Abstract
Aurora kinases representing a novel family of serine/threonine kinases have been identified as key regulators of the mitotic cell division process. The three members of this kinase family, identified so far, referred to as Aurora-A, Aurora-B and Aurora-C kinases, are close homologues of the prototypic yeast Ipl1 and Drosophila aurora kinases, which are known to be involved in the regulation of centrosome function, bipolar spindle assembly and chromosome segregation processes. All three members of the mammalian kinase family have a catalytic domain that is highly conserved with a short C-terminal domain and an N-terminal domain of varying sizes. Following their discovery about five years ago, extensive research has focused on understanding the biological roles of these kinases and elucidation of their pathways, which regulate cell proliferation and maintenance of normal cellular phenotypes. Significant interest in the subject was generated since all three Aurora kinases family members were reported to be overexpressed in many human cancers, and elevated expression has been correlated with chromosomal instability and clinically aggressive disease in some instances. Ectopic overexpression of one member of the family, Aurora-A, was shown to induce oncogenic transformation in cells. Unlike most other putative oncogenes identified, so far, members of this kinase family are expressed and active at the highest level during G2-M phase of the cell cycle. Aurora kinases are localized at the centrosomes of interphase cells, at the poles of the bipolar spindle and in the midbody of the mitotic apparatus. Substrates identified for the Aurora-A and Aurora-B kinases, include a kinesin-like motor protein, spindle apparatus proteins, histone H3 protein, kinetochore protein and the tumor suppressor protein p53. Identification of Aurora kinases as RasGAP Src homology 3 domain binding protein, also implicates these kinases as potential effectors in the Ras pathway relevant to oncogenesis. Abnormal elevated expression of Aurora kinases detected in human cancer cells could help explain the underlying biological mechanisms responsible for the development of many cellular phenotypes associated with malignant cells. Identification of these mechanisms offers the possibility of designing novel targeted therapies for cancer in the future.
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Gaglio T, Dionne MA, Compton DA: Mitotic spindle poles are organized by structural and motor proteins in addition to centrosomes. J Cell Biol 138: 1055–1066, 1997
Gaglio T, Saredi A, Bingham JB, Hasbani MJ, Gill SR, Schroer TA, Compton DA: Opposing motor activities are required for the organization of the mammalian mitotic spindle pole. J Cell Biol 135: 399–414, 1996
Stearns T: Motoring to the finish: Kinesin and dynein work together to orient the yeast mitotic spindle. J Cell Biol 138: 957–960, 1997
Nigg EA, Blangy A, Lane HA: Dynamic changes in nuclear architecture during mitosis: On the role of protein phosphorylation in spindle assembly and chromosome segregation. Exp Cell Res 229: 174–180, 1996
Nigg EA: Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2: 21–32, 2001
Anderson SS: Balanced regulation of microtubule dynamics during the cell cycle: A contemporary view. Bioessays 21: 53–60, 1999
Blangy A, Lane HA, d'Herin P, Harper M, Kress M, Nigg EA: Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83: 1159–1169, 1995
Blangy A, Arnaud L, Nigg EA: Phosphorylation by p34cdc2 protein kinase regulates binding of the kinesinrelated motor HsEg5 to the dynactin subunit p150. J Biol Chem 72: 19418–19424, 1997
Peter M, Nakagawa J, Doree M, Labbe JC, Nigg EA: In vitro disassembly of the nuclear lamina and M phasespecific phosphorylation of lamins by cdc2 kinase. Cell 61: 591–602, 1990
