Aurora A kinase

Aurora A is a member of a family of mitotic serine/threonine kinases. It is implicated with important processes during mitosis and meiosis whose proper function is integral for healthy cell proliferation. Aurora A is activated by one or more phosphorylationscite journal | quotes=no |author=Crane, R. et al. |year=2003|url=http://cellbio.med.harvard.edu/faculty/ruderman/publications/Crane_Aur_A_Biol_Cell_2004.pdf |title=Aurora A, Meiosis and Mitosis |journal=Biology of the Cell |volume=96 |pages=215–229 |doi=10.1016/j.biolcel.2003.09.008] and its activity peaks during the G2 phase to M phase transition in the cell cycle.cite journal | quotes=no |author=Hannak, E. et al. |year=2001|url=http://www.jcb.org/cgi/content/full/155/7/1109|title=Aurora-A kinase is required for centrosome maturation in Caenorhabditis elegans |journal=The Journal of Cell Biology |volume=155(7) |pages=1109–1115|doi=10.1083/jcb.200108051|pmid=11748251]

Discovery

The aurora kinases were first identified in 1990 during a cDNA screen of "Xenopus" eggs. The kinase discovered, Eg2, is now referred to as Aurora A.cite journal | quotes=no |author=Chunqi, M. et al. |year=2003|url=http://mcb.asm.org/cgi/content/abstract/23/5/1703|title=Biphasic Activation of Aurora A Kinase during the Meiosis I-Meiosis II Transition in Xenopus Oocytes |journal=Molecular and Cellular Biology |volume=23(5) |pages=1703–1706|pmid=12588989|doi=10.1128/MCB.23.5.1703-1716.2003|format=abstract page] It was not until 1998, however, that Aurora A's meiotic and mitotic importance was realized.

Aurora Kinase Family

The human genome contains three members the Aurora kinase family: Aurora A, Aurora B and Aurora C. The "Xenopus", "Drosophila", and "Caenorhabditis elegans" genomes, on the other hand, contain orthologues only to Aurora A and Aurora B.

In all studied species, the three Aurora mitotic kinases localize to the centrosome during different phases of mitosis. The family members have highly conserved C-terminal catalytic domains. Their N-terminal domains, however, exhibit a large degree of variance in the size and sequence.

Aurora A and Aurora B kinases play important roles in mitosis. The Aurora A kinase is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability. The Aurora B kinase is a chromosome passenger protein and regulates chromosome segregation and cytokinesis.

Although there is evidence to suggest that Aurora C might be a chromosomal passenger protein, the cellular function of it is less clear.

Localization

Aurora A localizes next to the centrosome late in the G1 phase and early in the S phase. As the cell cycle progresses, concentrations of Aurora A increase and the kinase associates with the mitotic poles and the adjacent spindle microtubules. Aurora A remains associated with the spindles through telophase. Right before mitotic exit, Aurora A relocalizes to the mid-zone of the spindle.cite journal | quotes=no |author=Marumoto, T. et al. |year=2003|url=http://www.jbc.org/cgi/content/abstract/278/51/51786|title=Aurora-A Kinase Maintains the Fidelity of Early and Late Mitotic Evens in HeLa Cells |journal=The Journal of Biological Chemistry |volume=278(51)|pages=51786–51795|doi=10.1074/jbc.M306275200|pmid=14523000|format=abstract page]

Mitosis

During mitosis, a mitotic spindle is assembled by using microtubules to tether together the mother centrosome to its daughter. The resulting mitotic spindle is then used to propel apart the sister chromosomes into what will become the two new daughter cells. Aurora A is critical for proper formation of mitotic spindle. It is required for the recruitment of several different proteins important to the spindle formation. Among these target proteins are TACC, a microtubule-associated protein that stabilizes centrosomal microtubules and Kinesin 5, a motor protein involved in the formation of the bipolar mitotic spindle. γ-tubulins, the base structure from which centrosomal microtubules polymerize, are also recruited by Aurora A. Without Aurora A the centrosome does not accumulate the quantity of γ-tubulin that normal centrosomes recruit prior to entering anaphase. Though the cell cycle continues even in the absence of deficient γ-tubulin, the centrosome never fully matures; it organizes fewer aster microtubules than normal. Furthermore, Aurora A is necessary for the proper separation of the centrosomes after the mitotic spindle has been formed. Without Aurora A, the mitotic spindle, depending on the organism, will either never separate or will begin to separate only to collapse back onto itself. In the case of the former, it has been suggested that Aurora A cooperates with the kinase Nek2 in "Xenopu"s to dissolves the structure tethering the cell's centrosomes together. Therefore, without proper expression of Aurora A, the cell's centrosomes are never able to separate.

