Biochemical Society Focused Meeting held at Royal College of Surgeons, Edinburgh, U.K., 9–12 January 2008. Organized and Edited by Gwyn Gould (Glasgow,
U.K.) and Iain Hagan (Manchester, U.K.).
Cytokinesis: the final stop for the chromosomal
passengers
Mar Carmena1
Wellcome Trust Centre for Cell Biology, School of Biological Sciences. University of Edinburgh, King’s Buildings, Mayfield Road, Edinburgh EH9 3JR, U.K.
Abstract
The CPC (chromosomal passenger complex) performs essential roles in the regulation and co-ordination
of chromosomal and cytoskeletal events during mitosis and meiosis. The first functional analyses showed
evidence of a role of the CPC in the regulation of cytokinesis. In this review, I summarize what we have
learned since then about the role of the CPC in the late stages of mitosis and cytokinesis.
Introduction: the start of the journey
Over 20 years ago, a screen for components of the chicken
chromosome scaffold led to the discovery of a new kind
of protein with a highly dynamic distribution in mitosis
[1]. These new chromosomal antigens associated generally
with chromatin in early mitosis, and by prometaphase they
concentrated in the inner centromere of the mitotic chromosomes. This localization gave the name to the INCENPs (inner centromere proteins). Most surprisingly, despite having
been isolated as tightly bound chromosome scaffold components, the INCENPs left the chromosomes altogether during
the metaphase to anaphase transition, transferred to the
midzone microtubules and then concentrated in the midbody
[1]. This particular distribution led Earnshaw and Cooke [2]
to hypothesize that the INCENPs travelled on chromosomes
in order to be transported to the spindle midzone and eventually the cleavage furrow, “where they performed essential
functions in the late stages of mitosis and cytokinesis”. The
chromosomal passengers had started their journey.
There was indeed evidence for a role of the chromosomal
passengers in cytokinesis from the start. In the earliest
studies it was already noticed that during anaphase the
INCENPs accumulated subjacent to the plasma membrane
in the position where the contractile ring would eventually
form but before there was any evidence of furrowing [2]
or accumulation of myosin heavy chain [3]. However, the
Key words: abcission, Aurora B, central spindle, chromosomal passenger complex, cytokinesis,
mitosis.
Abbreviations used: CDK, cyclin-dependent kinase; CPC, chromosomal passenger complex; GAP,
GTPase-activating protein; GEF, guanine-nucleotide-exchange factor; IF, intermediate filament;
INCENP, inner centromere protein; KLP, kinesin-like protein; MKLP, mitotic KLP; Plk1, Polo-like
kinase 1; RNAi, RNA interference.
1
email [email protected]
Biochem. Soc. Trans. (2008) 36, 367–370; doi:10.1042/BST0360367
first functional evidence for a role in cytokinesis came from
expressing a chimaeric protein in which INCENP was fused
to the centromeric protein CENP-B (centromere protein B):
when INCENP was tethered to the centromere it caused a
dominant cytokinesis failure [3]. In cells overexpressing an Nterminal fragment of INCENP, the cleavage furrow started
constricting but then regressed and cytokinesis failed [4].
There was also an early cytokinesis connection for Aurora B
kinase: AIM-1, a rat homologue of the Drosophila Aurora kinase, was localized similarly to INCENP in the midzone
and midbody. Overexpression of a kinase-dead version of
AIM-1 led to cleavage furrow disruption, failed cytokinesis
and polyploidy [5]. Also Caenorhabditis elegans embryos in
which AIR-2 (the Aurora B orthologue) levels were depleted
by RNAi (RNA interference) showed defects in the completion of cytokinesis: the cleavage furrow formed and initiated
in the correct place, but then regressed prematurely [6].
We now know that INCENP is a targeting and regulatory
subunit of Aurora B kinase, and that both of them are part of
a protein complex termed the CPC (chromosomal passenger
complex), which also comprises the proteins Survivin
and Borealin/Dasra B [7]. The CPC is a key regulator of
mitosis and meiosis whose activity is essential for the accurate distribution of genetic material. The three targeting and
activating subunits of the complex (INCENP, Survivin
and Borealin/Dasra B) guide the Aurora B kinase to its substrates and modulate its activity in the different stages of
cell division [7]. CPC function is required in various processes from early mitosis to metaphase, including regulation
of chromosome structure and cohesion, kinetochore maturation, kinetochore-microtubule attachment, chromosome
alignment and control of the spindle checkpoint [7]. In this
review, I summarize what we have learned about the role of
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Biochemical Society Transactions (2008) Volume 36, part 3
Figure 1 Diagram showing the interactions of the CPC in the late
stages of mitosis and cytokinesis
Red arrows indicate phosphorylation events. Green arrows indicate
requirement for central spindle localization.
the CPC in the late stages of mitosis and cytokinesis in the
last 20 years.
