Experimental Cell Research 301 (2004) 60 – 67

www.elsevier.com/locate/yexcr

Review

Aurora kinases in spindle assembly and chromosome segregation

Daniel Ducat, Yixian Zheng*
Department of Embryology, Carnegie Institution of Washington and Howard Hughes Medical Institute, Baltimore, MD 21210, United States
Department of Biology, Johns Hopkins University, Baltimore, MD 21218, United States

Received 9 July 2004

Available online 16 September 2004

Abstract

The Aurora kinase family consists of three members, Aurora A, B, and C. The Aurora A and B kinases have emerged as essential
regulators of cell division. While Aurora A kinase is implicated in regulating mitotic entry, centrosome maturation, and spindle assembly,
Aurora B is required for correct chromosome segregation and cytokinesis. In this review, we summarize the roles of Aurora A and B in
spindle assembly and chromosome segregation.
D 2004 Published by Elsevier Inc.

Keywords: Aurora kinase; Mitosis; Centrosome; Spindle; Chromosome segregation; Centromere; Kinetochore

Introduction and then concentrates at the centromeres in prometaphase and

Aurora kinases compose a family of serine/threonine
kinases whose multiple roles within each sub-family are
conserved throughout evolution. The founding member of
this protein family, Aurora A, originally derived its name
from a Drosophila mutant displaying morphologic defects at
the mitotic spindle pole, reminiscent of an aurora, a night sky
phenomenon in polar regions [1]. Homologs have since been
identified in a variety of species, with a single gene in
budding and fission yeasts, and up to three genes, Aurora A,
B, and C, in mammals. While Aurora A and B are essential for
mitosis, Aurora C plays a role in the regulation of cilia and
flagella [2]. Aurora A and B kinases have distinct local-
izations in the cell. Aurora A begins to accumulate on
centrosomes around S phase, and by mitosis, it is heavily
concentrated on centrosomes at the spindle poles in addition
to being detectable along spindle microtubules. Aurora B, on
the other hand, first localizes to chromosomes in prophase
* Corresponding author. Department of Embryology, Carnegie Institu-
tion of Washington, Howard Hughes Medical Institute, 115 West University
Parkway, Baltimore, MD 21210. Fax: +1 410 243 6311.
E-mail address: zheng@ciwemb.edu (Y. Zheng).
0014-4827/$ - see front matter D 2004 Published by Elsevier Inc.
doi:10.1016/j.yexcr.2004.08.016
metaphase. It departs chromosomes at the onset of anaphase
and is found on central spindles, where it plays a role in
cytokinesis. Consistent with their localization, Aurora A
primarily regulates spindle assembly, while Aurora B
regulates chromosomes segregation and cytokinesis. In this
review, we aim to outline the functions of Aurora A and B in
the assembly of the mitotic spindle and subsequent chromo-
some segregation.
Aurora A in spindle assembly
In early mitosis, before spindle assembly, the two
duplicated centrosomes recruit several proteins, a process
often called centrosome maturation. This maturation leads to
increased microtubule nucleation from the centrosomes,
which is important for spindle assembly. During spindle
assembly, the two centrosomes separate from each other by
several forces acting on microtubules through motor
proteins (reviewed in Ref. [3]). As the centrosomes separate
from each other, the condensed chromosomes attach to
microtubules through kinetochores and congress to the
middle of the spindle. A fully assembled mitotic spindle
exhibits bipolarity, which consists of kinetochore micro-
tubules that are connected to the congressed chromosomes
 D. Ducat, Y. Zheng / Experimental Cell Research 301 (2004) 60–67 61