Kumagai A, Dunphy WG: Purification and molecular cloning of Plx1, a Cdc25 regulatory kinase from Xenopus egg extracts. Science 273: 1377–1380, 1998
Patra D, Dunphy WG: Xe-p9, a Xenopus Suc1/Cks protein, is essential for the Cdc2-dependent phosphorylation of the anaphase-promoting complex at mitosis. Genes Dev 12: 2549–2559, 1998
Mayor T, Meraldi P, Stierhof YD, Nigg EA, Fry AM: Protein kinases in control of the centrosome cycle. FEBS Lett 452: 92–95, 1999
Straight AF: Cell cycle: Checkpoint proteins and kinetochores. Curr Biol 7: R613–616, 1997
Townsley FM, Ruderman JV: Proteolytic ratchets that control progression through mitosis. Trends Cell Biol 8: 238–244, 1998
Tyers M, Jorgensen P: Proteolysis and the cell cycle: With this RING I do thee destroy. Curr Opin Genet Dev 10: 54–64, 2000
Giet R, Prigent C: Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci 112: 3591–3601, 1999
Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S: tumor amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20: 189–193, 1998
Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD: A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17: 3052–3065, 1998
Farruggio DC, Townsley FM, Ruderman JV: Cdc20 associates with the kinase aurora2/Aik. Proc Natl Acad Sci USA 96: 7306–7311, 1999
Andresson T, Ruderman JV: The kinase Eg2 is a component of the Xenopus oocyte progesterone-activated signaling pathway. EMBO J 17: 5627–5637, 1998
Littlepage LE, Wu H, Andresson T, Deanehan JK, Amundadottir LT, Ruderman JV: Identification of phosphorylated residues that affect the activity of the mitotic kinase aurora-A. Proc Natl Acad Sci USA 99: 15440–15445, 2002
Walter AO, Seghezzi W, Korver W, Sheung J, Lees E: The mitotic serine/threonine kinase aurora2/AIK is regulated by phosphorylation and degradation. Oncogene 19: 4906–4916, 2000
Cheetham GM, Knegtel RM, Coll JT, Renwick SB, Swenson L, Weber P, Lippke JA, Austen DA: Crystal structure of aurora-2, an oncogenic serine/threonine kinase. J Biol Chem 277: 42419–42422, 2002
Katayama H, Zhou H, Li Q, Tatsuka M, Sen S: 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, 2001
Castro A, Arlot-Bonnemains Y, Vigneron S, Labbe JC, Prigent C, Lorca T: APC/Fizzy-related targets aurora-A kinase for proteolysis. EMBO Rep 3: 457–462, 2002
Littlepage LE, Ruderman JV: 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: 2274–2285, 2002
Castro A, Vigneron S, Bernis C, Labbe JC, Prigent C, Lorca T: 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, 2002
Kiat LS, Hui KM, Gopalan G: Aurora-A kinase interacting protein (AIP), a novel negative regulator of human aurora-A kinase. J Biol Chem 277: 45558–45565, 2002
Stenoien DL, Sen S, Mancini MA, Brinkley BR: Dynamic association of a tumor amplified kinase, aurora A, with the centrosome and mitotic spindle. Cell Motil Cyoskeleton, in press, 2003
Giet R, Prigent C: The non-catalytic domain of the Xenopus laevis aurora A kinase localises the protein to the centrosome. J Cell Sci 114: 2095–2104, 2001
Giet R, McLean D, Descamps S, Lee MJ, Raff JW, Prigent C, Glover DM: Drosophila aurora A kinase is required to localize D-TACC to centrosomes and to regulate astral microtubules. J Cell Biol 156: 437–451, 2002
Kufer TA, Sillje HH, Korner R, Gruss OJ, Meraldi P, Nigg EA: Human TPX2 is required for targeting aurora-A kinase to the spindle. J Cell Biol 158: 617–623, 2002
Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y: Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res 59: 2041–2044, 1999
Sen S, Zhou H, Zhang RD, Yoon DS, Vakar-Lopez F, Ito S, Jiang F, Johnston D, Grossman HB, Ruifrok AC, Katz RL, Brinkley W, Czerniak B: Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 94: 1320–1329, 2002