Aurora A also assures proper organization and alignment of the chromosomes during prometaphase. It is directly involved in the interaction of the kinetochore, the part of the chromosome at which the mitotic spindle attaches and pulls, and the mitotic spindle's extended microtubules. It is speculated that Aurora B cooperates with Aurora A to complete this task. In the absence of Aurora A mad2, a protein that normally dissipates once a proper kinetochore-microtubule connection is made, remains present even into metaphase.

Finally, Aurora A helps orchestrate an exit from mitosis by contributing to the completion of cytokinesis- the process by which the cytoplasm of the parent cell is split into two daughter cells. During citokinesis the mother centriole returns to the mid-body of the mitotic cell at the end of mitosis and causes the central microtubules to release from the mid-body. The release allows mitosis to run to completion. Though the exact mechanism by which Aurora A aids cytokinesis is unknown, it is well documented that it relocalizes to the mid-body immediately before the completion of mitosis.

Intriguingly, abolishment of Aurora A through RNAi interference results in different mutant phenotypes in different organisms and cell types. For example, deletion of Aurora A in "C. elegans" results in an initial separation of the cell's centrosomes followed by an immediate collapse of the asters. In "Xenopus", deletion disallows the mitotic spindle from ever even forming. And in "Drosophila", flies without Aurora A will effectively form spindles and separate but the asteral microtubules will be dwarfed. These observations suggests that while Aurora-A has orthologues in many different organisms, it may play a similar but slightly different role in each.

Meiosis

Aurora A phosphorylation directs the cytoplasmic polyadenylation translation of mRNA's, like the MAP kinase kinase kinase protein MOS, that are vital to the completion of meiosis in Xenopus Oocytes. Prior to the first meiotic metaphase, Aurora A induces the synthesis of MOS. The MOS protein accumulates until it exceeds a threshold and then transduces the phosphorylation cascade in the map kinase pathway. This signal subsequently activates the kinase RSK which in turn binds to the protein Myt1. Myt1, in complex with RSK, is now unable to inhibit cdc2. As a consequence, cdc2 permits entry into meiosis. A similar Aurora A dependent process regulates the transition from meiosis I-meiosis II.

Furthermore, Aurora A has been observed to have a biphasic pattern of activation during progression through meiosis. It has been suggested that the fluctuations, or phases, of Aurora A activation are dependent on a positive-feedback mechanism with a p13SUC1-associated protein kinase

Protein translation

Aurora A is not only implicated with the translation of MOS during meiosis but also in the polyadenylation and subsequent translation of neural mRNAs whose protein products are associated with synaptic plasticity.

Disease

Aurora A dysregulation has been associated with a high occurrence of cancer. For example, one study showed that 94% of the invasive tissue growth in breast cancer over expresses Aurora A. Meanwhile, the surrounding normal tissues, however, had normal levels of Aurora A expression. Dysregulation of Aurora A may lead to cancer because Aurora A is required for the completion of cytokinesis. If the cell begins mitosis, duplicates its DNA, but is then not able to divide into two separate cells it becomes an aneuploid- it contains more chromosomes than normal. Aneuploidy is a trait of many cancerous tumors.. Ordinarily, however, Aurora A expression levels are kept in check by the tumor suppressor protein p53.

Mutations of the chromosome region that contains Aurora A, 20q13, are generally considered to have a poor prognosis.