at the metaphase plate, pole-to-pole microtubules that form
anti-parallel interactions within the spindle, and astral
microtubules that interact with the cell cortex (Fig. 1A).
Studies in a variety of organisms show that Aurora A
regulates both centrosome maturation and bipolar spindle
assembly.
Centrosome maturation and microtubule nucleation
The centrosome is the major microtubule-organizing
center (MTOC) in animal cells. It consists of a pair of
centrioles embedded in a matrix-like proteinaceous structure
called the pericentriolar material (PCM). The PCM mediates
microtubule nucleation from the centrosome by concentra-
ting nucleation factors such as the g-tubulin ring complex
(gTuRC) and XMAP215, a microtubule-associated protein
found in Xenopus. Before spindle assembly, additional
gTuRC and XMAP215 are recruited to the PCM during
centrosome maturation and are therefore partly responsible
for the increased nucleation capacity observed in mature
centrosomes.
Aurora A plays a role in centrosome maturation in a
variety of organisms, as numerous centrosomal abnorma-
lities are observed in Aurora A-deficient cells. In C.
elegans, RNAi-mediated silencing of Aurora A results in
decreased density of centrosome-associated microtubules, a
decreased accumulation of g-tubulin, and a failure to
maintain centrosome separation in mitosis [4]. Similarly,
in Drosophila, Aurora A mutation or RNAi leads to a
reduction in the length and density of astral microtubules
[5,6]. Centrosomes also appear to be disorganized, with less
focused microtubule arrays, abnormal centriole numbers,
occasional failures in centrosome separation, and a reduced
recruitment of PCM proteins, including g-tubulin and
Minispindles (Msps), a XMAP215 homolog in Drosophila
[6,7].
Studies suggest that Aurora A regulates gTuRC recruit-
ment through another centrosomal protein called centroso-
min (CNN). Like many centrosomal proteins, CNN contains
primarily coiled-coil sequences that may be important in the
assembly of the structural core of the PCM to which
microtubule nucleators, such as gTuRC, may bind. Indeed,
depletion of CNN reduces the gTuRC concentration at the
centrosome, though CNN’s recruitment to the centrosome is
independent of g-tubulin [8]. More recently, the C-terminal
domain of CNN has been shown to bind Aurora A, while
the N-terminal domain interacts with gTuRC in several
binding assays [7]. The interaction between Aurora A and
CNN is important for the localization of both proteins to the
centrosome, as depletion of one results in the cytosolic
retention of the other. Interestingly, overexpression of either
CNN or its N-terminal fragment, in either Drosophila S2
cells or Chinese hamster ovary cells, induces CNN