Transfer to the spindle
During the metaphase to anaphase transition of mitosis (but
not meiosis, see [8,9]), the CPC leaves the inner centromere
and transfers to the spindle midzone microtubules. However, association of the complex with centromeres is not a
prerequisite for the transfer of the complex to the central
spindle and execution of cytokinesis. The Drosophila mutants
fusolo and solofuso show severe defects in chromosome
segregation in meiosis, producing secondary spermatocytes
that are devoid of chromosomes. These secondary spermatocytes recruit Aurora B normally to the central spindle in the
second meiotic division despite the absence of chromosomes
[10]. In mammalian cells, a Survivin mutant lacking an
intact BIR (baculovirus inhibitor of apoptosis protein repeat)
domain does not target properly to inner centromeres, and
does not recruit Aurora B, Borealin/Dasra B or BubRI.
However, the CPC localizes correctly to central spindle and
midbody and cytokinesis proceeds normally [11]. The protein
deubiquitinating enzyme hFAM regulates the dynamic
association of Survivin with the centromeres [12]. Depletion
of hFAM by RNAi disrupts normal centromeric localization of Survivin and Aurora B; however, targeting to the
central spindle microtubules and midbody is unaffected [12].
The dynamic properties of some CPC components change
when the complex moves to the spindle midzone in anaphase
[13]. The association of Survivin with centromeres until
metaphase is highly dynamic; however, it becomes almost immobile upon association with microtubules in anaphase [14].
The transfer of the CPC to the central spindle microtubules in anaphase is a highly regulated process that probably
involves changes in the ubiquitylation and phosphorylation
state of different CPC subunits and requires the activity of
several motor proteins.
Ubiquitylation may influence the transfer of Aurora B to
the central spindle microtubules. In human cells, the Cul3
E3 ligase complex (Cul3/KLHL9/KLHL13) is required to
remove Aurora B kinase from mitotic chromosomes [15].
In the absence of Cul3/KLHL9/KLHL13 activity, Aurora B
spreads along chromosomes and fails to dissociate from them
C The
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Authors Journal compilation during anaphase. Aurora B binds the substrate-recognition
modules of the E3 ligase complex, KLHL9 and KLHL13, and
is ubiquitylated in vivo in a Cul3- and KLHL9/KLHL13dependent manner. However the possibility that the Cul3
E3 ligase complex regulates another member of the CPC has
not been totally ruled out [15].
Transfer of Aurora B/INCENP (Ipl1/Sli15) to the central
spindle in budding yeast depends on the dephosphorylation
of INCENP by Cdc14 phosphatase upon activation by separase [16]. In higher eukaryotes, the kinesin 6 motor protein
MKLP2 [mitotic KLP (kinesin-like protein) 2] is required
to transfer the CPC, Plk1 (Polo-like kinase 1) [17,18] and
CDC14 [17] to the spindle midzone at the onset of anaphase.
Plk1 phosphorylates MKLP2, and this phosphorylation is in
turn required for targeting Plk1 to the midzone (Figure 1).
In human cells, MKLP2-mediated transfer of Aurora B to
the central spindle is required for Aurora B to phosphorylate
another kinesin, MKLP1 (see below; [19]). This specific
phosphorylation site (Ser911 ) overlaps a nuclear localization
sequence [19]. A non-phosphorylatable MKLP1 mutant is
imported to the nucleus prematurely and does not rescue the
cytokinesis defects produced by MKLP1 depletion [19].
Regulation of central spindle formation
and actomyosin ring formation
The central spindle is instrumental in the positioning and
formation of the actomyosin ring. Essential for central
spindle formation is the centralspindlin complex, a heterotetramer composed of the kinesin 6 superfamily member
MKLP1 and MgcRacGAP [a Rho family GAP (GTPaseactivating protein)] [20]. Centralspindlin’s ability to bundle
microtubules is negatively regulated by CDK1 (cyclindependent kinase 1) phosphorylation until metaphase [21].
MKLP1 transports MgcRacGAP to the equator where it
binds Ect2 [a Rho GEF (guanine-nucleotide-exchange factor)] [22,23]. Ect2 is required to activate the small GTPase
RhoA in a localized way in the equatorial region of the
cell membrane [22,23a]. This activation of RhoA in turn
promotes actin polymerization and myosin II activation, and
therefore causes contractile ring formation (Figure 1)
In order to understand how Aurora B regulates different
aspects of cytokinesis, it is essential to analyse the way in
which it regulates the centralspindlin complex. The localization of the CPC partially overlaps with centralspindlin
in the central spindle. CPC function is required for stable
association of centralspindlin with the spindle midzone in
C. elegans [24,25]. In human cells treated with Aurora B
inhibitors, centralspindlin is delocalized and central spindle
assembly is defective [26]. Aurora B phosphorylates MKLP1
on Ser708 . A non-phosphorylatable mutant localizes properly
to the central spindle, but impairs completion of cytokinesis
[27]. In Drosophila cells, depletion of CPC components by
RNAi led to conflicting results [28,29]; however, analysis
of Incenp mutants in meiosis revealed defects in central
spindle formation and Pavarotti-KLP (MKLP1 homologue)
localization (M. Carmena, unpublished work; Figure 2)
Biochem. Soc. Trans. (2008) 36, 368–370; doi:10.1042/BST0360367
Mechanics and Control of Cytokinesis
Figure 2 Drosophila Incenp mutants show defects in central
spindle organization and Pavarotti-MKLP localization in male
meiosis
Distribution of Pavarotti-KLP (PAV-KLP) in late meiosis I in wild-type (A)
or IncenpP(EP)2340 mutant spermatocytes (B and C). (B) Defective distribution. (C) Absent Pavarotti-KLP. Lower black-and-white panels show
just Pavarotti-KLP localization. Notice disorganized central spindle in
(B); red arrow points to absence of Pavarotti-KLP on the central spindle
in (C). The white arrow points to the presence of Pavarotti-KLP in ring
canals (intracellular bridges after incomplete cytokinesis). Staining: red,
Pavarotti-KLP; green, tubulin; blue, DNA.
