The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis

Key Points

  • The chromosomal passenger complex (CPC) is a 'master controller' of cell division that is formed by a kinase module (Aurora B kinase) and a localization module (the scaffolding protein inner centromere protein (INCENP), survivin and borealin).

  • Multiple post-translational modifications of CPC components contribute to the appropriate localization and regulation of Aurora B activity. Full activation of Aurora B kinase is a complex multistage process that is mediated by the other CPC components and other cell cycle kinases.

  • In early mitosis, CPC recruitment to the inner centromere is mediated by post-translational modifications of two histones: phosphorylation of histone H3 (by haspin kinase) and of histone H2A (by Bub1 kinase). The baculovirus IAP repeat (BIR) domain of survivin recognizes H3 phosphorylated at Thr3. Further enrichment of the CPC at the inner centromere is mediated by Aurora B-dependent regulatory feedback loops.

  • Roles of the CPC in early mitosis include the regulation of chromosome structure, kinetochore–microtubule attachments and the spindle assembly checkpoint.

  • The CPC relocalizes to central spindle microtubules at the onset of anaphase in a highly regulated process that is mediated by a decrease of cyclin-dependent kinase 1 (Cdk1) activity, interaction with the kinesin mitotic kinesin-like protein 2 (Mklp2) and under the control of several phosphatases and Aurora B kinase itself.

  • Functions of the CPC in late mitosis include the formation and stabilization of the spindle midzone in anaphase and the regulation of the contractile ring formation. The CPC has further roles later on in cytokinesis, in which it regulates furrow ingression and the abscission checkpoint.

Abstract

Successful cell division requires the precise and timely coordination of chromosomal, cytoskeletal and membrane trafficking events. These processes are regulated by the competing actions of protein kinases and phosphatases. Aurora B is one of the most intensively studied kinases. In conjunction with inner centromere protein (INCENP), borealin (also known as Dasra) and survivin it forms the chromosomal passenger complex (CPC). This complex targets to different locations at differing times during mitosis, where it regulates key mitotic events: correction of chromosome–microtubule attachment errors; activation of the spindle assembly checkpoint; and construction and regulation of the contractile apparatus that drives cytokinesis. Our growing understanding of the CPC has seen it develop from a mere passenger riding on the chromosomes to one of the main controllers of mitosis.

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Figure 1: Structure and regulation of the CPC.
Figure 2: Coupling of Aurora B kinase activation to CPC formation and localization.
Figure 3: The CPC produces spatial gradients of Aurora B activity throughout mitosis.
Figure 4: Recruitment of the CPC to centromeres during early mitosis.
Figure 5: CPC relocalization and function in mitotic exit.

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Acknowledgements

H.F. is supported by a US National Institutes of Health grant (R01GM075249). Work in the W.C.E. laboratory is funded by The Wellcome Trust (grant number 073915), of which W.C.E. is a Principal Research Fellow. The Wellcome Trust Centre for Cell Biology is supported by core grant numbers 077707 and 092076.

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Correspondence to Mar Carmena or Hironori Funabiki or William C. Earnshaw.

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Glossary

Spindle midzone

A region of the anaphase spindle that is composed of overlapping antiparallel microtubules from opposite spindle poles. It is also known as the central spindle.

Spindle assembly checkpoint

(SAC). The checkpoint that monitors chromosome attachment to the mitotic spindle and delays anaphase onset in response to unattached or tensionless kinetochores.

Guanine exchange factor

(GEF). Enzyme that activates small GTPases by stimulating the release of GDP and allowing the formation of the active GTP-bound form.

Kinetochores

Complex protein super-assemblies located at centromeres that mediate microtubule attachment and regulate chromosome segregation.

Baculovirus IAP repeat

(BIR). A Zn2+-coordinated globular domain that is involved in protein–protein interactions and is found in all inhibitor of apoptosis (IAP) proteins.

Centromere

Specialized chromatin at the primary constriction of mitotic chromosomes that is the site of kinetochore assembly and the focal point for sister chromatid cohesion.

Midbody

Dense structure that is derived from the remnants of the central spindle during late telophase. It is present in the intercellular bridge that connects daughter cells during cytokinesis.

Cyclin dependent kinases

(CDKs). A family of highly conserved Ser/Thr kinases that is involved in the regulation of cell cycle progression. CDKs are characterized by their association with and regulation by cyclins.

Polo-like kinases

(PLKs). Kinases first identified in Drosophila melanogaster that are involved in many aspects of cell cycle regulation, including chromosome–microtubule interactions and centrosome duplication.

Checkpoints

Biochemical signalling networks that monitor whether key processes have taken place before allowing progression to the next cell cycle stage.

Inner centromere

The region of the centromere that is located between paired sister chromatids.

Sumoylation

Post-translational modification by reversible conjugation of small ubiquitin-like modifier (SUMO) proteins. Sumoylated substrates are involved in regulation of the cell cycle, DNA repair, gene expression nuclear transport and protein stability.

E3 ligase

An enzyme that promotes the attachment of ubiquitin or small ubiquitin-like modifier (SUMO) to a protein. This leads to various outcomes, including changes in binding partners, sorting into different subcellular compartments or degradation.

FRET

(Förster resonance energy transfer). A method for the detection of associations between proteins by measuring the transfer of energy over distances of a few nanometres between fluorescent probes attached to the proteins.

KMN network

An important microtubule-binding module of the outer kinetochore that comprises the KNL1, Mis12 and Ndc80 complexes.

Condensin

A large heteropentameric complex that is essential for chromosome architecture. It is composed of two structural maintenance of chromosome (SMC) subunits and three auxiliary non-SMC subunits.

Kleisin

A subunit that bridges the ATPase heads of structural maintenance of chromosome (SMC) proteins in SMC complexes, thereby converting them into closed rings.

Merotelic attachments

A single kinetochore attaches to microtubules from both spindle poles.

Syntelic attachments

Both sister kinetochores attach to microtubules from the same pole.

Kinesin

A superfamily of microtubule associated motor proteins. Their functions include the transport of cargo along microtubules and the regulation of microtubule dynamics.

Formin

A protein that is defined by the presence of a catalytic FH2 (formin homology 2) domain. Formins interact with actin and regulate its polymerization.

AAA+ ATPase

Hexameric ATPases with associated and diverse cellular activities. They couple ATP hydrolysis to translocation or remodelling of macromolecules in several cellular processes.

DNA topoisomerase II

An abundant nuclear enzyme that relieves topological stress in DNA by passing one duplex through another using an ATP-regulated protein gate.

GTPase activating protein

(GAP). A protein that inactivates small GTPases by stimulating them to hydrolyze GTP into GDP.

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Carmena, M., Wheelock, M., Funabiki, H. et al. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol 13, 789–803 (2012). https://doi.org/10.1038/nrm3474

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