Fig. 1. Bipolar spindle assembly. (A) A functional bipolar spindle consists of two half-spindles connected through anti-parallel microtubule interactions and
attached to the kinetochores of chromosomes aligned along the metaphase plate. Microtubule minus ends are focused at opposing poles-typically around the
centrosomes, which also nucleate astral microtubules that interact with the cell cortex. (B) RanGTP and Aurora A are involved in bipolar spindle assembly through
a common pathway. RanGTP stimulates the release of TPX2 from the inhibitory importin a/h complex. Freed TPX2 can then bind to Aurora A and stimulate its
activation through autophosphorylation. Activated Aurora A may then regulate spindle bipolarity through additional downstream targets, such as Eg5.
62 D. Ducat, Y. Zheng / Experimental Cell Research 301 (2004) 60–67
aggregates containing g-tubulin which nucleate ectopic
assembly of microtubule asters [7]. Formation of the
aggregates is independent of microtubule assembly because
they persist when cells are treated by nocodazole, a
chemical that depolymerizes microtubules. This suggests
that CNN is able to induce the assembly of PCM-like
structures independent of microtubules and microtubule-
based motor proteins. The identification of a functional
homolog of CNN in fission yeast [9] has revealed the
existence of CNN homologs in a variety of species,
suggesting a conserved role of CNN in centrosome
assembly. Taken together, these studies suggest that Aurora
A-mediated localization of CNN influences the nucleation
capacity of the centrosome by increasing its recruitment of
gTuRC during mitosis.
Analyses in Drosophila suggest that Aurora A also
functions to recruit Drosophila transforming acidic coiled-
coil protein (D-TACC) and Msps (XMAP215). The TACC
family of proteins can nucleate and stabilize microtubules,
largely due to their direct interaction with the XMAP215/
Msps family of proteins [10]. In Drosophila, disruption of
D-TACC itself or its interaction with Msps leads to the
generation of centrosomes possessing microtubules with
reduced density and length [10,11]. Overexpression of D-
TACC generates aggregates containing Msps, which
nucleate microtubule asters without the assistance of
gTuRC [10,12]. Not only is the XMAP215/Msps protein
family able to nucleate microtubules, but it also stabilizes
microtubules by reducing catastrophe rates [13,14]. Inter-
estingly, both TACC and XMAP215/Msps can bind and
track the plus ends of polymerizing microtubules [10,13].
Aurora A can directly bind and phosphorylate D-TACC,
and the function of Aurora A is required to localize D-
TACC to the centrosome [5]. The requirement of Aurora A
to localize TACC has also been demonstrated in Caeno-
rhabditis elegans [15,16]. These studies suggest a mech-
anism whereby Aurora A concentrates TACC and
XMAP215/Msps to the centrosome to perform two roles:
to increase centrosomal microtubule nucleation, and to
preferentially stabilize spindle microtubules generated from
the centrosome.
Finally, studies in C. elegans suggest that Aurora A
regulates an additional centrosome protein, SPD-2, during
centrosome maturation. SPD-2 is a coiled-coil protein
whose full accumulation at the centrosome in mitosis is
dependent on Aurora A [17]. Recruitment of several PCM
components, including gTuRC and Zyg-9, a homolog of
XMAP215/Msps, is impaired in SPD-2-deficient cells,
suggesting that SPD-2 is near the top of the hierarchy of
the centrosome maturation process [17,18]. The exact role
of Aurora A in SPD-2-mediated centrosome maturation is
not yet clear, but it may involve phosphorylation of SPD-2
or its interacting proteins. Recently, SPD-2 homologs have
been identified in both humans and Drosophila [19],
suggesting a conserved role for SPD-2 in centrosome
maturation.
In summary, the above survey shows that Aurora A
regulates at least three conserved centrosome proteins,
CNN, TACC, and SPD-2, to ensure proper centrosome
maturation in mitosis. Considering the complexity of the
centrosome, Aurora A is likely to regulate additional
centrosome proteins. Future studies of the role of Aurora
A in centrosome maturation will undoubtedly shed light on
the detailed mechanism of this important process in mitosis.
Bipolar spindle assembly
