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Review
. 2015 Mar 5:3:14.
doi: 10.3389/fcell.2015.00014. eCollection 2015.

The chromosomal passenger complex (CPC) as a key orchestrator of orderly mitotic exit and cytokinesis

Mayumi Kitagawa  1 , Sang Hyun Lee  1
Affiliations
Review

The chromosomal passenger complex (CPC) as a key orchestrator of orderly mitotic exit and cytokinesis

Mayumi Kitagawa et al. Front Cell Dev Biol. .

Abstract

Understanding the molecular network of orderly mitotic exit to re-establish a functional interphase nucleus is critical because disordered mitotic exit inevitably leads to genomic instability. In contrast to the mechanisms of the entrance to mitosis, however, little is known about what controls the orderly exit from mitosis, particularly in mammalian cells. The chromosomal passenger complex (CPC), which is composed of Aurora B, INCENP, Borealin and Survivin, is one of the most widely studied and highly conserved hetero-tetrameric complexes. The CPC orchestrates proper chromosome segregation with cytokinesis by targeting to specific locations at different stages of mitosis. Recent studies reveal that controlling CPC localization and Aurora B kinase activity also serves as a key surveillance mechanism for the orderly mitotic exit. This ensures the reformation of a functional interphase nucleus from condensed mitotic chromosomes by delaying mitotic exit and cytokinetic processes in response to defects in chromosome segregation. In this review, we will summarize the latest insight into the molecular mechanisms that regulate CPC localization during mitotic exit and discuss how targeting Aurora B activity to different locations at different times impacts executing multiple mitotic exit events in order and recently proposed surveillance mechanisms. Finally, we briefly discuss the potential implication of deregulated Aurora B in inducing genomic damage and tumorigenesis with current efforts in targeting Aurora B activity for anti-cancer therapy.

Keywords: Aurora B kinase; abscission; chromosomal passenger complex; chromosome condensation; chromosome segregation; cytokinesis; mitotic exit; nuclear envelope reformation.