Han H, Bearss DJ, Browne LW, Calaluce R, Nagle RB, Von Hoff DD: Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res 62: 2890–2896, 2002
Miyoshi Y, Iwao K, Egawa C, Noguchi S: Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int J Cancer 92: 370–373, 2001
Brinkley BR, Goepfert TM: Supernumerary centrosomes and cancer: Boveri's hypothesis resurrected. Cell Motil Cytoskeleton 41: 281–288, 1998
Goepfert TM, Adigun YE, Zhong L, Gay J, Medina D, Brinkley WR: Centrosome amplification and overexpression of aurora A are early events in rat mammary carcinogenesis. Cancer Res 62: 4115–4122, 2002
Gigoux V, L'Hoste S, Raynaud F, Camonis J, Garbay C: Identification of aurora kinases as RasGAP Src homology 3 domain-binding proteins. J Biol Chem 277: 23742–23746, 2002
Chen SS, Chang PC, Cheng YW, Tang FM, Lin YS: Suppression of the STK15 oncogenic activity requires a transactivation-independent p53 function. EMBO J 21: 4491–4499, 2002
Terada Y, Tatsuka M, Suzuki F, Yasuda Y, Fujita S, Otsu M: AIM-1: A mammalian midbody-associated protein required for cytokinesis. EMBO J 17: 667–676, 1998
Sorensen CS, Lukas C, Kramer ER, Peters JM, Bartek J, Lukas J: Nonperiodic activity of the human anaphasepromoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis. Mol Cell Biol 0: 7613–7623, 2000
Mackay AM, Earnshaw WC: The INCENPs: Structural and functional analysis of a family of chromosome passenger proteins. Cold Spring HarbSymp Quant Biol 58: 697–706, 1993
Bolton MA, Lan W, Powers SE, McCleland ML, Kuang J, Stukenberg PT: 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: 3064–3077, 2002
Schumacher JM, Golden A, Donovan PJ: AIR-2: An aurora/Ipl1-related protein kinase associated with chromosomes and midbody microtubules is required for polar body extrusion and cytokinesis in Caenorhabditis elegans embryos. J Cell Biol 43:1635–1646, 1998
Hsu JY, Sun ZW, Li X, Reuben M, Tatchell K, Bishop DK, Grushcow JM, Brame CJ, Caldwell JA, Hunt DF, Lin R, Smith MM, Allis CD: Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102: 279–291, 2000
Tanaka TU, Rachidi N, Janke C, Pereira G, Galova M, Schiebel E, Stark MJ, Nasmyth K: Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108: 317–329, 2002
Murata-Hori M, Wang YL: The kinase activity of aurora B is required for kinetochore-microtubule interactions during mitosis. Curr Biol 12: 894–899, 2002
Shannon KB, Salmon ED: Chromosome dynamics: New light on aurora B kinase function. Curr Biol 12: R458–460, 2002
Cooke CA, Heck MM, Earnshaw WC: Related articles, links the inner centromere protein (INCENP) antigens: Movement from inner centromere to midbody during mitosis. J Cell Biol 105: 2053–2067, 1987
Mackay AM, Ainsztein AM, Eckley DM, Earnshaw WC: A dominant mutant of inner centromere protein (INCENP), a chromosomal protein, disrupts prometaphase congression and cytokinesis. J Cell Biol 140: 991–1002, 1998
Adams RR, Wheatley SP, Gouldsworthy AM, Kandels-Lewis SE, Carmena M, Smythe C, Gerloff DL, Earnshaw WC: INCENP binds the Aurora-related kinase AIRK2 and is required to target it to chromosomes, the central spindle and cleavage furrow. Curr Biol 10: 1075–1078, 2000
Bishop JD, Schumacher JM: Phosphorylation of the carboxyl terminus of inner centromere protein (INCENP) by the aurora B kinase stimulates aurora B kinase activity. J Biol Chem 277: 27577–27580, 2002
Speliotes EK, Uren A, Vaux D, Horvitz HR: The survivinlike C. elegans BIR-1 protein acts with the aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Mol Cell 6: 211–223, 2000
Zeitlin SG, Shelby RD, Sullivan KF: CENP-A is phosphorylated by aurora B kinase and plays an unexpected role in completion of cytokinesis. J Cell Biol 155: 1147–1157, 2001
Tatsuka M, Katayama H, Ota T, Tanaka T, Odashima S, Suzuki F, Terada Y: 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: 4811–4816, 1998