The establishment of a bipolar mitotic spindle requires a
coordinated action of microtubule-based motor proteins, such
as the minus-end directed motor dynein and the plus-end
directed motor Eg5. Forces generated by minus-end directed
motors must be counter-balanced by forces of plus-end-
directed motors to establish the anti-parallel microtubule
interactions essential for spindle bipolarity. The balance of
forces on the mitotic spindle is also necessary to create a rigid
framework, allowing chromosome separation during ana-
phase [3]. Aurora A may regulate bipolar spindle assembly by
coordinating the action of motor proteins.
Experiments have demonstrated a conserved role for
Aurora A in maintaining spindle bipolarity, consistent with
the spindle localization of this kinase. In the original
Drosophila study, an Aurora A mutant led to defects in
centrosome separation, resulting in a single MTOC within
the cell and a failure to establish a bipolar spindle [1].
Similarly, in C. elegans, depletion of Aurora A using RNAi
generated monopolar arrays of microtubules in the embryos.
Live imaging demonstrated that the initial separation of
centrosomes appeared normal in C. elegans embryos, but
immediately following nuclear envelope breakdown, cen-
trosomes collapsed back together to form a single pole [4].
Experiments in Xenopus egg extracts echo these results,
showing that the addition of a dominant negative form of
Aurora A, which does not have kinase activity, can cause the
collapse of pre-assembled bipolar spindles [20]. Therefore,
Aurora A function is necessary for spindle assembly.
Recent studies showed that Aurora A acts downstream of
the RanGTPase-signaling pathway that regulates multiple
aspects of spindle assembly (Fig. 1B). GTP-bound Ran
stimulates Aurora A kinase activity by displacing TPX2
from importin a/h [21]. The free TPX2 in turn binds
efficiently to Aurora A, resulting in autophosphorylation
and activation of the kinase [21,22]. Co-crystallization of
TPX2 and Aurora A shows that the N-terminus of TPX2
binds to the catalytic domain of the kinase, which creates an
active conformation of the kinase ready for substrate
binding and catalysis [23]. Moreover, this active conforma-
tion protects Aurora A from inactivation by phosphatase I
(PPI) [21,23].
Aurora A activation stimulated by RanGTP may be
essential for bipolar spindle assembly, since kinase-dead
Aurora A mutants disrupt spindle formation without
affecting aster assembly in Xenopus egg extracts [21,24].
Interestingly, while RanGTP stimulates bipolar spindle
 D. Ducat, Y. Zheng / Experimental Cell Research 301 (2004) 60–67
assembly in part by activating Eg5 indirectly [25], Aurora A
is implicated in directly binding to and phosphorylating Eg5
[24]. An attractive idea is that Aurora A may mediate
RanGTPase signaling in mitosis by directly phosphorylating
and activating Eg5. The activated Eg5 may then counter-
balance the forces generated by minus-end directed motors
such as dynein, leading to the establishment of anti-parallel
microtubule interactions and bipolar spindle assembly.
However, it is important to note that Aurora A was only
shown to phosphorylate a fragment of bacterially expressed
Eg5 in vitro [24]. Whether Aurora A phosphorylates Eg5 in
vivo and whether the phosphorylation activates Eg5 remains
to be established.
Aurora B in chromosome alignment and segregation
While Aurora A regulates spindle assembly in mitosis,
Aurora B ensures proper chromosome attachment to the
mitotic spindle. The activity of Aurora B is required to
localize several proteins to the centromere and kinetochore
regions. In addition, Aurora B regulates chromosome
biorientation by monitoring and/or correcting microtubule-
kinetochore attachments. Finally, Aurora B may also be
involved in regulating the spindle checkpoint.
Regulation of Aurora B
Aurora B forms a complex with two other proteins,
Survivin and INCENP. Together, they are often called
chromosome passenger proteins [26]. Like Aurora B,
Survivin and INCENP first localize to chromosomes in
prophase, then become concentrated at the centromere in
prometaphase and metaphase, and eventually move to the
central spindle in anaphase. All components of the Aurora B
complex are required for its correct localization, since