Aurora B and Rho kinases are involved in these phosphorylation events, which are believed to play a role in the local
breakdown of the filaments [36,37]. Some of the phosphorylation sites in IF proteins are shared by Aurora B and Rho
kinase [Thr7 , Ser13 and Ser38 in GFAP (glial fibrillar acidic
protein) and Thr16 in Desmin]; others are specific for Aurora
B kinase (Ser59 in Desmin). Mutation of the Aurora B or
Rho kinase phosphorylation sites in Desmin lead to defects
in filament separation between daughter cells [37]. Aurora
B also phosphorylates vimentin at Ser72 . Mutation of the
Aurora B phosphorylation site leads to formation of IF
bridges and multinucleation [38].
Abcission: the NoCut pathway
Aurora B may also be involved in the inhibition of abcission.
In budding yeast, Ipl1 is required for a signalling pathway
that is proposed to delay cytokinesis while there is still
chromatin in the midzone. The NoCut pathway involves the
anillin-like proteins Boi1 and Boi2 which depend on Ipl1 for
their correct localization [39].
Conclusions and perpectives
Aurora B may also regulate MgcRacGAP directly. Aurora
B phosphorylates MgcRacGAP, and overexpression of a
non-phosphorylatable mutant disrupts the final stages of
cytokinesis. MgcRacGAP phosphorylation by Aurora B
was reported to induce GAP activity towards RhoA in vitro,
and may therefore be important for the regulation of
MgcRacGAP activity in vivo [30].
It has recently been reported that Aurora B may also participate in the activation of RhoA through GEF-H1, a microtubule-binding Rho GEF. Aurora A/Aurora B and Cdk1/
cyclin B are involved in the inhibitory phosphorylation
of GEF-H1; dephosphorylation of GEF-H1 promotes the
activation of Rho A [31].
Septin regulation
Septins are GTP-binding cytoskeletal proteins that assemble
filamentous structures and are required for diverse functions
in development and cytokinesis [32]. In budding yeast, septins
are essential for polarized growth, and during cytokinesis
they provide a scaffold for the assembly of the contractile
ring. Studies in budding yeast have led to the proposal that
a CPC subcomplex consisting of Bir1p-Sli15 (SurvivinINCENP homologues) is involved in the regulation of septin
dynamics in anaphase [33]. There is no evidence of a similar
regulatory mechanism in higher eukaryotes, though it has
been shown that septin 1 is an Aurora B substrate in vitro
and the two proteins interact in vivo in human cells [34].
Abcission: IF (intermediate filament)
regulation
Protein phosphorylation and dephosphorylation of IFs in
the cleavage furrow is important for the efficient segregation
of IFs into the daughter cells (for a review see [35]). Both
Almost two decades of research into CPC function have
confirmed the early indications that the complex plays an
important role in cytokinesis. Aurora B is required for the
regulation of the components of the centralspindlin complex,
which is essential for central spindle formation and assembly
of the actomyosin ring through RhoA activation. Aurora
B may also contribute to the activation of RhoA through
the regulation of GEF-H1. During abscission, Aurora B
phosphorylates IF proteins in the midbody, contributing
to the local breakdown of filaments. In yeast, Ipl1 is also
involved in the regulation of septins.
In the near future, it will be of special interest to find out
if Aurora regulates anillin-like proteins in animal cells by a
mechanism similar to the NoCut pathway in yeast. It will
also be important to determine whether Aurora B has a role in
regulating components involved in the membrane trafficking
events of abcission. Future research will undoubtedly reveal
further targets of Aurora B in cytokinesis.
I thank William C. Earnshaw, Sandrine Ruchaud, Kumiko Samejima
and Richard R. Adams for critical reading of the manuscript and
comments. M.C.’s work is supported by a Wellcome Trust Programme
Grant to W.C. Earnshaw.
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Received 19 December 2007
doi:10.1042/BST0360367