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Polo-like kinases: structural variations lead to multiple functions

Key Points

  • Polo-like kinases (PLKs) are a family of Ser/Thr kinases that have a pivotal role in cell cycle progression, the centrosome cycle, mitosis and cellular responses to DNA damage, which makes them attractive targets for treatments against several diseases.

  • PLK1 is the most ancestral and best-conserved member of the family; it is found in most eukaryotic organisms, except for higher land plants. PLK4 is the most divergent member of the family. PLK2, PLK3 and PLK5 have evolved very recently, probably from a PLK1 gene duplication in vertebrates.

  • PLK1 and PLK4 have distinct structural organizations and are phosphorylated at different residues, which correlate with different mode of actions. The amino-terminal kinase domain and carboxy-terminal polo box domains that characterize PLKs are crucial for regulation of their kinase catalytic activity in time and space, and for controlling subcellular PLK localization.

  • Recent studies show non-canonical functions for PLKs in asymmetric cell division and cilia disassembly.

  • PLKs function in centriole and centrosome biogenesis; PLK1 integrates various external stimuli with cell cycle inputs to coordinate mitotic progression and the centrosome cycle, whereas PLK4 drives centriole assembly.

  • PLK2 and PLK3 have roles in DNA replication and in the DNA damage response and are also expressed in non-proliferative tissues, in which they have a role in cell differentiation and homeostasis (for example, PLK2 and PLK5 regulate neuronal activity).

Abstract

Members of the polo-like kinase (PLK) family are crucial regulators of cell cycle progression, centriole duplication, mitosis, cytokinesis and the DNA damage response. PLKs undergo major changes in abundance, activity, localization and structure at different stages of the cell cycle. They interact with other proteins in a tightly controlled spatiotemporal manner as part of a network that coordinates key cell cycle events. Their essential roles are highlighted by the fact that alterations in PLK function are associated with cancers and other diseases. Recent knowledge gained from PLK crystal structures, evolution and interacting molecules offers important insights into the mechanisms that underlie their regulation and activity, and suggests novel functions unrelated to cell cycle control for this family of kinases.

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Figure 1: The organization of structural domains regulates the function of PLKs.
Figure 2: PLK4 has a key role in a conserved pathway of centriole biogenesis.
Figure 3: Schematic presentation of PLK functions and localizations during the mammalian cell cycle.
Figure 4: PLK1 functions in mitotic entry and G2/M checkpoint.
Figure 5: PLK1 functions during spindle assembly, mitotic exit and cytokinesis.

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Acknowledgements

The authors thank M. Petronczki, J. R. Hutchins, I. Hoffmann, V. Archambault, I. Hagan, J. Loncarek and D. Glover for critical reading of the manuscript. The authors apologize to colleagues whose publications were not cited owing to space limitations. The Cell Cycle Regulation laboratory (CCR) and M.B.-D. are supported by an European Molecular Biology Organization (EMBO) installation grant, a European Research Council (ERC) grant and grants from the Fundação para a Ciência e a Tecnologia (FCT): HMSP-CT/SAU-ICT/0075/2009, PTDC/BIA-BCM/105602/2008, PTDC/BIA-BCM/112736/2009 and PTDC/SAU-OBD/105616/2008.

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Correspondence to Sihem Zitouni or Mónica Bettencourt-Dias.

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Deregulation of Polo-like kinases in human cancer. (PDF 821 kb)

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Glossary

Cyclin-dependent kinases

(CDKs). A family of Ser/Thr kinases that have major roles in the regulation of the cell cycle. CDKs bind to their regulatory subunits, the cyclins, the concentrations of which oscillate throughout the cell cycle, which regulates CDK activity.

T-loop

A conserved structural loop in the catalytic domain of protein kinases. Phosphorylation of specific residues in the T-loop is usually required for activation of the kinase.

Phosphomimetic mutants

Mutants with altered phosphorylation sites, in which an amino acid is replaced by a phosphomimetic residue that confers a constitutively phosphorylated state to the protein. In general, Ser and Thr residues are altered to Asp or Glu residues, whereas Tyr is replaced by Glu.

SCF

A multisubunit ubiquitin ligase complex that targets proteins for degradation by the proteasome. It is composed of S phase kinase-associated protein 1 (SKP1), a member of the cullin family, a RING-finger-containing protein and an F-box-containing protein, which specifically recognizes target substrates. SCF-mediated ubiquitylation is often dependent on previous phosphorylation of its substrates at a specific degron.

Kinetochores

Protein complexes that assemble at the centromere during cell division, attach chromosomes to the microtubules of the mitotic spindle and regulate sister-chromatid separation.

Midbody

A transient proteinaceous structure that forms the cytoplasmic bridge that physically links two daughter cells at the end of cytokinesis. Its main function is localization to the site of abscission.

Spindle pole bodies

(SBP). Microtubule-organizing centres without centrioles in yeast. They are functionally equivalent to the animal centrosome.

Centromeres

Specific regions of chromosomes where the sister chromatids are tightly joined, by cohesin, and where the kinetochore is assembled.

Pericentriolar material

(PCM). A structured protein network surrounding centrioles that promotes the nucleation of microtubules.

γ-tubulin ring complex

(γTuRC). An assembly of γ-tubulin and several associated proteins that forms a structure involved in microtubule nucleation. This complex is typically found in microtubule organizing centres, which function as scaffolds for the polymerization of α-tubulin–β-tubulin dimers.

Cohesin

A ring-like protein complex that holds sister chromatids together after their replication. It is released or cleaved in a regulated manner in mitosis and meiosis, which ensures accurate chromosome segregation.

Abscission

The physical separation of two daughter cells at the completion of cytokinesis.

PAR complex

(Partition complex). A protein complex with conserved function in establishing cell polarity. It is important in asymmetric cell division and can also be involved in oncogenic signalling pathways.

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Zitouni, S., Nabais, C., Jana, S. et al. Polo-like kinases: structural variations lead to multiple functions. Nat Rev Mol Cell Biol 15, 433–452 (2014). https://doi.org/10.1038/nrm3819

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