depletion of any one of the three components, or loss of
Aurora B kinase activity, results in mislocalization and
instability of the other two components [27]. In addition,
INCENP stimulates the kinase activity of Aurora B [27–29],
possibly by using a mechanism reminiscent of TPX2-
mediated activation of Aurora A. Survivin may also
stimulate the kinase activity of Aurora B [30], although
this remains controversial [27].
Studies also indicate that the enrichment of Aurora B to
the centromere region in prometaphase and metaphase
requires Aurora A-mediated phosphorylation of CENP-A.
CENP-A is a histone H3 variant, which associates with
centromeric DNA and is necessary for assembly of the
kinetochore. Initial studies showed that Aurora B phospho-
rylates CENP-A on Ser7 and this modification seems to
stabilize the association of a few proteins, including Aurora
B, to the centromere [31]. Subsequently, Aurora A was also
shown to phosphorylate CENP-A on the same residue in
early prophase, before Aurora B concentrates to the
centromere [32]. In fact, early CENP-A phosphorylation is
required to efficiently recruit Aurora B to the centromere in
63
prometaphase, whereupon Aurora B maintains the Ser7
phosphorylation of CENP-A. Once Aurora B is correctly
positioned at the centromere, it plays multiple roles in
establishing correct microtubule–kinetochore interactions.
Establishing chromosome biorientation
In order for chromosomes to align properly on the
metaphase plate and segregate equally to daughter cells
through the action of the bipolar spindle, correct micro-
tubule–kinetochore interactions must be established linking
sister kinetochores to opposite poles (chromosome biorien-
tation). Kinetochores geometrically promote chromosome
biorientation due to back-to-back positioning and indenta-
tion of microtubule binding sites. However, incorrect
kinetochore–microtubule attachments, where one kineto-
chore is attached to microtubules from both poles (merotelic
attachment) or both sister kinetochores are attached to
microtubules from the same pole (syntelic attachment), can
still occur (Fig. 2A). If merotelic/syntelic connections are
not corrected before the onset of anaphase, lagging
chromosomes and unequal distribution of genetic material
can result. Therefore, additional regulation is needed to
eliminate improper microtubule–kinetochore associations to
allow for correct cell division.
Studies in various organisms show that Aurora B
regulates chromosome biorientation by monitoring incorrect
microtubule–kinetochore attachments. Aurora B mutants
display a greater proportion of chromosomes with incorrect
microtubule–kinetochore attachments and a corresponding
increase in chromosome misalignment and lagging chro-
mosomes in metaphase and anaphase, respectively [33,34].
The function of Aurora B is linked to sensing tension across
the centromere, established once sister kinetochores are
attached to opposite spindle poles. In budding yeast, activity
of the single Aurora protein, Ipl1, prevents stable micro-
tubule attachments to kinetochores that do not experience
tension [35]. Similarly, studies using unreplicated centro-
meres, which cannot establish tension and biorientation,
have demonstrated that Ipl1 activity causes the kinetochore
to alternate microtubule attachments between opposing
poles [34,36]. Therefore, Ipl1 may allow kinetochores to
continuously sample microtubule attachments until correct
biorientation and tension are established. Additional studies
using Aurora B inhibitors have also discovered a role for
Aurora B in correcting or preventing improper microtubule–
kinetochore attachments in mammalian cells [37–39].
The interaction of Aurora B with mitotic centromere-
associated kinesin (MCAK) could provide a mechanism
linking Aurora B to proper chromosome biorientation and
alignment. MCAK is a member of the KinI subfamily of
kinesins that use their catalytic domains to depolymerize
microtubules [40,41]. MCAK localizes to the inner cen-
tromere during prometaphase [42], overlapping the zone of
Aurora B localization. Recent independent research has
shown that Aurora B is able to bind and recruit MCAK to
the centromere. In addition, Aurora B can directly phos-
64 D. Ducat, Y. Zheng / Experimental Cell Research 301 (2004) 60–67

