About Aurora Kinase

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that

in humans is encoded by the AURKA gene.[5][6]
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 phosphorylations[7] and
its activity peaks during the G2 phase to M phase transition in the cell cycle.[8]

Discovery
The aurora kinases were first identified in 1990 during a cDNA screen of Xenopus eggs.
[7]
 The kinase discovered, Eg2, is now referred to as Aurora A.[9] It was not until 1998,
however, that Aurora A's meiotic and mitotic importance was realized.[7]

Aurora kinase family

The human genome contains three members the Aurora kinase family: Aurora A
kinase, Aurora B kinase and Aurora C kinase. The Xenopus, Drosophila,
and Caenorhabditis elegans genomes, on the other hand, contain orthologues only to
Aurora A and Aurora B.[7]
In all studied species, the three Aurora mitotic kinases localize to
the centrosome[9] during different phases of mitosis.[7] 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.[9]
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.[7] Right before mitotic exit,
Aurora A relocalizes to the mid-zone of the spindle.[10]

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.[7] 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.[8]
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.[8] In the case of the former, it has been suggested that Aurora A
cooperates with the kinase Nek2 in Xenopus to dissolve the structure tethering the cell's
centrosomes together. Therefore, without proper expression of Aurora A, the cell's
centrosomes are never able to separate.[10]
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.[10]
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.[10]
Intriguingly, abolishment of Aurora A through RNAi interference results in different
mutant phenotypes in different organisms and cell types.[10] 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.[8] And in Drosophila, flies without Aurora A will
effectively form spindles and separate but the aster 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.[10]

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.[9] 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.[7] 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[10]

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.[10]

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.[7] Aurora A has also been shown to be involved in the Epithelial–
mesenchymal transition and Neuroendocrine Transdifferentiation of Prostate
Cancer cells in aggressive disease.[11]
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- containing more
chromosomes than normal. Aneuploidy is a trait of many cancerous tumors.
[10]
 Ordinarily, Aurora A expression levels are kept in check by the tumor suppressor
protein p53.[7]
Mutations of the chromosome region that contains Aurora A, 20q13, are generally
considered to have a poor prognosis.[7]
Osimertinib and rociletinib, two anti cancer drugs for lung cancer, work by shutting off
mutant EGFR, which initially kills cancerous tumors, but the tumors rewire and activate
Aurora kinase A, becoming cancerous growths again. According to a 2018 study,
targeting both EGFR and Aurora prevents return of drug resistant tumors.[12]

Interactions
Aurora A kinase has been shown to interact with:

 MBD3,[13]
 NME1,[14]
 P53,[15]
 TACC1,[16][17]
 TPX2,[18] and
 UBE2N.[19]
References

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Role of AurA and AurB in mitosis. The cell-cycle dependent transcription of AurA and
AurB are under the control of the CDE/CHR elements, which are recognized by the
E4TF1 transcription factor. AurA is mainly activated after Thr288 auto-
phosphorylation. Bora, a key AurA co-factor, is phosphorylated by AurA and, in return,
Bora enhances the kinase activity of AurA. Once activated, AurA phosphorylates and
activates CDK1-Cyclin B to allow G2/M checkpoint unlock through various mechanisms,
including: (i) PLK1-dependent targeting of Wee1 and CDC25C, (ii) CDC25B-dependent
activation of CDK1 and (ii) direct phosphorylation of CDK1. Then, PLK1 mediates Bora
degradation to permit mitosis progression. At G2/M, AurA localizes in the centrosome
and also contributes to their maturation before mitotic entry. At prophase, AurA—whose
activity is maintained by Ajuba- recruits and phosphorylates several PCM proteins (i.e.
γ-TuRC, centrosomin, NDEL1, TACC, LATS2 and BRCA1) to organize the MTOC. At
metaphase, AurA moves to the proximal MT and targets MT-associated proteins (i.e.
Ki2a, TACC3, CKAP5-a) to organize the mitotic spindle. At this time, TPX2 allows the
maintenance of the activate state of AurA. AurB binds INCENP, Survivin and Borealin
to form the CPC complex and to be activated upon Thr232 auto-phosphorylation. AurB,
firstly localized on chromosomes, contributes to their proper alignment at metaphase.
Prior anaphase, AurB concentrates to the kinetochore to allow the spindle assembly
checkpoint (SAC) crossing through (i) H2AX-dependent activation of SAC sensors and
(ii) Kif2C recruitment. Then, AurB moves to the central MT to trigger sister chromatids
separation through Centralspindlin and SGO1 recruitment at anaphase. Finally, AurB
targets various cytoskeleton regulatory proteins (RhoA, Vimentin, Desmin, GFAP) at the
midbody in order to organize the cleavage furrow for cytokinesis. At the end of mitosis,
both AurA and AurB undergo ubiquitination and proteasome degradation by APC/C,
which happen subsequently to their dephosphorylation by PP2A or PP1.