Aurora A kinase

Aurora A kinase also known as serine/threonine-protein kinase 6 is an is_associated_with::enzyme that in humans is encoded by the AURKA is_associated_with::gene.

Aurora A is a member of a family of mitotic serine/threonine is_associated_with::kinases. It is implicated with important processes during mitosis and meiosis whose proper function is integral for healthy is_associated_with::cell proliferation. Aurora A is activated by one or more is_associated_with::phosphorylations and  its activity peaks during the is_associated_with::G2 phase to is_associated_with::M phase transition in the cell cycle.

Discovery
The aurora kinases were first identified in 1990 during a is_associated_with::cDNA screen of is_associated_with::Xenopus eggs. The kinase discovered, Eg2, is now referred to as Aurora A. It was not until 1998, however, that Aurora A's meiotic and mitotic importance was realized.

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

In all studied species, the three Aurora mitotic kinases localize to the is_associated_with::centrosome during different phases of mitosis. The family members have highly conserved is_associated_with::C-terminal catalytic domains. Their is_associated_with::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 is_associated_with::mitosis. The Aurora A kinase is associated with centrosome maturation and separation and thereby regulates spindle assembly and stability. The is_associated_with::Aurora B kinase is a is_associated_with::chromosome passenger protein and regulates chromosome segregation and is_associated_with::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 is_associated_with::G1 phase and early in the is_associated_with::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 is_associated_with::telophase. Right before mitotic exit, Aurora A relocalizes to the mid-zone of the spindle.

Mitosis
During mitosis, a is_associated_with::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 is_associated_with::microtubule-associated protein that stabilizes centrosomal microtubules and is_associated_with::Kinesin 5, a motor protein involved in the formation of the bipolar mitotic spindle. is_associated_with::γ-tubulins, the base structure from which centrosomal microtubules is_associated_with::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 is_associated_with::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 Xenopus 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 is_associated_with::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 is_associated_with::cytokinesis- the process by which the cytoplasm of the parent cell is split into two daughter cells. During citokinesis the mother is_associated_with::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 is_associated_with::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 is_associated_with::polyadenylation translation of mRNA's, like the is_associated_with::MAP kinase kinase kinase protein MOS, that are vital to the completion of meiosis in Xenopus is_associated_with::Oocytes. Prior to the first meiotic is_associated_with::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 is_associated_with::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.

Clinical significance
Aurora A dysregulation has been associated with high occurrence of cancer. For example, one study showed over-expression of Aurora A in 94 percent of the invasive tissue growth in breast cancer, while surrounding, healthy tissues had normal levels of Aurora A expression. Aurora A has also been shown to be involved in the is_associated_with::Epithelial–mesenchymal transition and Neuroendocrine Transdifferentiation of is_associated_with::Prostate Cancer cells in aggressive disease.

Dysregulation of Aurora A may lead to cancer because Aurora A is required for the completion of is_associated_with::cytokinesis. If the cell begins mitosis, duplicates its DNA, but is then not able to divide into two separate cells it becomes an is_associated_with::aneuploid- containing more chromosomes than normal. Aneuploidy is a trait of many cancerous tumors. Ordinarily, Aurora A expression levels are kept in check by the tumor suppressor protein is_associated_with::p53.

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

Interactions
Aurora A kinase has been shown to interact with:


 * is_associated_with::BRCA1,
 * is_associated_with::MBD3,
 * is_associated_with::NME1,
 * is_associated_with::P53,
 * is_associated_with::TACC1,
 * is_associated_with::TPX2, and
 * is_associated_with::UBE2N.