Fig. 2. Chromosome biorientation. (A) Correctly aligned chromosomes have sister kinetochores with microtubule attachments to opposing spindle poles
(bioriented). Incorrect attachments can occur if both kinetochores establish microtubule connections to the same pole (syntelic), or if one kinetochore is
attached to both poles (merotelic). (B) Aurora B and MCAK co-localize at the inner centromere on unattached chromosomes, allowing Aurora B to maintain
inhibitory phosphorylation on MCAK. Upon microtubule attachment and the establishment of tension across the kinetochore, MCAK’s position is changed
relative to Aurora B, bringing it into a region containing protein phosphatase 1 (PPI). PPI can locally induce MCAK’s microtubule depolymerization activity by
reversing Aurora B-mediated phosphorylation. The spatial regulation of MCAK activity may be important in correcting improper microtubule attachments and
in chromosome congression, leading to a properly aligned and oriented chromosome.

phorylate MCAK on several conserved residues, which
decreases the ability of MCAK to depolymerize micro-
tubules [43–45]. Inhibition of MCAK by siRNA, by
injection of antibodies targeting phosphorylated MCAK,
or by expression of unphosphorylatable/phopho-mimic
MCAK leads to an increased proportion of incorrectly
attached kinetochores [43–46].
Careful examination of the localization patterns of
MCAK and Aurora B at the inner centromere has provided
additional insight into how the two proteins may regulate
chromosome biorientation. Upon chromosome biorienta-
tion, MCAK localization is stretched outside of the area
where Aurora B is localized [43] (Fig. 2B). In addition,
MCAK is more concentrated near the leading kinetochore of
congressing chromosomes in prometaphase [46]. These
subtle changes of protein localization may explain how
Aurora B regulates chromosome alignment and biorienta-
tion through controlling the microtubule depolymerization
activity of MCAK. PPI is localized to the outer centromere
upon mitotic entry and is known to oppose the activity of
Aurora B kinase [47,48]. Different microtubule–kinetochore
attachments may change kinetochore geometry in different
manners, bringing MCAK into PPI-rich regions away from
Aurora B-rich areas, to activate local microtubule depoly-
merization. Reiteration of MCAK activation and inactiva-
tion on one or the other kinetochore, and in different regions
of kinetochores, would allow repeated searching for a
proper complement of kinetochore–microtubule attach-
ments, leading to biorientation.
It is important to note that while recent studies on MCAK
and Aurora B have begun to shed light on the mechanism of
chromosome biorientation, many questions remain. For
example, it is not clear exactly how merotelic and syntelic
attachments are corrected. Furthermore, although the estab-
lishment of biorientation is supposed to stretch MCAK
away from Aurora B, and consequently activate MCAK, it
is uncertain how the active MCAK is kept from continu-
ously depolymerizing the microtubules attached to the
bioriented kinetochores before anaphase onset. It is possible
that as maximal tension is reached upon microtubule
attachment to all kinetochore-binding sites, MCAK is
sequestered away from the microtubule binding sites and a
stable interaction is generated [46]. Further characterization
of MCAK localization and other regulators at the kine-
tochores/centromeres, such as the recently discovered
centromere protein ICIS [49], should help to answer these
questions.
Aside from its role in regulating MCAK, Aurora B may
control the interaction between microtubules and kineto-
chores by altering their affinity for one another. In budding
yeast, Ipl1 directly phosphorylates several proteins that
compose a few large complexes found at the kinetochore.
Ipl1 phosphorylation is prominent on the Dam1 complex
(also known as the DASH or DDD complex), as several
subunits in the complex are targeted by Ipl1 [50]. Since the
Dam1 complex can bind directly to both microtubules and
to the other kinetochore protein complexes, it is proposed
that Dam1 links microtubule ends to kinetochore compo-
 D. Ducat, Y. Zheng / Experimental Cell Research 301 (2004) 60–67
nents, thereby stabilizing microtubule association with the
kinetochore [29,51–53]. Mutation of Ipl1 phosphorylation
sites on kinetochore components or loss of Dam1 subunits
generates segregation defects and misoriented chromosomes
[50,54], suggesting that Ipl1 plays a role in biorientation
through these complexes. Furthermore, studies show that
the strength of interaction between the Dam1 complex and
the Ndc80 complex, a complex which may play a role in
tethering Dam1 to the kinetochore, is reduced when the
complexes contain mutant subunits mimicking phosphor-
ylation at Ipl1 target residues [55]. Overall, these studies
suggest that Ipl1 may directly regulate the stability of
microtubule–kinetochore interactions by reducing the teth-
ering force holding microtubules to the kinetochore. Aurora
B might play a similar role in higher eukaryotes, although
no Dam1 homologs have yet been reported.
Aurora B in the spindle checkpoint
The role of Aurora B in monitoring microtubule–
kinetochore interactions also invites the intriguing possibi-
lity that Aurora B might directly regulate the spindle
checkpoint. The spindle checkpoint promotes correct
segregation of genetic material by preventing cellular
transition into anaphase in the presence of kinetochores
lacking microtubule connections and tension. Aurora B-
deficient cells fail to arrest in the absence of kinetochore
tension [35,38,56,57]. Aurora B-impaired cells occasionally
also lack the ability to maintain mitotic arrest when
incubated with microtubule depolymerizing drugs that
prevent microtubule–kinetochore attachments [37,38]. Con-
sistently, cells in which Aurora B function is impaired often
proceed through anaphase despite the presence of mis-
aligned chromosomes. The loss of the spindle checkpoint
under these conditions may be due to a lower concentration
of Mad2 and BubR1, proteins involved in sensing correct
chromosome attachment, at kinetochores in Aurora B-
deficient cells [38,57].
Recent studies show that the initial recruitment of Mad2
and BubR1 is not impaired by the loss of Aurora B function,
but that the ability for these spindle checkpoint proteins to
remain associated at the kinetochore requires Aurora B. One
report found that Mad2 and BubR1 are recruited to
kinetochores normally during prophase in cells with
impaired Aurora B function, but these checkpoint proteins
dissociate as mitosis progresses [57]. Others have observed
that although BubR1 can initially be recruited to kineto-
chores without the Aurora B complex, it is unable to
maintain localization under an extended treatment with
microtubule depolymerizing agents [58]. Additionally, cells
with inhibited Aurora B show a lack of hyper-phosphory-
lated BubR1 normally seen in wild-type cells [37]. Taken
together, these studies suggest a role for Aurora B in
regulating spindle checkpoint proteins.
Here, we focused our review on two important functions
of Aurora A and B in spindle assembly and chromosome
segregation. It is important to note that the two kinases have
65
additional functions in cell division, including roles in
mitotic entry and cytokinesis. Their importance in the equal
partitioning of genetic material to daughter cells makes them
essential for maintaining genomic integrity and for the
prevention of tumorigenesis. The rapid advance of know-
ledge of these kinases since their discovery promises to shed
light on not only the mechanism of eukaryotic cell division
but also on the mechanism of tumorigenesis.
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