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Polo-like kinases and the orchestration of cell division

Key Points

  • The genomic stability of all eukaryotic organisms depends on the error-free segregation of chromosomes during mitotic and meiotic cell divisions.

  • Polo-like kinases (Plks) are conserved regulators of several stages of mitosis and meiosis, and transiently associate with many mitotic structures such as centrosomes and spindle poles, kinetochores and the central spindle.

  • Plks have a similar architecture, with a canonical serine/threonine kinase domain at the amino terminus and a carboxy-terminal regulatory domain that contains two signature motifs, known as polo boxes. The polo-box domain (PBD) binds to phosphopeptides and is required for Plk localization and activation.

  • Plks are activated by direct phosphorylation within the kinase domain by upstream kinases and via the binding of the PBD to phosphorylated docking proteins. Plk1 has maximal activity in mitosis and is then rapidly targeted by the APC/C–Cdh1 pathway for degradation by the proteasome as cells exit mitosis.

  • Plk1 contributes to the entry into mitosis through the regulation of kinases (Wee1/Myt1) and phosphatases (Cdc25 family members) that function in an important regulatory loop that controls the activation of the Cdk1–cyclin-B mitotic kinase. Plk1 is also important for the maturation of the centrosomes at the G2/M transition, which leads to increased microtubule nucleation and bipolar spindle formation.

  • Plks have been localized to kinetochores and shown to phosphorylate the APC/C ubiquitin ligase, which suggests that they have a role in chromosome segregation.

  • Plks are implicated in signalling pathways that control mitotic exit and cytokinesis, although the precise details of this regulation differ depending on the organism.

Abstract

Polo-like kinases (Plks) are increasingly recognized as key regulators of mitosis, meiosis and cytokinesis. In agreement with a broad range of proposed functions during cell division, Plks are subject to complex temporal and spatial control. Recent findings are uncovering the mechanisms of Plk regulation, notably their targeting to different cellular structures through interactions with phosphorylated docking proteins. Moreover, information is emerging on the substrate specificity of Plks and the role of individual substrates in M-phase progression.

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Figure 1: Cell-cycle functions and localizations of Plk1.
Figure 2: Key features of Plks.
Figure 3: Plk1 activation and polo-box-domain-mediated targeting.

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Acknowledgements

We would like to thank U. Grüneberg, C. Baumann, O. Stemmann and T. Mayer for discussions, L. Johnson for the Plk1 PBD structure, and C. McInerny for providing information before publication.

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Correspondence to Erich A. Nigg.

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DATABASES

Flybase

Asp

Polo

Locuslink

ASPM

Saccharomyces cerevisiae genome database

Cdc5

S. pombe gene database

Fin1

Plo1

Swiss-Prot

Cdc25

katanin

Myt1

NEK2

Plk1

Plx1

Plkk1

Scc1

stathmin

TCTP

Wee1

Glossary

CYTOKINESIS

The process of cytoplasmic division in animal cells.

MITOTIC SPINDLE

A highly dynamic array of microtubules that forms during mitosis and serves to move the duplicated chromosomes apart.

CDK1–CYCLIN-B

The principal mitotic serine/threonine kinase, which regulates entry into mitosis. It is comprised of a catalytic subunit (Cdk1), and a regulatory subunit (cyclin B).

SEPTATION

The cytoplasmic division process in fungi, which is analogous to cytokinesis in animal cells.

PROTEASOME

A large multisubunit protease that degrades polyubiquitylated proteins.

ANAPHASE-PROMOTING COMPLEX/CYCLOSOME

(APC/C). A multi-component ubiquitin ligase that targets proteins for degradation by the proteasome.

SPINDLE CHECKPOINT

A mechanism that detects unattached kinetochores in mitosis and arrests the cell cycle.

CENTROSOME

The main microtubule-organising centre of animal cells.

KINETOCHORE

A proteinaceous structure that is assembled on a specialized region of the chromosome, the centromere, to which microtubules attach during mitotic-spindle formation.

SPINDLE POLE

The region of the mitotic spindle where microtubule minus ends are focused.

γ-TUBULIN

A special isoform of tubulin that is highly enriched at centrosomes and forms part of a complex that is required for microtubule nucleation.

MICROCEPHALY

A reduction in the size of the cerebral cortex that leads to mental retardation of varying degrees of severity.

DNA-DAMAGE CHECKPOINT

A mechanism that detects damage to DNA and chromosomes, and arrests the cell cycle until this damage is repaired (or triggers apoptosis).

SISTER CHROMATIDS

Duplicated chromosomes.

SECURIN

A regulator of the protease separase.

SEPARASE

A protease that is required for the cleavage of the centromeric cohesin complexes that hold sister chromatids together until the metaphase to anaphase transition.

COHESINS

Protein complexes that hold sister chromatids together.

MEIOSIS

The process of gamete generation from a diploid cell, in which two rounds of chromosome segregation, known as meiosis I and II, follow a single round of DNA replication.

MITOTIC EXIT NETWORK

(MEN). A signalling network in S. cerevisiae that coordinates exit from mitosis with the formation of the division septum after proper chromosome segregation has occurred.

SEPTATION INITIATION/INDUCING NETWORK

(SIN). A signalling network in S. pombe that regulates the formation of the division septum after proper chromosome segregation has occurred.

EQUATORIAL MICROTUBULE-ORGANISING CENTRE

(EMTOC). An array of microtubules that is found at the cell equator in S. pombe, and is required for cytokinesis.

KINESIN

A family of microtubule-based motors, which typically move towards the plus ends of microtubules.

DYNEIN

A multi-subunit microtubule-based motor, which typically moves towards the minus ends of microtubules.

MONOPOLINS

Proteins that attach to kinetochores to ensure monopolar attachment of sister chromatids during the first meiotic division.

CLEAVAGE FURROW

The invagination of the cell surface that dictates where cytokinesis will occur.

MIDBODY

A dense proteinaceous structure that is associated with microtubules and is found at the site of division in animal cells.

AURORA-A

A serine/threonine kinase that is required for centrosome and spindle function in mitosis.

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Barr, F., Silljé, H. & Nigg, E. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol 5, 429–441 (2004). https://doi.org/10.1038/nrm1401

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