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Nigg EA |title=Mitotic kinases as regulators of cell division and its checkpoints. |journal=Nat. Rev. Mol. Cell Biol. |volume=2 |issue= 1 |pages= 21–32 |year= 2001 |pmid= 11413462 |doi= 10.1038/35048096
*cite journal | author=Kimura M, Kotani S, Hattori T, "et al." |title=Cell cycle-dependent expression and spindle pole localization of a novel human protein kinase, Aik, related to Aurora of Drosophila and yeast Ipl1. |journal=J. Biol. Chem. |volume=272 |issue= 21 |pages= 13766–71 |year= 1997 |pmid= 9153231 |doi=
*cite journal | author=Sen S, Zhou H, White RA |title=A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. |journal=Oncogene |volume=14 |issue= 18 |pages= 2195–200 |year= 1997 |pmid= 9174055 |doi= 10.1038/sj.onc.1201065
*cite journal | author=Shindo M, Nakano H, Kuroyanagi H, "et al." |title=cDNA cloning, expression, subcellular localization, and chromosomal assignment of mammalian aurora homologues, aurora-related kinase (ARK) 1 and 2. |journal=Biochem. Biophys. Res. Commun. |volume=244 |issue= 1 |pages= 285–92 |year= 1998 |pmid= 9514916 |doi= 10.1006/bbrc.1998.8250
*cite journal | author=Kimura M, Matsuda Y, Eki T, "et al." |title=Assignment of STK6 to human chromosome 20q13.2-->q13.3 and a pseudogene STK6P to 1q41-->q42. |journal=Cytogenet. Cell Genet. |volume=79 |issue= 3-4 |pages= 201–3 |year= 1998 |pmid= 9605851 |doi=
*cite journal | author=Zhou H, Kuang J, Zhong L, "et al." |title=Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. |journal=Nat. Genet. |volume=20 |issue= 2 |pages= 189–93 |year= 1998 |pmid= 9771714 |doi= 10.1038/2496
*cite journal | author=Farruggio DC, Townsley FM, Ruderman JV |title=Cdc20 associates with the kinase aurora2/Aik. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue= 13 |pages= 7306–11 |year= 1999 |pmid= 10377410 |doi=
*cite journal | author=Walter AO, Seghezzi W, Korver W, "et al." |title=The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. |journal=Oncogene |volume=19 |issue= 42 |pages= 4906–16 |year= 2000 |pmid= 11039908 |doi= 10.1038/sj.onc.1203847
*cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=
*cite journal | author=Simpson JC, Wellenreuther R, Poustka A, "et al." |title=Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. |journal=EMBO Rep. |volume=1 |issue= 3 |pages= 287–92 |year= 2001 |pmid= 11256614 |doi= 10.1093/embo-reports/kvd058
*cite journal | author=Katayama H, Zhou H, Li Q, "et al." |title=Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle. |journal=J. Biol. Chem. |volume=276 |issue= 49 |pages= 46219–24 |year= 2002 |pmid= 11551964 |doi= 10.1074/jbc.M107540200
*cite journal | author=Deloukas P, Matthews LH, Ashurst J, "et al." |title=The DNA sequence and comparative analysis of human chromosome 20. |journal=Nature |volume=414 |issue= 6866 |pages= 865–71 |year= 2002 |pmid= 11780052 |doi= 10.1038/414865a
*cite journal | author=Crosio C, Fimia GM, Loury R, "et al." |title=Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. |journal=Mol. Cell. Biol. |volume=22 |issue= 3 |pages= 874–85 |year= 2002 |pmid= 11784863 |doi=
*cite journal | author=Tanaka M, Ueda A, Kanamori H, "et al." |title=Cell-cycle-dependent regulation of human aurora A transcription is mediated by periodic repression of E4TF1. |journal=J. Biol. Chem. |volume=277 |issue= 12 |pages= 10719–26 |year= 2002 |pmid= 11790771 |doi= 10.1074/jbc.M108252200
*cite journal | author=Meraldi P, Honda R, Nigg EA |title=Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells. |journal=EMBO J. |volume=21 |issue= 4 |pages= 483–92 |year= 2002 |pmid= 11847097 |doi=
*cite journal | author=Lauffart B, Howell SJ, Tasch JE, "et al." |title=Interaction of the transforming acidic coiled-coil 1 (TACC1) protein with ch-TOG and GAS41/NuBI1 suggests multiple TACC1-containing protein complexes in human cells. |journal=Biochem. J. |volume=363 |issue= Pt 1 |pages= 195–200 |year= 2002 |pmid= 11903063 |doi=
*cite journal | author=Gigoux V, L'Hoste S, Raynaud F, "et al." |title=Identification of Aurora kinases as RasGAP Src homology 3 domain-binding proteins. |journal=J. Biol. Chem. |volume=277 |issue= 26 |pages= 23742–6 |year= 2002 |pmid= 11976319 |doi= 10.1074/jbc.C200121200
*cite journal | author=Kufer TA, Silljé HH, Körner R, "et al." |title=Human TPX2 is required for targeting Aurora-A kinase to the spindle. |journal=J. Cell Biol. |volume=158 |issue= 4 |pages= 617–23 |year= 2002 |pmid= 12177045 |doi= 10.1083/jcb.200204155
*cite journal | author=Chen SS, Chang PC, Cheng YW, "et al." |title=Suppression of the STK15 oncogenic activity requires a transactivation-independent p53 function. |journal=EMBO J. |volume=21 |issue= 17 |pages= 4491–9 |year= 2002 |pmid= 12198151 |doi=

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