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Figures

Figure 1
Figure 1
The proposed mechanisms of CPC enrichment at the inner centromeres. Aurora B-dependent phosphorylation of histone H3 on Ser10 (H3-S10) dissociates the CPC from the chromosome arm. Subsequently, the CPC enriches at the inner centromeres. This involves the direct and indirect interaction of Survivin and Borealin with the centromere-specific phosphorylated histone markers (p-H3-T3, p-H2A-T120) at the inner centromeres created by Haspin and Bub1 kinases. Cdk1 phosphorylation of Borealin is required for Borealin binding to the histone marker H2A-T120 phosphorylated by Bub1 kinase. In contrast, PP1γ/Repo-Man phosphatase acts antagonistically by dephosphorylating the histone makers at the chromosome arm. At the centromeres, Aurora B phosphorylation of Repo-Man on Ser893 prevents PP1γ/Repo-Man recruitment to histones, thereby the CPC is enriched at the inner centromeres. Conversely, PP2A reverses this inhibitory phosphorylation of Repo-Man by Aurora B.
Figure 2
Figure 2
The proposed mechanisms of CPC relocation from anaphase chromosomes to the cell equator, which promote the stability of the spindle midzone and furrow ingression. Cdk1 phosphorylates multiple sites of INCENP, Borealin and MKLP2 in early mitosis. These phosphorylation events are required for targeting the CPC to the histone markers at the inner centromere that are phosphorylated by Haspin and Bub1 kinases (see Figure 1). Cdk1 phosphorylation is also required for inhibiting MKLP2's microtubule binding, oligomerization/clustering and recruitment to mitotic chromosomes. Upon anaphase onset, however, reversing Cdk1 phosphorylation and the histone markers by PP1 and PP2A phosphatases is necessary to release the CPC from and stop targeting the CPC to the inner centromere. The dephosphorylation of MKLP2 promotes its kinesin function to relocate the CPC from anaphase chromosomes to the cell equator, possibly via INCENP binding. The dephosphorylation of INCENP on Thr59 and sufficient Aurora B activity are also required for CPC relocation, but the underlying mechanisms remain unclear. Alternatively, the CPC is proposed to be removed from anaphase chromosomes via ubiquitination of the Aurora B by CUL3-KLHL9–KLHL13 and CUL3–KLHL21 E3 enzymes. Ubiquitylated Aurora B (and presumably the CPC) is removed from anaphase chromosomes by AAA+ ATPase Cdc48/p97 and its adaptor proteins Ufd1–Npl4. This process may contribute to the levels and distribution of the CPC on chromosomes even before anaphase onset, and it may support chromosome decondensation and NER in late anaphase. Whether MKLP2 and Cdc48/p97 collaborate to remove the CPC from anaphase chromosomes is unknown. In the cell equator, the involvement of MKLP2 in microtubule binding, bundling, and oligomerization/clustering may contribute to central spindle assembly/stabilization and clustering/activation of the CPC at the cell equator. This clustering event may also stably deliver the CPC close to the cell cortex for robust furrow ingression directly or indirectly via Aurora B phosphorylation gradients. In the spindle midzone, Aurora B also phosphorylates MKLP1, KIF4, and KIF2a to regulate central spindle size and bundle central spindles.
Figure 3
Figure 3
The Aurora B phosphorylation gradient condenses chromosomes lagging close to the cleavage furrow and delays nuclear envelope reformation (NER) during mitotic exit. During mitotic exit, partitioning of anaphase chromosomes to the opposite spindle poles requires sister chromatids to be condensed enough to allow their segregation away from the ingressing cleavage furrow. The Aurora B phosphorylation gradient (yellow) is centered at the spindle midzone. Aurora B activity emanating from the spindle midzone promotes hyper-condensation of trailing and lagging chromosome arms until they are cleared away from the ingressing cleavage furrow via phosphorylation of histone H3 on Ser10 and the condensin I complex. Therefore, the CPC relocated to the spindle midzone provides a surveillance mechanism to prevent premature decondensation of trailing and lagging chromosomes. Furthermore, NER is inversely correlated with Aurora B activity on anaphase chromosomes and with the proximity of the spindle midzone. Thus, CPC relocation to the cell equator delays NER near the spindle midzone while it promotes NER near the spindle poles. In contrast, NER occurs simultaneously on all segregating chromosomes if Aurora B is retained on anaphase chromosomes or by global inhibition of Aurora B activity. Furthermore, CPC relocation from anaphase chromosomes to the spindle midzone also serves as a conserved feedback regulator that delays NER in response to incomplete chromosome separation, which may allow for the correction and reintegration of lagging chromosomes into the main nuclei before the completion of NER, thereby preventing micronuclei formation. PP1 and PP2A phosphatases are required for counteracting Aurora B activity to promote NER. NE, nuclear envelope.
Figure 4
Figure 4
Aurora B activity suppresses breakage of chromosomes trapped in the midbody and stabilizes the midbody to prevent tetraploidization caused by furrow regression. In contrast to cleavage furrow formation and ingression, the inhibition of Aurora B activity at the stage of abscission facilitates fission of the intercellular bridge, indicating that Aurora B activity must decrease enough to allow abscission to occur. This mechanism may also prevent chromosome breakage and protect cells from tetraploidization. This delay in abscission (called the abscission checkpoint) requires sustained Aurora B activity, and its downstream targets include MKLP1 and the ESCRT component CHMP4C. Aurora B phosphorylation of MKLP1 seems to stabilize the integrity of the midbody and intercellular bridge. Aurora B phosphorylation of CHMP4C on Ser210 imposes an abscission delay in response to a chromosome bridge that is trapped in the midbody. In concert with CHMP4C, ANCHR prevents VPS4 relocalization from the midbody ring to the abscission zone while it is relieved following the inactivation of Aurora B, thereby promoting membrane scission. However, it is unclear whether MKLP1, CHMP4C, and ANCHR-VPS4 act in the same pathway or whether they function independently downstream of Aurora B activity. Additionally, whether phosphatases antagonize Aurora B activity to promote abscission remains unknown.
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