Sasai
  1. 1.Anderson Cancer CenterHoustonUSA

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