Adams RR, Eckley DM, Vagnarelli P, Wheatley SP, Gerloff DL, Mackay AM, Svingen PA, Kaufmann SH, Earnshaw WC: Human INCENP colocalizes with the aurora-B/AIRK2 kinase on chromosomes and is overexpressed in tumor cells. Chromosoma 10: 65–74, 2001
Ambrosini G, Adida C, Altieri DC: A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3: 917–921, 1997
Wei Y, Yu L, Bowen J, Gorovsky MA, Allis CD: Phosphorylation of histone H3 is required for proper chromosome condensation and segregation. Cell 97: 99–109, 1999
Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, Bazett-Jones DP, Allis CD: Mitosisspecific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma 106: 348–360, 1997
Howman EV, Fowler KJ, Newson AJ, Redward S, MacDonald AC, Kalitsis P, Choo KHA: Early disruption of centromeric chromatin organization in centromere protein A (Cenpa) null mice. Proc Natl Acad Sci USA 97: 1148–1153, 2000
Palmer DK, Margolis RL: A 17-kD centromere protein (CENP-A) copurifies with nucleosome core particles and with histones. J Cell Biol 104: 805–815, 1987
Oegema K, Desai A, Rybina S, Kirkham M, Hyman AA: Functional analysis of kinetochore assembly in Caenorhabditis elegans. J Cell Biol 153: 1209–1225, 2001
MacCallum DE, Losada A, Kobayashi R, Hirano T: ISWI remodeling complexes in Xenopus egg extracts: Identification as major chromosomal components that are regulated by INCENP-aurora B. Mol Biol Cell 13: 25–39, 2002
Kallio MJ, McCleland ML, Stukenberg PT, Gorbsky GJ: Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis. Curr Biol 12: 900–905, 2002
Kaitna S, Pasierbek P, Jantsch M, Loidl J, Glotzer M: The aurora B kinase AIR-2 regulates kinetochores during mitosis and is required for separation of homologous chromosomes during meiosis. Curr Biol 12: 798–812, 2002
Ota T, Suto S, Katayama H, Han ZB, Suzuki F, Maeda M, Tanino M, Terada Y, Tatsuka M: Increased mitotic phosphorylation of histone H3 attributable to AIM-1/ aurora-B overexpression contributes to chromosome number instability. Cancer Res 62: 5168–5177, 2002
Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T: Regulation of chromatin structure by sitespecific histone H3 methyltransferases. Nature 406: 593–599, 2000
Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T: Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410: 116–120, 2001
Nicol L, Jeppesen P: Human: Autoimmune sera recognize a conserved 26 kD protein associated with mammalian heterochromatin that is homologous to heterochromatin protein 1 of drosophila. Chromosome Res 2: 245–253, 1994
Wreggett KA, Hill F, James PS, Hutchings A, Butcher GW, Singh PB: A mammalian homologue of drosophila heterochromatin protein 1 (HP1) is a component of constitutive heterochromatin. Cytogenet Cell Genet 66: 99–103, 1994
Ainsztein AM, Kandels-Lewis SE, Mackay AM, Earnshaw WC: INCENP centromere and spindle targeting: Identification of essential conserved motifs and involvement of heterochromatin protein HP1. J Cell Biol 143: 1763–1774, 1998
Kimura M, Matsuda Y, Yoshioka T, Okano Y: Cell cycledependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem 274: 7334–7340, 1999
Hu HM, Chuang CK, Lee MJ, Tseng TC, Tang TK: Genomic organization, expression, and chromosome localization of a third aurora-related kinase gene, Aie1. DNA Cell Biol 19: 679–688, 2000
Chen SH, Tang TK: Mutational analysis of the phosphorylation sites of the Aie1 (Aurora-C) kinase in vitro. DNA Cell Biol 21: 41–46, 2002
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Katayama, H., Brinkley, W.R. & Sen, S. The Aurora kinases: Role in cell transformation and tumorigenesis. Cancer Metastasis Rev 22, 451–464 (2003). https://doi.org/10.1023/A:1023789416385
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DOI: https://doi.org/10.1023/A:1023789416385